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GLUCOSE BLOCKER

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INTRODUCING

INTERSTELLAR BLEND™

GLUCOSE BLOCKER

MASTER GLUCOSE TRANSPORT INHIBITOR

200:1 Concentration

Stop sugar dead in its tracks! The lower you keep your blood sugar the slower you age.

mTOR Overactivation (induced by unchecked high blood glucose) is a Key Factor in Aging

During the progression to type 2 diabetes there is a chronic activation of mTORC1 signaling, which induces aging and acts as an endogenous inhibitor of autophagy.

Directions: Take 1/8-1/4 tsp every 4-6 hours in coffee, water or fresh squeezed grapefruit juice. Check blood sugar upon waking, afternoon, before dinner and 2 hours after. Follow 22/2 one meal a day protocol.

*Fasting blood sugar should be between 70-90. Post meal blood sugar between 90-120 and quickly drop back under 100. Adjust dosage accordingly.

Pairs well with:

Jing Force, Thermo, Peel, Spice.

BEST ONE TOUCH GLUCOSE MONITOR TO BUY; zero mess or fuss takes 10 seconds. Check anywhere.

Featuring: Acanthopanax Senticosus (Rupr. Maxim.) Harms • Acer Nikoense Maxim. • Achyranthesbidentata Blume • Alchemilla Vulgaris Leaves And Flowers • Alisma Orientalis(Sam.)Juzep • Allium Cepa L. • Alstonia Macrophylla Wall. Ex G. Don. • Andrographis Paniculata (Burm. F.) Nees） • Anemarrhena Asphodeloides Bunge • Angelica Dahurica (Fisch.Ex Hoffm.) Benth. Et Hook.F. • Angelica Sinensis (Oliv.) Diels • Anthocyanin-Rich Berry- – Blueberry • Apigenin – Celery Seed • Apium Graveolens L. • Arbutus Unedo L. Roots Bark Aqueous • Arctium Lappa L • Asparagus Racemosus Willd • Astragalus Mongholicus Bunge • Astragaus Membrana- Ceus (Milkvetch Root) • Atractylodes Lancea( Thunb.)Dc. • Atractylodes Macrocephala Koidz. • Bauhinia Megalandra Leaves • Blackcurrant Polyphenols – Ribes Nigrum L • Cardamonin • Catalpol From Rehmannia Glutinosa (Chinese Foxglove Root • Chlorogenic Acid – Green Coffee Bean • Chrysin – Pinus Mon-Ticola Dougl. • Cinnamomum Cassia (Cassia Bark) • Cistanche Tubulosa • Citrus Maxima (Burm) Merr. • Citrus Medica Leaves • Coix Lachryma Jobi L. • Coptis Chinensis Franch. • Cordyceps Sinensis( Berk.)Sacc. • Cornus Officinalis (Asiatic Cornelian Cherry Fruit) • Crataegus Pin.Nati Fida Bge • Curcumin – Curcuma Longa L. • Cynodon Dactylon • Cytochalasin B – Drechslera Dematioidea • Daidzein – Soybean • Dendrobium Nobile Lindl • Egcg • Epicatechin • Epigallocatechin • Eriobotrya Japonica (Loquat Leaf) • Euonymus Alatus (Thunb.) Sieb. • Euphorbia Humifusa • Fenugreek (Trigonella Foenum-Graecum L. Seed) • Ficus Carica Linn • Fisetin – Cotinus Coggygria Scop. • Formononetin – Astragalus Mongholicus Bunge • Fructus Ligustri Lucidi • Fucoxanthin – Thallus Japonica • Ganoderma Lucidum（Leyss. Ex Fr.）Karst. • Gaultheria Phillyreifolia And G. Poeppigii Berries • Genistein – Glycine Max (Linn.) Merr • Glycyrrhiza Inflata • Gneyulins A And B From The Bark Of Gnetum Gnemonoides – Gnetum Gnemonoides • Gossypol – Cottonseed • Graviola (Annona Muricata) – Annona Muricata • Guava (Psidium Guajava) – Psidium Guajava • Gymnema Sylvestre (Retz.) Schult • Gynostemma Pentaphyllum • Helichrysum (Helichrysum Italicum) • Herba Fumariae • Honeybush (Cyclopia Genistoides) • Hordeurn Vulgare L. • Isoquercitrin • Kaempferol Galanga L • Kaempferol 3-O-Α-Rhamnoside Purified From Bauhinia Megalandra Leaves • Kurarinone From Sophora Flavescens Root • Lagerstroemia Speciosa • Laminaria Japonica • Lavandula Stoechas • Levisticum Officinale (Apiaceae) Leaf And Stem • Litchi Chinensis Sonn.Seed – Litchi Chinensis Sonn.Seed • Lonicera Japonica Thunb. (Honeysuckle Flower) • Lycium Barbarum L. Polysaccharide • Lycium Chinense Mill. • Maqui Berries (Aristotelia Chilensis) • Momordica Charantia L. • Morus Alba L Root And Peel • Mulberry Leaf • Myricetin – Myrica Rubra (Lour.) S. Et Zucc • Naringenin – Amacardi-Um Occidentale L. • Naringin – Citrus Grandis • Nelumbo Nucifera Gaertn • Nigella Sativa L. (Ranunculaceae) Seeds • Ophiopogon Japonicaus (Dwarf Lilyturf Tuber) • Oridonin – Rabdosia Rubescens • Oroxylum Indicum Seed • Paeonia Lactiflora Pall • Panax Ginseng C. A. Meye • Panax Notoginseng(Burk.)F.H.Chen • Pelargonidin-3-O-Glucoside Fragaria Virginiana • Persimmon Tannin • Phloretin – Bark Of Apple Trees • Phlorizin – Bark Of Apple Trees • Platycodon Grandifloru Seed And Root • Polygonatum Odoratum (Mill.) Druce • Polygonatum Sibiricum Delar. Ex Redoute • Polygonum Multiflorum (Fleeceflower Root) • Poria Cocos(Schw.)Wolf • Portulaca Oleracea L. • Prunella Vulgaris L. • Psidium Guajava Linn. Leaf • Pterocarpus Marsupium Roxb • Quercetin – • Quercetin-3-O-Glucoside – • Quercetin-4′-O-Glucoside (Q4′Glc) – Sophora Flavescens Ai • Quinidine (9S)-6′-Methoxycinchonan-9-Ol; • Radix Bupleuri • Ranawara (Cassia Auriculata) Dried Flowers • Resveratrol – Polygonum Cuspidatum Sieb.Et Zucc. • Rhodiola Rosea L • Rosa Laevigata Michx. • Salvia Miltiorrhiza Bge • Schisandrae Chinensis Fructus • Silybin – Silybum Marianum (L.) Gaertn. • Sophora Flavescens • Sophoraflavanone – Sophora Moorcroftiana, • Syzygium Aromaticum-Derived Triterpenes Oleanolic Acid (Oa) And Maslinic Acid (Ma) • Tangeretin – Citrus Reticulata Blanco Peel • Taraxacum Mongolicum Hand.-Mazz. • Thymus Praecox Subsp. Skorpilii Var. Skorpilii (Syn. Thymus Praecox Subsp. Jankae (Celak.) Jalas) • Tiliroside – Tribulus Terrestris L. • Trichosanthes Kirilowii Maxim. • TURKESTERONE • Xanthohumol – Humulus Lupulus Linn. • Zea Mays L. • (+)-Cryptocaryone – Cryptocarya Concinna Hance • (+)-Pteryxin – Peucedanum Harry-Smithii Var. Subglabrum

SCIENCE:

sodium–glucose cotransporter 2 (SGLT2 ) inhibitors from natural products : discovery of next-generation antihyperglycemic agents

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions , leading to the development of life-threatening complications . Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia , weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium –glucose cotransporter 2 (SGLT2 ) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes . Since the discovery of the first natural SGLT2 inhibitor , phlorizin , several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing.

This review introduces the history of research on the development of early-generation SGLT2 inhibitors , and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine .

“Plant‐derived glucose transport inhibitors with potential antitumor activity

Glucose , a key nutrient utilized by human cells to provide cellular energy and a carbon source for biomass synthesis, is internalized in cells via glucose transporters that regulate glucose homeostasis throughout the human body . glucose transporters have been used as important targets for the discovery of new drugs to treat cancer, diabetes , and heart disease, owing to their abnormal expression during these disease conditions. Thus far, several glucose transport inhibitors have been used in clinical trials, and increasing numbers of natural products have been characterized as potential anticancer agents targeting glucose transport.

The present review focuses on natural product glucose transport inhibitors of plant origin, including alkaloids, flavonoids and other phenolic compounds, and isoprenoids, with their potential antitumor properties also discussed.

SGLT2 inhibitors as calorie Restriction mimetics: Insights on longevity pathways and Age-related diseases

Sodium–glucose cotransporter -2 (SGLT2 ) inhibitors induce glycosuria , reduce insulin levels , and promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin /IGF1 , and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways . Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favor a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation . downregulation of insulin /IGF1 pathways and mTOR signaling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms, including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK , and can deacetylate and activate transcription factors, such as PCG-1α, mitochondrial transcription factor A (TFAM), and nuclear factor E2-related factor (NRF)-2, that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases , attenuate vascular inflammation and arterial stiffness , improve mitochondrial function and reduce oxidative stress–induced tissue damage.

Compared with other calorie restriction mimetic such as metformin, rapamycin, resveratrol, and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of aging –related diseases , due to their regulation of multiple longevity pathways that closely resembles that achieved by calorie restriction and their established efficacy in reducing cardiovascular events and all-cause mortality .

Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-aging therapeutics.

flavonoids CAPABLE OF inhibitING glucose uptake in cells

Flavonoids are a group of polyphenolic compounds ubiquitously found in plants including fruits, and vegetables. Broad ranges of the biological activities of flavonoids have been reported using in vitro studies. I report that several natural flavonoids blocked glucose uptake in myelocytic U937 cells. Although there were some variations in the blocking activity of individual flavonoids , approximately half of the glucose uptake was blocked by flavonoids at the concentrations of 8–50 μM. The decreasing order of the blocking activity was fisetin ≥ myricetin ≥ quercetin ≥ apigenin > genistein > cyanidin > daidzein ≥ hesperetin > naringenin > catechin. Fisetin showed approximately 50% inhibition of glucose uptake at a concentration of 8 μM. Similar patterns of the inhibition were observed in lymphocytic Jurkat cells. Fisetin and quercetin inhibited glucose transport in a competitive manner. K_i values for fisetin and quercetin were proximately 9 and 12 μM, respectively.

This study showed that some types of natural flavonoids block glucose uptake in U937 cells and that natural flavonoids could be used as alternative blockers of glucose uptake in vitro.

organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2 ) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation—an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate.

By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improve ments in cardiac and renal function observed with this class of therapeutics.

improve ment of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use

Background and Aims: It is currently unclear whether sodium–glucose co-transporter 2 (SGLT2 ) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation.

Methods and Results: This single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients’ metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulin emic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment , while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity , were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment .

Conclusion: SGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

natural products as lead compounds for sodium glucose cotransporter (SGLT) inhibitors

glucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glucose absorption, gluconeogenesis, biosynthesis and mobilization of glycogen, glucose consumption in all tissues and glomerular filtration, and reabsorption of glucose in the kidneys. Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the family of facilitative glucose transporters (GLUTs) or to the family of sodium glucose cotransporter s (SGLTs).

The intestinal glucose absorption by endothelial cells is managed by SGLT1 , the transfer from them to the blood by GLUT2 . In the kidney SGLT2 and SGLT1 are responsible for reabsorption of filtered glucose from the primary urine, and GLUT2 and GLUT1 enable the transport of glucose from epithelial cells back into the blood stream. The flavonoid phlorizin was isolated from the bark of apple trees and shown to cause glucosuria . phlorizin is an inhibitor of SGLT1 and SGLT2 . With phlorizin as lead compound, specific inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of type 2 diabetes . inhibition of SGLT2 eliminates excess glucose via the urine.

In recent times, the dual SGLT1 /SGLT2 inhibitory activity of phlorizin has served as a model for the development and testing of new drugs exhibiting both activities. Besides phlorizin , also some other flavonoids and especially flavonoid enriched plant extracts have been investigated for their potency to reduce postprandial blood glucose levels which can be helpful in the prevention and supplementary treatment especially of type 2 diabetes.

inhibition of the intestinal glucose transporter GLUT2 by flavonoids

We tested whether the dominant intestinal sugar transporter GLUT2 was inhibited by intestinal luminal compounds that are inefficiently absorbed and naturally present in foods. Because of their abundance in fruits and vegetables, flavonoids were selected as model compounds. Robust inhibition of glucose and fructose transport by GLUT2 expressed in Xenopus laevis oocytes was produced by the flavonols myricetin, fisetin, the widely consumed flavonoid quercetin, and its glucoside precursor isoquercitrin. IC₅₀s for quercetin, myricetin, and isoquercitrin were ∼200‐ to 1000‐fold less than glucose or fructose concentrations, and noncompetitive inhibition was observed. The two other major intestinal sugar transporters, GLUT5 and SGLT1 , were unaffected by flavonoids . sugar transport by GLUT2 overexpressed in pituitary cells and naturally present in Caco‐2E intestinal cells was similarly inhibited by quercetin. GLUT2 was detected on the apical side of Caco‐2E cells, indicating that GLUT2 was in the correct orientation to be inhibited by luminal compounds. Quercetin itself was not transported by the three major intestinal glucose transporters.

Because the flavonoid quercetin, a food component with an excellent pharmacology safety profile, might act as a potent luminal inhibitor of sugar absorption independent of its own transport, flavonols show promise as new pharmacologic agents in the obesity epidemic.

Development of glucose transporter (GLUT) inhibitors

The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells.

This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction

glucose control by the kidney: an emerging target in diabetes

The full significance of the kidney‘s role in glucose homeostasis is now well recognized. For example, it is now known that renal gluconeogenesis contributes substantially to total-body glucose release in the postabsorptive state. The kidney contributes to glucose homeostasis by filtering and reabsorbing glucose. Under normal circumstances, glucose filtered by glomeruli is completely reabsorbed, but glucosuria may occur under conditions of hyperglycemia or reduced reabsorptive capacity. The sodium–glucose cotransporter SGLT2 (encoded by the SLC5A2 gene), which is expressed almost exclusively in proximal tubules, mediates approximately 90% of active renal glucose reabsorption. This transporter can be blocked by SGLT2 inhibitors, a class of compound that may prove effective in managing type 2 diabetes. The glucosuria induced by these compounds has a naturally occurring parallel in familial renal glucosuria (FRG), a condition in which SGLT2 mutations reduce renal reabsorptive capacity. Interestingly, the chronic glucosuria of patients with FRG does not appear to be associated with other pathological changes, and patients with FRG are mostly asymptomatic.

This suggests that glucosuria is not intrinsically detrimental. Selective SGLT2 inhibitors are currently in clinical trials.

INGREDIENTS:

Acanthopanax senticosus (Rupr. Maxim.) Harms extract

Fundamental studies on the inhibitory action of Acanthopanax senticosus Harms on glucose absorption

Aim of the study: Acanthopanax senticosus Harms extract (ASE) is used as an ingredient of over-the-counter drugs and function al foods, such as health supplements, in Japan. ASE exhibits a hypoglycemic effect; however, the mechanism of the hypoglycemic effect is not clear. In the present study, we investigated whether ASE has a glucose absorption inhibitory action.

Materials and methods: We examined the effects of ASE on α-amylase and α-glucosidase activities, and on glucose uptake in Caco-2 cells. We also examined the effects of ASE oral administration on glucose tolerance in type 2 diabetes mellitus model db/db mice.

Results: The addition of ASE inhibited α-glucosidase activity but not α-amylase activity . The α-glucosidase inhibitory activity of ASE was approximately 1/13 of that of acarbose. The addition of ASE inhibited 2′-deoxy-d-glucose (DG) uptake in human intestinal Caco-2 cells, and the inhibitory activity of ASE was approximately 1/40 of that of phloretin. Kinetic analysis of glucose uptake indicated that ASE has no effects on DG uptake through passive diffusion, but that ASE inhibits intracellular DG uptake chiefly by inhibiting transport via a glucose transporter . In the glucose tolerance study, db/db mice orally administered ASE for 3 days showed significantly lower plasma glucose level than the control group 30 min after sucrose loading, without affecting plasma insulin levels . In addition, ASE oral administration significantly inhibited α-glucosidase activity in the small intestine mucosa extirpated from the mice.

Conclusion: These findings indicate that ASE may be useful as an ingredient of functional foods to improve postprandial hyperglycemia and prevent type II diabetes mellitus. Acanthopanax senticosus Harms extract (ASE) suppressed glucide absorption by the inhibition of intestinal α-glucosidase activity and glucose uptake . ASE is expected to inhibit the rapid rise in blood glucose level immediately after a meal and to improve impaired glucose tolerance in type II diabetes mellitus .

Acer nikoense

Cyclic diarylheptanoids as Na+-glucose cotransporter (SGLT) inhibitors from Acer nikoense

Two cyclic diarylheptanoids, acerogenins A (1) and B (2) have been isolated from the bark of Acer nikoense as inhibitors of Na⁺–glucose cotransporter (SGLT). Acerogenins A (1) and B (2) inhibited both isoforms, SGLT1 and SGLT2 . Structure–activity relationship of acerogenin derivatives on inhibitory activity of SGLT as well as conformational analysis of 1 and 2 on the basis of J-resolved HMBC spectra and X-ray analysis were discussed.

Achyranthes bidentata Bl.root extract

Unexplored Potential of traditional Chinese medicine in diabetes mellitus

Diabetes is one of the most prevalent disease worldwide and is associ–ated with one of the highest morbidities and mortality rates associated. Like the western and conventional medicines, traditional Chinese medicine (TCM ) has promising results in the ailment of diabetes and its associated complications. But still the use of TCM is refrained for further explorations due to inadequate knowledge of active pharmaceutical ingredient and its isolation. Thus, this review will highlight some of the key concepts and rational behind the therapeutic regimen of TCM aiming towards diabetes treatment. A detailed study of all the articles including research as well as reviews, which were available on the world wide web was performed. The review includes MEDLINE and EMBASE databases using keywords alone or in combinations, such as diabetes, diabetic complications, Chi–nese therapy, traditional chinese medicine, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic complications , α-amylase and several others. TCM collectively is an effective and comparatively safe in the treatment of diabetes mellitus and its associated complications. Sig–nificant results are seen in monotherapy and in combination therapy with current conventional drugs. The effects include controlling glycemic levels along with the mitigation of diabetes associated complications. Focus on clinical trials and further investigations might help in concluding TCM as one of the most effective and safe treatment therapies. TCM holds enor–mous potential by virtue of its mechanism of action by maintaining the homeostasis in the body and thereby exhibiting pharmacological action.

Alchemilla vulgaris

Phytochemical Screening of Alchemilla Vulgaris, Sophora Japonica, Crataegus Azarolus, and Their inhibitory activity on Lipase and α-amylase

Phytochemical screening of Alchemilla Vulgaris (leaves and flowers), Sophora Japonica, and Crataegus Azarolus (leaves and fruits), have been determined, and the results showed that the different plant parts of the studied plants contained the following compounds: phenols, carbohydrates, flavonoids, saponins, tannins, and glycosides.

While it has shown the absence of alkaloids and cardinols, except the leaves of Crataegus Azarolus that contained alkolois. The effect of Alchemilla Vulgaris (leaves and flowers), Sophora Japonica, and Crata egus Azarolus (leaves and fruits) on lipase activity and α–amylase activity were screened by used different extracts[MeOH; MeOH 70% EtOH; EtOH70%; Hexane; Chloroform]. to test their anti-obesity activity using porcine pancreatic lipase inhibitory assay, and porcine pancreatic α–amylase.

The results showed that the extract obtained with polar solvents have a good inhibitory activity, and the highest effect on lipase activity was in the MeOH extracts but the highest effect onα –amylase activity was in the MeOH 70% extracts, on the contrary the non-polar solvents (Hexane; Chloroform) have a very weak effect on lipase and α–amylase activity, also we showed that the polar extracts of Alchimalla Vulgaris (leaves and flowers) have the highest effect on lipase activity and α–amylase activity comparative with the extracts of Sophora Japonica, and Crata egus Azarolus (leaves and fruits).

These results suggest that the chemical content of polar extracts of these plants might be of therapeutic interest with respect to the treatment of obesity. International Journal of Ac ademic Scientific Research.

Alisma orientalis (Sam.) Juzep extract

Chemical constituents from Alisma orientalis extracts with hypoglycemic effect

Objective: To study the chemical constituents in Alisma orientalis extracts with hypoglycemic effect.

Methods: To study the in vivo hypoglycemic effects of A. orientalis extracts, high fat diet (HFD)-induced insulin resistance male C57BL/6J mice were treated with water and ethanol extracts of A. orientalis in diet, and glucose tolerance test was carried out following the intervention. Silica gel, ODS, and preparative HPLC were used to isolate the compounds. Their chemical structures were elucidated on the basis of NMR and MS spectral data.

Results: Sixteen compounds were identified as sitosterol (1), palmitic acid (2), heptadecanoic acid (3), eicosanoic acid (4), 11-deoxy-alisol B (5), 23-acetate alisol B (6), 23-acetate alisol C (7), alisol B (8), 24-acetate alisol A (9), alisol G (10), 24-acetate alisol F (11), alisol L (12), alisol C (13), alisol F (14), alisol A (15), and 16-oxo-24-acetate alisol A (16), and nine of the triterpenes could improve glucose uptake in HepG2 cells.

Conclusion: Compounds 3 and 4 are isolated from A. orientalis for the first time. The water and ethanol extracts of A. orientalis could improve glucose tolerance test. Triterpenes may be one of the therapeutic material basis in hypoglycemic activities in A. orientalis.

Allium cepa L.extract

Extracts and flavonoid s from onion inhibit the intestinal sodium-coupled glucose transporter 1 (SGLT1 ) in vitro but show no anti-hyperglycaemic effects in vivo in normoglycaemic mice and human volunteers

Extracts and flavonoids from onion are described as having anti-diabetic activities. We here demonstrate that an onion extract and individual flavonoids thereof diminish glucose uptake mediated by the intestinal glucose transporter SGLT1 when expressed in oocytes and studied in mouse intestinal segments in vitro. Strongest inhibition of SGLT1 was observed for quercetin-4′-O-glucoside (Q4′glc) in oocytes but with only moderate inhibition in jejunal segments of mice. An oral glucose tolerance test (OGTT) performed in obese/hyperglycaemic mice revealed that the onion extract to reduce blood glucose increases significantly. However, an OGTT performed in healthy volunteers after administration of the onion extract failed to reveal an effect on glucose and insulin levels .

Despite its capability to inhibit intestinal glucose uptake via SGLT1 in vitro and in mice in vivo, the onion extract did not alter blood glucose levels during an OGTT in human volunteers and this may predominantly be due to a dosing effect.

Alstonia macrophylla

Alstiphyllanines E–H, picraline and ajmaline-type alkaloids from Alstonia macrophylla inhibiting sodium glucose cotransporter

Three new picraline-type alkaloids, alstiphyllanines E–G (1–3) and a new ajmaline-type alkaloid, alstiphyllanine H (4) were isolated from the leaves of Alstonia macrophylla together with 16 related alkaloids (5–20). Structures and stereochemistry of 1–4 were fully elucidated and characterized by 2D NMR analysis. Alstiphyllanines E and F (1 and 2) showed moderate Na⁺–glucose cotransporter (SGLT1 and SGLT2 ) inhibitory activity.

A series of a hydroxy substituted derivatives 21–28 at C-17 of the picraline-type alkaloids have been derived as having potent SGLT inhibitory activity . 10-Methoxy-N(1)-methylburnamine-17-O-veratrate (6) exhibited potent inhibitory activity, suggesting that the presence of an ester side chain at C-17 may be important to show SGLT inhibitory activity. Structure activity relationship of alstiphyllanines on inhibitory activity of SGLT was discussed.

Andrographis paniculata Nees

Mechanistic understanding of PtyroneTM: A plant based natural anti diabetic product

Objective: To investigate the combinatorial effect of hydroalcoholic extracts of Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. plants prospective to diabetes management.

Methods: Taking a lead from the scientific literature, in silico studies have also been designed for the screening of anti-diabetic targets against andrographolide and pterostilbene compounds followed by in vivo studies from Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. Furthermore, the diabetes was induced by STZ model and the impact of Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. have been conformed by relative expression studies by qPCR.

Results: Our results have shown that andrographolide and pterostilbene are SGLT2 inhibitors and selective PPARγ agonists in in silico studies. Later, during in vivo mRNA expression studies confirming the same pattern. The findings of the study has shown to overcome the common knowledge of the only C–glycoside based molecules inhibiting the SGLT2 .

Conclusions: The possible mechanism for Ptyrone^TM in the management of diabetes could be a selective PPARγ agonist, GLUT4 translocation and SGLT2 inhibition molecule.

Anemarrhena asphodeloides Bunge extract

antidiabetic activity of a xanthone compound, mangiferin

Mangiferin (MF) isolated from Anemarrhena asphodeloides Bunge rhizome, was tested for antidiabetic activity in KK-Ay mice, an animal model of type-2 diabetes. MF lowered the blood glucose level of KK-Ay mice 3 weeks after oral administration (p < 0.01). However, no effect on the blood glucose level in normal mice was seen, indicating that MF could be useful in treating type-2 diabetes.

In addition, MF improve d hyperinsulin emia and, on insulin tolerance test, reduced blood glucose levels of KK-Ay mice. From these findings, it seems likely that MF exerts its antidiabetic activity by decreasing insulin resistance.

Angelica dahurica (Fisch.ex Hoffm.) Benth. et Hook.f. extract

Phellopterin isolated from Angelica dahurica reduces blood glucose level in diabetic mice

Insulin resistance is the critical condition for the development of metabolic syndrome s including type II diabetes and heart disease. To investigate the active components of Angelica dahurica root which is known to increase insulin sensitivity, its methanol extract was subfractionated. The ethyl acetate (EtOAc) fraction of the Angelica dahurica root extract significantly promote d adipocyte differentiation in 3T3-L1 preadipocyte cells. Among the three compounds isolated from the EtOAc extract (bergapten (1), imperatorin (2) and phellopterin (3)), phellopterin (3) induced the highest adipocyte differentiation at 25 and 50 μg/mL. In addition, treatment with imperatorin (2) and phellopterin (3) increased the mRNA expression of peroxisome proliferator-activated receptors γ (PPARγ).

In diabetic animal model induced by high-fat diets (HFD) and streptozotocin (STZ), administration of phellopterin (3), 1 mg/kg and 2 mg/kg) significantly reduced the levels of blood glucose, triglycerides and total cholesterol. Taken together, these results indicate that phellopterin (3) enhances adipocytes differentiation in 3T3-L1 preadipocytes, phellopterin (3) significantly prevents HFD/STZ-induced type Ⅱ diabetes.

The present study also provides phellopterin (3) may be a valuable therapeutic alternative for enhancing insulin sensitivity through promotion of adipocyte differentiation and by increasing mRNA expression levels of PPARγ, which is a major mediator of insulin sensitivity.

Angelica sinensis extract

chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice

This study aimed to investigate the therapeutic effects of Angelica sinensis polysaccharide (ASP), an active component derived from a water extract of Angelica sinensis, in high-fat diet (HFD)-fed BALB/c mice. The potential mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters were evaluated and key proteins involved in the lipid/glucose metabolism were analyzed. Long-term feeding with a HFD induced severe fatty liver and hyperglycemia .

Histological examination clearly showed that ASP reduced lipid accumulation in the liver and attenuate d hepatic steatosis in HFD-fed mice. In addition, ASP markedly alleviated serum and liver lipid disorders and fatty liver via the upregulation of PPARγ expression and the activation of adiponectin-SIRT1-AMPK signaling. Furthermore, ASP also significantly relieved severe oxidative stress , demonstrating that ASP might attenuate nonalcoholic fatty liver disease via a “two-hit” mechanism. In addition, ASP reduced blood glucose levels and ameliorated insulin resistance via the regulation of related metabolic enzymes and by activating the PI3K/Akt pathway in HFD-fed mice.

Our findings revealed that ASP might be used as an alternative dietary supplement or health care product to ameliorate metabolic syndrome in populations that consistently consume HFDs.

anthocyanin-rich berry-extract

Regulation of glucose transporter Expression in Human intestinal Caco-2 Cells following Exposure to an Anthocyanin-Rich Berry Extract

Polyphenols contained within plant tissues are consumed in significant amounts in the human diet and are known to influence a number of biological processes. This study investigated the effects of an anthocyanin-rich berry-extract on glucose uptake by human intestinal Caco-2 cells. Acute exposure (15 min) to berry extract (0.125%, w/v) significantly decreased both sodium-dependent (Total uptake ) and sodium-independent (facilitated uptake ) ³H-D-glucose uptake .

In longer-term studies, SGLT1 mRNA and GLUT2 mRNA expression were reduced significantly. Polyphenols are known to interact directly with glucose transporters to regulate the rate of glucose absorption . Our in vitro data support this mechanism and also suggest that berry flavonoids may modulate post-prandial glycaemia by decreasing glucose transporter expression.

Further studies are warranted to investigate the longer term effects of berry flavonoids on the management of glycaemia in human volunteers.

apigenin

glucose transporter .14.aspx Apigenin Inhibits the GLUT-1 glucose transporter and the Phosphoinositide 3-Kinase/Akt Pathway in Human Pancreatic cancer cells

Objectives: The antiproliferative mechanisms of flavonoid drugs inpancreatic cancer cells remain unclear. In this study, we evaluated the effects of the flavonoid apigenin on glucose uptake , on the expression of the glucose transporter 1 (GLUT-1), and on the phosphoinositide 3-kinase (PI3K)/Akt pathway in human pancreatic cancer cells.

Methods: Human pancreatic cancer cells were treated with apigenin and then underwent glucose uptake assays. Real-time reverse transcription-polymerase chain reaction and Western blot analysis were conducted to evaluate GLUT-1 and pAkt expression in CD18 and S2-013 human pancreatic cancer cells after treatment with apigenin or PI3K inhibitors (LY294002 and wortmannin).

Results: Apigenin (0-100 μM) significantly inhibited, in a dose-dependent fashion, glucose uptake in CD18 and S2-013 human pancreatic cancer cell lines. Apigenin inhibited both GLUT-1 mRNA and protein expression in a concentration- and time-dependent fashion. The PI3K inhibitors , like apigenin, downregulated both GLUT-1 mRNA and protein expression.

Conclusions: Our results demonstrate that the flavonoid apigenin decreases glucose uptake and downregulates the GLUT-1 glucose transporter in human pancreatic cancer cells . In addition, the inhibitory effects of apigenin and the PI3K inhibitors on GLUT-1 are similar, indicating that the PI3K/Akt pathway is involved in mediating apigenin’s effects on downstream targets such as GLUT-1.

Unraveling the inhibition of intestinal glucose Transport by Dietary Phenolics: A Review

Background: Glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium-dependent glucose transporter (SGLT1 ) and the facilitated-transporter glucose transporter (GLUT2 ). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2.

Methods: Phenolic inhibition of intestinal glucose transport has been examined using brush border membrane vesicles from rats, pigs or rabbits, Xenopus oocytes and more recently Caco-2 cells, which are the most promising for harmonizing in vitro experiments.

Results: Phenolic concentrations above 100 μM has been proved to successfully inhibit the glucose transport. Generally, the aglycones quercetin, myricetin, fisetin or apigenin have been reported to strongly inhibit GLUT2, while quercetin-3-O-glycoside has been demonstrated to be more effective in SGLT1. Additionally, epigallocatechin as well as epicatechin and epigallocatechin gallates were observed to be inhibited on both SGLT1 and GLUT2.

Conclusion: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and aglycones exert significant inhibition , and also the inhibition of phenolic acids remains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters. A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interaction s is also included.

Apium graveolens L. extract

The effects of celery leaf (apium graveolens L.) treatment on blood glucose and insulin level s in elderly pre-diabetics

Objectives: To analyze the effect of celery leaf extract on blood glucose and plasma insulin levels in elderly pre-diabetics.

Methods: This study was conducted between March and November 2014 at the Faculty of medicine , Syiah Kuala University, Banda Aceh, Indonesia. A quasi-experimental pretest-posttest with a control group was conducted with elderly pre-diabetic volunteers. The subjects included 16 elderly pre-diabetics older than 60 (6 males and 10 females). The subjects were randomly divided into 2 groups: a control group (placebo-treated) and a treatment group (celery-treated). The treatment consisted of celery leaf extract capsules at the dose of 250 mg, 3 times per day (morning, afternoon and evening), 30 minutes before a meal, for 12 days. Data analysis was performed using the t-test (p<0.05).

Results: There was a significant decrease in pre-prandial plasma glucose levels (p=0.01) and post-prandial plasma glucose levels (p=0.00), but no significant increase in plasma insulin levels (p=0.15) after celery leaf treatment in elderly pre-diabetics.

Conclusion: Celery was effective at reducing blood glucose levels , but there was a lack of association between blood glucose levels and plasma insulin levels in elderly pre-diabetics.

Arbutus unedo L. roots bark

Arbutus unedo L., (Ericaceae) inhibits intestinal glucose absorption and improves glucose tolerance in rodents

Ethnopharmacological relevance: Arbutus unedo L., (Ericaceae) is one of the most traditional plants commonly used to treat diabetes in people living in Eastern Morocco region particularly in Taza and Beni Mellal.

Aim of the study: The aim of the study was to find if there is a scientific support to the ethnopharmacological relevance use of Arbutus unedo L., roots bark (AU) to treat diabetes .

Materials and methods: We studied the effects of crude aqueous extract of AU on intestinal glucose absorption using short-circuit current technique in vitro and oral glucose tolerance test in vivo.

Results: The aqueous extract of AU (10 µg/mL to 1 mg/mL) induced concentration-dependent inhibition of sodium -dependent glucose transport across isolated mouse jejunum. The maximal inhibition was obtained with 1 mg/mL, which exhibited more than 80% of the Phloridzin inhibition with an IC50 close to 216 µg/mL. A 6-week AU ingestion (2 g/(kg day)), improved oral glucose tolerance as efficiently as metformin (300 mg/(kg day)). Arbutus unedo L. and metformin also reduced body weight.

Conclusions: Arbutus unedo L. roots bark aqueous extract directly inhibited the electrogenic intestinal absorption of glucose in vitro. In addition it improved oral glucose tolerance and lowered body weight in rats after chronic oral administration in vivo. These results add a scientific support to the ethnopharmacological relevance use of Arbutus unedo L. roots bark to treat diabetes .

Arctium lappa L extract

Arctium lappa contributes to the management of type 2 diabetes mellitus by regulating glucose homeostasis and improving oxidative stress: A critical review of in vitro and in vivo animal-based studies

diabetes is a metabolic disease highly widespread worldwide, and the most common form is the type 2 diabetes mellitus (T2DM). A large number of synthetic drugs are currently available for the treatment of diabetes ; however, they present various side effects and, for this reason, people are increasingly inclined to search natural alternative treatments . Among these, Arctium lappa (A. lappa) has interesting anti-diabetic activities, exerted by improving glucose homeostasis and reducing insulin -resistance. In addition, A. lappa exerts a marked antioxidant activity , an effect known to play a pivotal role in the treatment of T2DM.

The purpose of this review is to analyse scientific evidence in order to evaluate the role of A. lappa and its bioactive compounds in management of T2DM. The literature search performed provided only in vitro and animal-based studies. No clinical studies have been conducted in order to investigate the effect of A. lappa on T2DM patients. However, available literature provides evidence for further clinical trials in order to confirm these claimed activities on humans .

Asparagus Racemosus

>Antihyperglycaemic activity of Asparagus racemosus roots is partly mediated by inhibition of carbohydrate digestion and absorption, and enhancement of cellular insulin action

Asparagus racemosus roots have been shown to enhance insulin secretion in perfused pancreas and isolated islets. The present study investigated the effects of ethanol extracts of A. racemosus roots on glucose homeostasis in diabetic rats, together with the effects on insulin action in 3T3 adipocytes. When administered orally together with glucose, A. racemosus extract improved glucose tolerance in normal as well as in two types of diabetic rats. To investigate the possible effects on carbohydrate absorption, the sucrose content of the gastrointestinal tract was examined in 12 h fasted rats after an oral sucrose load (2·5 g/kg body weight). The extract significantly suppressed postprandial hyperglycaemia after sucrose ingestion and reversibly increased unabsorbed sucrose content throughout the gut. The extract also significantly inhibited the absorption of glucose during in situ gut perfusion with glucose.

Furthermore, the extract enhanced glucose transport and insulin action in 3T3-L1 adipocytes. Daily administration of A. racemosus to type 2 diabetic rats for 28 d decreased serum glucose , increased pancreatic insulin, plasma insulin , liver glycogen and total oxidant status. These findings indicate that antihyperglycaemic activity of A. racemosus is partly mediated by inhibition of carbohydrate digestion and absorption, together with enhancement of insulin secretion and action in the peripheral tissue. Asparagus racemosus may be useful as a source of novel antidiabetic compounds or a dietary adjunct for the management of diabetes.

Astragaus membrana

Meta-analysis of the clinical value of Astragalus membranaceus in diabetic nephropathy

Aim of study: Nowadays diabetic nephropathy (DN) has become a serious problem. Astragalus membranaceus is a traditional herb used for thousands of years in China and East Asia for kidney disease. In modern medicine , Astragalus shows significant renal protective effect in DN. We aimed to systematically review the randomized and semi-randomized control trials to ascertain its role in the treatment of DN.

Materials and methods: PUBMED, MEDLINE, Chinese journal full-test database (CJFD), Chinese biological and medical database were searched by computer and manual searching. Two assessors independently reviewed each trial. 25 studies comprising 21 RCTs and 4 CCTs were involved including 1804 patients (945 in treatment group and 859 in control group).

Results and conclusions: Astragalus injection had more therapeutic effect in DN patients including renal protective effect (BUN, SCr, CCr and urine protein) and systemic state improve ment (serum albumin level ) compared with the control group.

Ethnopharmacological relevance: This study investigates the effect of Astragalus in DN patients. It suggests that although of unknown bioactive ingredients and mechanism of renal protection , the role of Astragalus in the treatment of DN can be disclosed and of profound significance.

Astragalus mongholicus Bunge extract

Astragalus polysaccharides alleviates glucose toxicity and restores glucose homeostasis in diabetic states via activation of AMPK

Aim of the study: To establish the mechanism underlying the improve ment of glucose toxicity by Astragalus polysaccharide (APS), which occurred via an AMP activated protein kinase (AMPK )-dependent pathway.

Methods: In vivo and in vitro effects of APS on glucose homeostasis were examined in a type 2 diabetes mellitus (T2DM) rat model. The T2DM rat model was duplicated by a high-fat diet (58% fat, 25.6% carbohydrate, and 16.4% protein) and a small dose of streptozotocin (STZ, 25 mg/kg, ip). After APS therapy (700 mg·kg−1·d−1, ig) for 8 weeks, blood glucose , glycosylated hemoglobin, and serum insulin were measured. insulin sensitivity was evaluated by the comprehensive analysis of oral glucose tolerance tests (OGTT) and HOMA IR index. Hepatic glycogen was observed by the PAS staining method. The expression and activity of skeletal muscle AMPK α and acetyl-CoA carboxylase (ACC), and the phosphorylation of hepatic glycogen synthase (GS), the glycogen synthase (GS),were measured by Western blotting. Glucose uptake was measured with the 2-deoxy-[3H]-D-glucose method in C2C12 cells.

Results: The hyperglycemia status, insulin sensitivity , glucose uptake , and activation level of AMPK in diabetic rats were improve d in response to APS administration. APS could also alleviate glucose toxicity in cultured mouse cells by the activation of AMPK.

Conclusion: APS can alleviate glucose toxicity by increasing liver glycogen synthesis and skeletal muscle glucose translocation in the T2DM rat model, via activation of AMPK.

Atractylodes lancea (Thunb.) DC. extract

Effects of Atractylodes lancea on plasma glucose and Lipid Profile in Streptozotocin Induced diabetic Rats

The purpose of this study was to examine the effects of Atractylodes lancea (A.l.) in a dose-dependent manner on lipid levels and plasma glucose in diabetic rats induced with streptozotocin (STZ). The Sprague-Dawley rats were randomly classified into five groups: normal, STZ-control and three experimental groups [A.l.-1, diabetic treated with ethanolic extract of A.l. (1 g/kg b.w.), A.l.-2, diabetic administered with ethanolic extract of A.l. (2 g/kg b.w.), and A.l.-3, diabetic administered with ethanolic extract of A.l. (3 g/kg b.w.)]. The normal and STZ-control group were fed an AIN-93 diet and the three experimental groups were administered with A.l. extract at doses of 1, 2, and 3 g/kg b.w./day, respectively, for 14 days. The plasma glucose levels in all the experimental groups were significantly lower than the STZ-control group after 14 days of treatment .

The total cholesterol of the A.l.-3 and triglyceride levels , atherogenic index (AI) of all three experimental groups were significantly lower than the STZ-control group. The ALT and AST activities at A.l.-2, A.l.-3 were significantly lower than the STZ-control group.

This result that demonstrate the administration of Atractylodes lancea can reduce hyperglycemia and hyperlipidemia risk in diabetic rats.

Atractylodes macrocephala Koidz extract

[Studies on physico-chemical properties and hypoglycemic activity of complex polysaccharide AMP-B from Atractylodes macrocephala Koidz]

Aim of the study: To isolate a complex polysaccharide (AMP-B) from Atractylodes macrocephala Koidz and study its phtsico-chemical properties and hypoglycemic activity .

Methods: The root of Atractylodes macrocephala K. was extracted with water and precipitated with ethanol, dialyzed against water and freeze-dried to get the crude polysaccharides (AMP). A complex polysaccharide (AMP-B) was isolated and purified on DEAE-cellulose column. The model of diabetes rats was established with alloxan injection through the tail vein. Male rats were divided into 5 groups: the normal group, the control group, and three AMP-B-fed groups. Measuring the blood glucose, water and food consumption, thymus and pancreas index, and studying cut sections of pancreas tissues.

Results: AMP-B is a complex-polysaccharide, elemental analysis of AMP-B shown C 32.84%, H 5.68%, and N 1.79%. The neutral polysaccharide content of AMP-B was 50.3%, uronic acid was 40.4%, and protein was 11.5%. Monosaccharide composition of AMP-B was determined by GC, AMP-B composed of Glc, Gal, Man, Ara and Rha in a molar ratio of 3.0:2.5:1.3:3.5:1.0. AMP-B was found to reduce blood glucose level in alloxan-diabetic rats markedly at doses of 50, 100 and 200 mg.kg-1 by ig, but no effect in normal rat. AMP-B was found to decrease the consumption of water and food, recover pancreas damage of diabetic rats obviously, inhibited the atrophy of thymus and pancreas of the diabetic rats induced by alloxan.

Conclusion: AMP-B showed significant hypo-glycemic effect on the experimental hyperglycemia s rats induced by alloxan.

Bauhinia megalandra leaves

Effects of Bauhinia megalandra aqueous leaf extract on intestinal glucose absorption and uptake by enterocyte brush border membrane vesicles

Aqueous extract of Bauhinia megalandra leaves was able to inhibit the intestinal glucose absorption in a concentration-dependent way and additive to phlorizine. Moreover, B. megalandra leaf extract drastically reduced the ¹⁴C-glucose uptake by enterocyte brush border membrane vesicles. The B. megalandra leaf extract administrated orally, simultaneously with glucose improve d the glucose tolerance with a significant reduction of the 30-min peak. The extract did not have an effect on the glucose tolerance when glucose was administrated subcutaneously.

blackcurrant polyphenols

Apple and blackcurrant polyphenol-rich drinks decrease postprandial glucose , insulin and incretin response to a high-carbohydrate meal in healthy men and women

Postprandial glycemic responses to meals are inhibited by polyphenol-rich plant foods. Combinations of polyphenols may be particularly effective through complementary mechanisms. A randomized, controlled, double-blinded cross-over trial was conducted in healthy volunteers to test the hypothesis that apple and blackcurrant polyphenol-rich drinks would reduce postprandial blood glucose concentrations .

Secondary outcomes included insulin and glucose -dependent insulin otropic polypeptide (GIP) secretion. Twenty men (mean age 26 y, SD 8) and 5 postmenopausal women (mean age 57 y, SD 3) consumed a placebo drink (CON) and 2 polyphenol-rich drinks containing fruit extracts: either 1200 mg apple polyphenols (AE), or 600 mg apple polyphenols+600 mg blackcurrant anthocyanins (AE+BE), in random order with a starch and sucrose meal. Incremental areas under the curve (iAUC) for plasma glucose concentrations were lower following AE+BE over 0–30 and 0–120 min compared with CON; mean differences (95% CI) −32 mmol/L·min (−41, −22, P<.0005) and −52 mmol/L min (−94, −9, P<.05), respectively. AE significantly reduced iAUC 0–30 min (mean difference −26 mmol/L min, −35, −18, P<.0005) compared with CON, but the difference over 120 min was not significant.

Postprandial insulin , C-peptide and GIP concentrations were significantly reduced relative to CON. A dose response inhibition of glucose transport was demonstrated in Caco-2 cells, including total and GLUT-mediated transport, and SGLT1 -mediated glucose transport was strongly inhibited at all doses in Xenopus oocytes, following 10 min incubation with 0.125–4 mg apple polyphenols/ml.

In conclusion, ingestion of apple and blackcurrant polyphenols decreased postprandial glycemia, which may be partly related to inhibition of intestinal glucose transport.

cardamonin

inhibitory Effect of Tangeretin and Cardamonin on Human intestinal SGLT1 activity In Vitro and blood glucose levels in Mice In Vivo

Tangeretin and cardamonin did not affect the uptake of L-leucine, L-glutamate, and glycyl-sarcosine. Tangeretin, but not cardamonin, inhibited fructose uptake, suggesting that the inhibitory effect of tangeretin was specific to the monosaccharide transporter, whereas that of cardamonin was specific to SGLT1. Kinetic analysis suggested that the suppression of SGLT1 activity by tangeretin was associated with a reduction in V_max and an increase in K_m, whereas suppression by cardamonin was associated with a reduction in V_max and no change in K_m. Oral glucose tolerance tests in mice showed that tangeretin and cardamonin significantly suppressed the rapid increase in blood glucose levels.

In conclusion, tangeretin and cardamonin were shown to inhibit SGLT1 activity in vitro and lower blood glucose level in vivo.

Catalpol from Rehmannia glutinosa

plasma glucose Lowering Mechanisms of Catalpol, an Active Principle from Roots of Rehmannia glutinosa, in Streptozotocin-Induced diabetic Rats

Catalpol is one of the active principles from roots of Rehmannia glutinosa Steud (Scrophulariaceae) that is widely used to treat diabetic disorders in Chinese traditional medicine using the name of Di-Huang, which is used to investigate the mechanisms for lowering of plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats). Catalpol decreased plasma glucose in a dose-related manner, and this action was reduced by pretreatment with naloxone or naloxonazine. An increase of plasma β-endorphin by catalpol was also observed in parallel.

The plasma glucose lowering action of catalpol was deleted in bilateral adrenalectomized rats. Moreover, catalpol enhanced β-endorphin release from the isolated adrenal medulla of STZ-diabetic rats. Otherwise, plasma glucose lowering action of catalpol failed to produce in opioid μ-receptor knockout mice. Also, repeated administration of catalpol for 3 days in STZ-diabetic rats resulted in a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. These effects were also reversed by blockade of opioid μ-receptors.

Our results suggested that catalpol increased glucose utilization through increase of β-endorphin secretion from adrenal gland in STZ-diabetic rats.

Hypoglycemic effect of Rehmannia glutinosa oligosaccharide in hyperglycemic and alloxan-induced diabetic rats and its mechanism

The hypoglycemic and anti-diabetic effect of Rehmannia glutinosa oligosaccharide (ROS) in glucose -induced hyperglycemic and alloxan-induced diabetic rats and its mechanism was investigated in this paper.

It was found that pretreatment of ROS in normal rats with 100 mg/kg for 3 days, i.p., induced a partial prevention of hyperglycemia caused by glucose (2 g/kg, i.p.), while when hyperglycemia was induced in adrenalectomized (ADX) rats, the preventive effect of ROS on hyperglycemia was lost. In alloxan-induced diabetic rats, ROS (100 mg/kg for 15 days, i.p.) showed a significant decrease in blood glucose level and hepatic glucose -6-phosphatase activity with an increase in hepatic glycogen content.

Furthermore, ROS raised plasma insulin level and lowered plasma corticosterone level in alloxan-induced diabetic rats. The results indicated that oligosaccharide of Rehmannia glutinosa Libosch. exerted a significant hypoglycemic effect in normal and alloxan-induced diabetic rats.

The regulatory mechanism of ROS on glucose metabolism was adrenal dependent and had a close relation with the neuroendocrine system.

Stachyose extract from Rehmannia glutinosa Libosch. to lower plasma glucose in normal and diabetic rats by oral administration

The hypoglycemic effects of water extract and stachyose extract (Part III) from Rehmannia glutinosa Libosch. were investigated in this paper by oral administration to normal, glucose – and adrenaline-induced hyperglycemic and alloxan-induced diabetic rats.

The results showed that Part III had the effect of lowering fasted plasma glucose level and partially preventing hyperglycemia induced by glucose (2.5 g · kg⁻¹, i.p.) and adrenaline (300 μg · kg⁻¹, i.p.), respectively, but no obvious dose-dependent effect was found when it was administered at the doses of 100, 200 and 400 mg · kg⁻¹ for 6 days, i.g. In alloxan-induced diabetic rats, Part III (200 mg · kg⁻¹ for 15 days, i.g.) gave a significant decrease in blood glucose level .

The results suggested that Part III, which is mainly composed of stachyose from Rehmannia glutinosa Libosch., had a significant hypoglycemic effect in glucose – and adrenaline-induced hyperglycemic and alloxan-induced diabetic rats.

Hypoglycemic activity of polysaccharide fraction from rhizome of Rehmannia glutinosa Libosch. f. hueichingensis Hsiao and the effect on carbohydrate metabolism in normal mouse liver

The ethanol precipitate fraction (RG-WP) obtained from the hot water extract from rhizome of Rehmannia glutinosa Libosch. f. hueichingensis Hsiao is mainly composed of pectin-like polysaccharide, and exhibited hypoglycemic activity in normal and streptozotocin-induced mice by intraperitoneal administration of the fraction.

The results obtained after chemical modification and proteinase treatments of RG-WP suggest that the activity exists in the polysaccharide moiety. Furthermore, the effect of RG-WP on the activities of enzymes responsible for the glucose metabolism in the liver of normal mouse was studied to elucidate the mechanism of the hypoglycemic activity.

Administration of RG-WP to normal mice significantly increased the activities of hepatic glucokinase and glucose -6-phosphatase dehydrogenase, but decreased those of hepatic glucose-6-phosphatase and phosphofructokinase. RG-WP stimulated the secretion of insulin and reduced the glycogen content in the liver of normal mouse.

chlorogenic acid

Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia

The effects of chlorogenic acid (CA) on hepatic glucose output, blood glucose levels and on glucose tolerance were analysed. Hepatic uptake of CA and its effects on hepatic catabolism of L-alanine and glucose -6-phosphatase (G-6-Pase) activity were also evaluated. CA (1 mM) inhibited about 40% of G-6-Pase activity (p < 0.05) in the microsomal fraction of hepatocytes, but no effect was observed on production of glucose from gluconeogenesis or on L-alanine catabolism, at various concentrations of CA (0.33, 0.5 and 1 mM), in liver perfusion experiments.

Since there were indications of a lack of uptake of CA by the liver, it is possible that this compound did not reach sufficiently high intracellular levels to inhibit the target enzyme. Accordingly, intravenous administration of CA also failed to provoke a reduction in blood glucose levels. However, CA did promote a significant reduction (p < 0.05) in the plasma glucose peak at 10 and 15 min during the oral glucose tolerance test, probably by attenuating intestinal glucose absorption, suggesting a possible role for it as a glycaemic index lowering agent and highlighting it as a compound of interest for reducing the risk of developing type 2 diabetes.

Chlorogenic acid Maintains glucose homeostasis through Modulating the Expression of SGLT-1, GLUT-2, and PLG in Different intestinal Segments of Sprague-Dawley Rats Fed a High-Fat Diet

Objective: To reveal the effects and related mechanisms of chlorogenic acid (CGA) on intestinal glucose homeostasis.

Methods: Forty male Sprague-Dawley rats were randomly and equally divided into four groups: normal chow (NC), high-fat diet (HFD), HFD with low-dose CGA (20 mg/kg, HFD-LC), and HFD with high-dose CGA (90 mg/kg, HFD-HC). The oral glucose tolerance test was performed, and fast serum insulin (FSI) was detected using an enzyme-linked immunosorbent assay. The mRNA expression levels of glucose transporters (Sglt-1 and Glut-2) and proglucagon (Plg) in different intestinal segments (the duodenum, jejunum, ileum, and colon) were analyzed using quantitative real-time polymerase chain reaction . SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.

Results: At both doses, CGA ameliorated the HFD-induced body weight gain, maintained FSI, and increased postprandial 30-min glucagon-like peptide 1 secretion. High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression. Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.

Conclusion: An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis . CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg, thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis .

Chrysin

Effect of dietary polyphenols on fructose uptake by human intestinal epithelial (Caco-2) cells

Intake of high-fructose products is associated with metabolic syndrome development. We investigated if dietary polyphenols can interfere with fructose absorption by the human intestinal epithelial Caco-2 cell line.

Acutely, several polyphenols induced a significant decrease (15–20%) in ¹⁴C-fructose uptake. Chronically, ¹⁴C-fructose uptake was also affected by polyphenols; quercetin, chrysin and apigenin (100 µM) were the most effective (±25% decrease). These compounds (100 µM) appear to interfere with both GLUT2 and GLUT5 activity; accordingly, they caused a very marked decrease in the mRNA expression levels of GLUT2 (≅90%) and GLUT5 (≅75%). The effect of these compounds on ¹⁴C-fructose uptake does not involve interference with PKC, PKA, PI3K and p38 MAPK intracellular signaling pathways.

Quercetin, apigenin and chrysin might decrease the intestinal absorption of fructose. Further studies are needed to test for their beneficial effects on metabolic syndrome.

Cinnamomum cassia

Cinnamon extract lowers glucose , insulin and cholesterol in people with elevated serum glucose

Cinnamon (肉桂 ròu guì) has in vitro insulin potentiating activity , and proanthocyanidins from cinnamon prevent in vitro formation of advanced glycation end products. Some human studies were equivocal, but several have shown beneficial effects of cinnamon supplementation on circulating glucose, lipids, and/or insulin.

This placebo-controlled double-blind trial tested the effects of a dried water extract of cinnamon (Cinnamomum cassia) on circulating glucose, lipids, insulin, and insulin resistance. Men and women from Beijing and Dalian, China, were invited to participate if they had fasting serum glucose >6.1 mmol/L or 2-h glucose >7.8 mmol/L. Participants, (173 were enrolled and 137 completed the study) were randomly assigned to receive either a spray-dried, water extract of cinnamon (Cinsulin ®), 250 mg/capsule, or a placebo, twice a day for two months. Mean ± SEM age of participants was 61.3 ± 0.8 years, BMI was 25.3 ± 0.3 and M/F ratio was 65/72.

After 2 mo, fasting glucose decreased (p < 0.001) in the cinnamon extract-supplemented group (8.85 ± 0.36 to 8.19 ± 0.29 mmol/L) compared with the placebo group (8.57 ± 0.32 to 8.44 ± 0.34 mmol/L, p = 0.45). glucose 2 h after a 75 g carbohydrate load, fasting insulin , and HOMA-IR also decreased with cinnamon extract compared with placebo. Total and LDL-cholesterol decreased with cinnamon extract and HDL-cholesterol decreased in both the cinnamon-extract and placebo groups.

In conclusion, supplementation with 500 mg of water-extract of cinnamon for two months reduced fasting insulin , glucose , total cholesterol, and LDL cholesterol and enhanced insulin sensitivity of subjects with elevated blood glucose.

Cistanche tubulosa

Anti-hyperglycemic and hypolipidemic effects of Cistanche tubulosa in type 2 diabetic db/db mice

Ethnopharmacological relevance: The dried succulent stem of Cistanche tubulosa (Schenk) R. Wight is one component of traditional Chinese medicine prescriptions for diabetes. However, there have been no modern scientific reports to confirm this traditional claim for the Cistanche species until now. Thus, we investigated the effects of Cistanche tubulosa on glucose homeostasis and serum lipids in male BKS.Cg-Dock7^m +/+ Lepr^db/J (db/db) mice, a model of type 2 diabetes.

Materials and methods: The verbascoside and echinacoside contents of Cistanche tubulosa powder were evaluated using HPLC. The total phenolic content, polysaccharide content and antioxidant activity of Cistanche tubulosa powder were also evaluated. Then, different doses of Cistanche tubulosa (equivalent to 120.9, 72.6 or 24.2 mg verbascoside/kg) were administered orally once daily for 45 days to male db/db mice. Age matched db/+ mice were used as normal controls. body weight, fasting blood glucose, postprandial blood glucose and insulin tolerance test were measured during the experiment. At the time of sacrifice, blood was collected for measurement of insulin level, the homeostatic model assessment of insulin resistance (HOMA-IR), and total cholesterol, triglyceride, HDL-c, LDL-c and VLDL-c levels ; liver and muscle were harvested for measurement of glycogen levels.

Results: Cistanche tubulosa significantly suppressed the elevated fasting blood glucose and postprandial blood glucose levels, improve d insulin resistance and dyslipidemia, and suppressed body weight loss in db/db mice. However, Cistanche tubulosa did not significantly affect serum insulin levels or hepatic and muscle glycogen levels.

Conclusion: This study provides scientific evidence for the traditional use of Cistanche tubulosa to treat diabetes, suggesting that Cistanche tubulosa has the potential for development into a functional food ingredient or drug to prevent hyperglycemia and treat hyperlipidemia.

Major constituents of Cistanche tubulosa, echinacoside and acteoside, inhibit sodium-dependent glucose cotransporter 1-mediated glucose uptake by intestinal epithelial cells

Echinacoside (ECH) and acteoside (ACT), the major constituents of Cistanche tubulosa, suppress the increase in postprandial blood glucose level. Although ECH and ACT have been reported to weakly inhibit α-glucosidases, the underlying mechanism remains unclear. Therefore, we focused on the regulatory mechanism of dietary glucose absorption.

In this study, we aimed to clarify the inhibitory effects of ECH and ACT on sodium-dependent glucose cotransporter (SGLT) 1-mediated gastro intestinal glucose absorption. Uptake experiments were performed using human intestinal Caco-2 cells and the fluorescence glucose analogue, 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-d–glucose (2-NBDG). Sodium-dependent 2-NBDG uptake was successfully estimated and this uptake was completely inhibited by an SGLT inhibitor phlorizin. ECH and ACT inhibited sodium-dependent 2-NBDG uptake in a concentration-dependent manner. However, this inhibition was not observed under sodium-free condition.

This study suggested that the inhibitory effects of ECH and ACT on SGLT1-mediated glucose uptake contribute to suppression of increased postprandial blood glucose level.

Citrus maxima (Burm) Merr. extract

antihyperglycemic EFFECT AND ANTIOXIDANT PROPERTY OF CITRUS MAXIMA LEAF IN STREPTOZOTOCININDUCED diabetic RATS

The aim of the present study was to evaluate antihyperglycemic activity of methanol extract of Citrus maxima leaf (MECM) in streptozotocin (STZ; 65 mg/kg b.w.) induced diabetic rats. Three days after STZ induction, diabetic rats received MECM orally at a dose of 200 and 400 mg kg-1 body weight daily for 15 days. Glibenclamide (0.5 mg kg -1 p.o.) was used as a reference drug. blood glucose levels were measured on days 0, 4, 8 and 15.

Serum biochemical parameters viz. SGOT, SGPT and ALP were estimated. The TBARS and GSH levels of the pancreas, kidney and liver were determined. MECM significantly (P<0.001) and in a dose dependent manner normalized blood glucose levels, serum biochemical parameters, decreased lipid peroxidation, and recovered GSH as compared to those of STZ control.

The present study inferred that in STZ-induced diabetic Wistar rats, C. maxima leaf demonstrated a potential antihyperglycemic effect that might be attributed to its antioxidant property.

Citrus medica L. var.sarcodactylis Swingle extract

Phytochemical and antihyperglycemic Studies on Citrus medica l.Leaves (Etrog) Growing in Egypt

From 70% aqueous methanol extract of the defatted powdered leaves of Citrus medica L. var. Etrog, six compounds,namely, β–sitosterol–glucoside (1), sakuranetin (2), 7–O–methylaromadendrin (3), dihydrokaempferide (4), hesperitin (5)and rutin (6) were isolated and identified by physicochemical and spectral data (UV, MS and NMR). Compounds 2–4 arenewly reported from the genusand 5 is newly reported from the species. The extract was safe up to 2g/kg.bwt. Thehistopathological changes on liver, kidney and pancreas were assessed.

The antioxidant activity was calculated to102.9μ g/ml. The antihyperglycemic activity exerted a significant reduction in blood glucose level to (105.2±8.35) indiabetic rats after one month of treatment with a dose of 200 mg/kg and to (87.4±6.30) with 400mg, when compared toGliclazide standard (110.8±7.24) (P< 0.05).

As a conclusion, the methanol extractof the defatted powdered leaves of Etrogexhibits a significant antihyperglycemic activity which might be attributed to the presence of flavonoid compounds.

Coix seed extract

Coix Seed Polysaccharide Has Effect on Model Rats with glucose and Lipid metabolism Disorder Induced by Clozapine

Objective: To discuss the effect of coix seed polysaccharide on model rats with glucose and lipid metabolism disorder induced by clozapine.

Methods: Divided 50 SD rats of SPF grade into five groups randomly according to the body mass,namely the normal control group,the model group,the metformin group and the coix seed polysaccharide group of high-dose and low-dose,10 rats in each group. Model rats with glucose and lipid metabolism disorder were induced by clozapine. The normal control group and the model group were given saline solution by gavage;the metformin group was given 0.2 g/kg of metformin twice a day by gavage;the coix seed polysaccharide group of high-dose and low-dose were respectively given 0.2 g/kg and 0.1 g/kg of coix seed polysaccharide twice a day by gavage. Detected the body mass, the levels of fasting plasma glucose and postprandial 2 h plasma glucose, and the content of leptin and adiponcetin in serum of rats.

Results: Compared with those in the normal control group,the body mass and the levels of fasting plasma glucose ,postprandial 2 h plasma glucose and leptin in serum of rats in the model group from the 14 th day to the56 thday were obviously increased,while the level of adiponcetin in serum was obviously decreased,differences being significant(P 0.05,P 0.01). Compared with those in the model group,the body mass and the levels of fasting plasma glucose ,postprandial 2 h plasma glucose and leptin in serum of rats in the coix seed polysaccharide group of high-dose and low-dose and the metformin group from the 42 thday to the 56 thday were obviously decreased, while the levels of adiponcetin in serum were obviously decreased,differences being significant(P 0.05,P 0.01).

Conclusion: Coix seed polysaccharide has good prevention and treatment for model rats with glucose and lipid metabolism disorder induced by clozapine. Its mechanism probably is related to the regulation of the levels of glucose, leptin and adiponcetin.

Coptis chinensis Franch.extract

Hypoglycemic and Hypocholesterolemic Effects of Coptis chinensis Franch Inflorescence

Hypocholesterolemic and hypoglycemic activities of Coptis chinensis franch inflorescence (Coptis inflorescence) were studied using animal models. Serum total and LDL cholesterol of rats fed a diet containing 1% cholesterol and 0.5% cholic acid increased, as compared with those of rats fed a normal diet. The level of total and LDL cholesterol were reduced markedly in a dose dependent manner, in rats given Coptis inflorescence extract orally at doses of 0.25, 0.5 g/kg.day for 4 weeks. In diabetic rats induced by alloxan, Coptis inflorescence extract showed a significant (p < 0.05) blood sugar lowering activity at all experimented doses (0.125, 0.25 and 0.5 g/kg.day). The highest reduction of blood sugar was about 58% when the rats were given Coptis inflorescence extract orally at a dose of 0.5 g/kg.day for 3 weeks. The 100 g dried water extract of Coptis inflorescence contained 8.11 g total alkaloid, 3.34 g berberin, 1.08 g palmatine and 0.66 g jatrorrhizine, which had long been identified as active compounds in Coptis chinensis franch root (Coptis root). Thus, the results suggest that Coptis inflorescence would be effective in the prevention and management of coronary artery disease by lowering serum cholesterol and blood sugar .

Cordyceps

4-Acetoxyscirpendiol of Paecilomyces tenuipes Inhibits Na+/D-glucose cotransporter Expressed in Xenopus laevis Oocytes

Cordyceps, an entomopathogenic fungus, contains many health-promoting ingredients. Recent reports indicate that the consumption of cordyceps helps reduce blood–sugar content in diabetics. However, the mechanism underlying this reduction in circulatory sugar content is not fully understood. Methanolic extracts were prepared from the fruiting bodies of Paecilomyces tenuipes, and 4-beta acetoxyscirpendiol (4-ASD) was eventually isolated and purified. $N a^{+}$ /glucose transporter-1 (SGLT-1) was expressed in Xenopus oocytes, and the effect of 4-ASD on SGLT-1 was analyzed utilizing a voltage clamp and by performing 2-deoxy-D-glucose (2-DOG) uptake studies. 4-ASD was shown to significantly inhibit SGLT-1 activity compared to the non-treated control in a dose-dependent manner.

In the presence of the derivatives of 4-ASD (diacetoxyscirpenol or 15-acetoxyscirpendiol), SGLT-1 activity was greatly inhibited in an 4-ASD-like manner. Of these derivatives, 15-acetoxyscirepenol inhibited SGLT-1 as well as 4-ASD, whereas diacetoxyscirpenol was slightly less effective.

Taken together, these results strongly indicate that 4-ASD in P. tenuipes may lower blood sugar levels in the circulatory system. We conclude that 4-ASD and its derivatives are effective SGLT-1 inhibitors.

Cornus officinalis Sieb. et Zucc extract

Biochemical and histopathological study of the anti-hyperglycemic and anti-hyperlipidemic effects of cornelian cherry (Cornus mas L.) in alloxan-induced diabetic rats

Background: Anthocyanins are phytochemicals with a multitude of pharmacological actions including anti-diabetic and anti-hyperlipidemic effects. This study was undertaken to evaluate the anti-hyperglycemic and anti-hyperlipidemic effects of cornelian cherry (Cornus mas L., CM) fruits – that are rich in anthocyanins and known to have medicinal properties– in alloxan-induced diabetic rats.

Methods: Twenty-eight adult male rats were randomly assigned to four groups of seven animals each: non-diabetic control, diabetic control, glibenclamide-treated (0.6 mg/kg/day; 4 weeks) and CM fruit-treated (2 g/day; 4 weeks) group. diabetes was induced by a single injection of alloxan (120 mg/kg). Fasting serum levels of glucose , total cholesterol (TC), low- (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), aspartate (AST) and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were measured at the end of study period.

Results: diabetic rats had significantly elevated levels of serum glucose , LDL-C, TG, AST, ALP and ALT and decreased levels of HDL-C compared to the non-diabetic group (p<0.05). treatment with either glibenclamide or CM counterbalanced the above-mentioned abnormalities. The effects of CM were comparable to those of glibenclamide at the doses tested in this study. Serum glucose , TG, ALP and HDL concentrations in the normal group were significantly changed compared to the diabetic control group (p<0.05). There were no significant changes in evaluated biochemical parameters between the glibenclamide and CM groups with normal group. Histopathological examinations revealed a less severe hepatic portal inflammation in the CM-treated vs. other study groups.

Results: Dietary supplementation with CM fruits effectively prevents the development of diabetes mellitus , dyslipidemia and hepatic inflammation in alloxan-induced diabetes .

Crataegus pin.nati fida Bge extract

Regulation Effects of Crataegus pinnatifida Leaf on glucose and Lipids metabolism

The leaf of Crataegus pinnatifida (Rosaceae) is commonly consumed either raw or cooked to improve digestion and promote blood circulation in China. To investigate the regulation effects of it on glucose and lipid metabolism , the flavonoids fraction was prepared and analyzed by HPLC and LC−MS. In vivo, at doses of 250 and 500 mg/kg, the flavonoids fraction showed inhibitory effects on TG and glucose absorption , accelerating effects on gastrointestinal transit but no effect on gastric emptying. In vitro, treatment of 3T3-L1 preadipocytes with 30 μg/mL flavonoids fraction significantly suppressed the accumulation of TG and free fatty acid . It also suppressed the gene expressions of C/EBPα, PPARγ, SREBP 1c, aP2 and adiponectin but did not affect that of leptin. C. pinnatifida leaf may be useful for type 2 diabetics and hyperlipidemics as a foodstuff.

Cynodon dactylon

Isolation and in silico evaluation of antidiabetic molecules of Cynodon dactylon (L.)

Cynodon dactylon is a potential source of metabolites such as flavanoids, alkaloids, glycosides and β-sitosterol and has been traditionally employed to treat urinary tract and other microbial infections and dysentery. The present work attempts to evaluate the activity of C. dactylon extracts for glycemic control.

Aqueous extracts of C. dactylon analyzed by HPLC–ESI MS have identified the presence of apigenin, luteolin, 6-C-pentosyl-8-C-hexosyl apigenin and 6-C-hexosyl-8-C-pentosyl luteolin. Evaluation of hypoglycemic activity through an extensive in silico docking approach with PPARγ (Peroxisome Proliferator-Activated Receptor), GLUT-4 (glucose transporter -4) and SGLT2 (sodium glucose co-transporter -2) revealed that luteolin, apigenin, 6-C-pentosyl-8-C-hexosyl apigenin, 6-C-hexosyl-8-C-pentosyl luteolin interact with SGLT2 . Interaction s of these molecules with Gln 295 and Asp 294 residues of SGLT2 have been shown to compare well with that of the phase III drug, dapagliflozin.

These residues have been proven to be responsible for sugar sensing and transport. This work establishes C. dactylon extract as a potential SGLT2 inhibitor for diabetic neuropathy thus enabling a possibility of this plant extract as a new alternative to existing diabetic approaches.

Cytochalasin B

Cytochalasin B: inhibition of glucose and Glucosamine Transport

Cytochalasin B has been shown to potently inhibit the transport of glucose , deoxyglucose , and glucosamine by Novikoff hepatoma cells in suspension culture without affecting their intracellular phosphorylation and metabolism . Deoxyglucose transport is inhibited by cytochalasin B in a simple competitive manner. Although this inhibition is not sufficient to explain the biological action of the drug on cytokinesis, it does explain earlier observations on inhibition by cytochalasin B of the incorporation of glucose and glucosamine, and probably of other extracellular precursors, into macromolecules by various types of cells.

Curcumin

Effect of curcumin supplementation on blood glucose , plasma insulin , and glucose homeostasis related enzyme activities in diabetic db/db mice

We investigated the effect of curcumin on insulin resistance and glucose homeostasis in male C57BL/KsJ-db/db mice and their age-matched lean non-diabetic db/+ mice. Both db/+ and db/db mice were fed with or without curcumin (0.02%, wt/wt) for 6 wks. Curcumin significantly lowered blood glucose and HbA_1c levels , and it suppressed body weight loss in db/db mice. Curcumin improved homeostasis model assessment of insulin resistance and glucose tolerance, and elevated the plasma insulin level in db/db mice.

Hepatic glucokinase activity was significantly higher in the curcumin-supplemented db/db group than in the db/db group, whereas glucose -6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly lower. In db/db mice, curcumin significantly lowered the hepatic activities of fatty acid synthase, β-oxidation , 3-hydroxy-3-methylglutaryl coenzyme reductase, and acyl-CoA: cholesterol acyltransferase. Curcumin significantly lowered plasma free fatty acid , cholesterol, and triglyceride concentrations and increased the hepatic glycogen and skeletal muscle lipoprotein lipase in db/db mice.

Curcumin normalized erythrocyte and hepatic antioxidant enzyme activities (superoxide dismutase, catalase, gluthathione peroxidase) in db/db mice that resulted in a significant reduction in lipid peroxidation. However, curcumin showed no effect on the blood glucose , plasma insulin , and glucose regulating enzyme activities in db/+ mice.

These results suggest that curcumin seemed to be a potential glucose-lowering agent and antioxidant in type 2 diabetic db/db mice, but had no affect in non-diabetic db/+ mice.

daidzein

Daidzein, its effects on impaired glucose and lipid metabolism and vascular inflammation associated with type 2 diabetes

Over the last decades, the incidence of type 2 diabetes (T2D) is increasing substantially. Emerging evidences from epidemiological studies have shown the association between higher intake of soy isoflavones and reduced risk of T2D and its associated health risks. Daidzein, a soy isoflavone, has been found to have a promising therapeutic potential in managing T2D pathophysiology. Fermented soybean is the major source of daidzein; however, it can also be formed via the consumption of its glycosylated moiety, daidzin with subsequent hydrolysis by intestinal bacterial enzyme.

Many studies reported the prophylactic effect of daidzein on the improve ment of hyperglycemia , insulin resistance, dislipidemia, obesity , inflammation , and other complications associated with T2D. The molecular mechanisms underlying the action of daidzein include diverged pathways where daidzein has been shown to interact with several signaling molecules and receptors to achieve desirable effect. Although the specific molecular mechanism is still elusive, further studies are thus needed to understand it in detail.

In this review, we discuss the antidiabetic potential of daidzein with respect to the evidences from various clinical, preclinical, and cell culture studies and the underlying molecular mechanism in a precise way to have a comprehensive account on this isoflavone with promising therapeutic potential.

Dendrobium nobile Lindl extract

Effects of the extracts from Dendrobium nobile lindl on blood sugar in normal and hyperglycemic mice

Objective: To observe hypoglycemic effects of polysaccharide and alkaloids from Dendrobium nobile lindl in hyperglycemic mice induced by adrenalin.

Methods: The hyperglycemic model was induced by adrenalin. After intragastric administration of polysaccharide and alkaloids, the blood glucose level of each groups mice were determined.

Results: The polysaccharide and alkaloids could significantly lower the blood glucose level in the model mice, but no significantly effect was observed in the normal mice.

Conclusions: The polysaccharide and alkaloids from Dendrobium nobile lindl have hypoglycemic action on adrenal model mice.

epigallocatechin gallate

Green Tea Polyphenols Inhibit the sodium-Dependent glucose transporter of intestinal Epithelial Cells by a Competitive Mechanism

Intestinal glucose uptake is mainly performed by the sodium-dependent glucose transporter, SGLT1. The transport activity of SGLT1 was markedly inhibited by green tea polyphenols, this inhibitory activity being most pronounced in polyphenols having galloyl residues such as epicatechin gallate (ECg) and epigallocatechin gallate (EGCg). Experiments using brush-border membrane vesicles obtained from the rabbit small intestine demonstrated that ECg inhibited SGLT1 in a competitive manner, although ECg itself was not transported via SGLT1.

The present results suggest that tea polyphenols such as ECg interact with SGLT1 as antagonist-like molecules, possibly playing a role in controlling the dietary glucose uptake in the intestinal tract.

Regulation of intestinal glucose transport by tea catechins

Intestinal glucose uptake is mainly performed by its specific transporters, such as SGLT 1, GLUT 2 and 5 expressed in the intestinal epithelial cells. By using human intestinal epithelial Caco-2 cells we observed that intestinal glucose uptake was markedly inhibited by tea extracts. While several substances in green tea seem to be involved in this inhibition, catechins play the major role and epicatechin gallate (ECg) showed the highest inhibitory activity.

Since our Caco-2 cells did not express enough amount of SGLT 1, the most abundant intestinal glucose transporter, the effect of ECg on SGLT 1 was evaluated by using brush border membrane vesicles obtained from the rabbit small intestine. ECg inhibited SGLT 1 in a competitive manner, although ECg itself was not transported via the glucose transporters.

These results suggest that tea catechins could play a role in controlling the dietary glucose uptake at the intestinal tract and possibly contribute to blood glucose homeostasis.

Dietary polyphenols decrease glucose uptake by human intestinal Caco-2 cells

The effect of different classes of dietary polyphenols on intestinal glucose uptake was investigated using polarised Caco-2 intestinal cells. glucose uptake into cells under sodium -dependent conditions was inhibited by flavonoid glycosides and non-glycosylated polyphenols whereas aglycones and phenolic acids swere without effect. Under sodium -free conditions, aglycones and non-glycosylated polyphenols inhibited glucose uptake whereas glycosides and phenolic acids were ineffective.

These data suggest that aglycones inhibit facilitated glucose uptake whereas glycosides inhibit the active transport of glucose. The non-glycosylated dietary polyphenols appear to exert their effects via steric hindrance, and (−)-epigallochatechingallate, (−)-epichatechingallate and (−)-epigallochatechin are effective against both transporters.

Suppressing glucose metabolism with epigallocatechin-3-gallate (EGCG) reduces breast cancer cell growth in preclinical models

Numerous studies propose that epigallocatechin-3-gallate (EGCG), an abundant polyphenol in green tea, has anti-cancer properties. However, its mechanism of action in breast cancer remains unclear. This study investigated the capacity of EGCG to suppress breast cancer cell growth in vitro and in vivo, characterizing the underlying mechanisms, focusing on the effect of EGCG on glucose metabolism. EGCG reduced breast cancer 4T1 cell growth in a concentration- (10–320 μM) and time- (12–48 h) dependent manner. EGCG induced breast cancer apoptotic cell death at 24 h, as evidenced by annexin V/PI, caspase 3, caspase 8 and caspase 9 activation. Furthermore, EGCG affected the expression of 16 apoptosis-related genes, and promoted mitochondrial depolarization. EGCG induced autophagy concentration-dependently in 4T1 cells by modulating the levels of the autophagy –related proteins Beclin1, ATG5 and LC3B.

Moreover, EGCG affected glucose, lactate and ATP levels. Mechanistically, EGCG significantly inhibited the activities and mRNA levels of the glycolytic enzymes hexokinase (HK), phosphofructokinase (PFK), and lactic dehydrogenase (LDH), and to a lesser extent the activity of pyruvate kinase (PK). In addition, EGCG decreased the expression of hypoxia-inducible factor 1α (HIF1α) and glucose transporter 1 (GLUT1), critical players in regulating glycolysis.

In vivo, EGCG reduced breast tumor weight in a dose-dependent manner, reduced glucose and lactic acid levels and reduced the expression of the vascular endothelial growth factor (VEGF). In conclusion, EGCG exerts an anti-tumor effect through the inhibition of key enzymes that participate in the glycolytic pathway and the suppression of glucose metabolism.

Polyphenol-Induced inhibition of the Response of Na+/glucose cotransporter Expressed in Xenopus Oocytes

To study the effects of polyphenols on the Na⁺/glucose cotransporter (SGLT1 ) response, SGLT1 was expressed in Xenopus oocytes by injecting cRNA synthesized from the cloned cDNA of the small intestine cotransporter of rats, and the electrical response elicited by glucose or galactose was measured by a voltage clamping method. Most phenol derivatives had no effect on the response. However, the polyphenols (+)-catechin, (−)-epicatechin gallate (ECg), and (−)-epigallocatechin gallate (EGCg), which are components of green tea, caused an inhibition of the response, which was almost independent of glucose concentration.

The inhibition constants were estimated to be 2.3 mM for (+)-catechin and 0.45 mM for both ECg and EGCg, assuming the noncompetitive inhibition mechanism. Saponin prepared from tea seeds also inhibited the response significantly. Tannic acid and aqueous extracts of teas induced nonspecific electrical responses in both cRNA-injected and noninjected oocytes at lower concentrations than those that caused an inhibition of the SGLT1 response when their dose-dependent effects were examined.

These results are possibly helpful in the development of a dietary supplement for diabetic patients.

Hypoglycemic effect of soluble polysaccharide and catechins from green tea on inhibiting intestinal transport of glucose

Background: Water soluble polysaccharide derived from green tea (WSP) is produced as byproducts when catechins were extracted from green tea. Although inhibitory effect of green tea catechins on the glucose transport in small intestine has been studied, the hypoglycemic efficacy of the WSP or its combinational effect has not been studied. In order to investigate hypoglycemic efficacy of the WSP or its combinational effect with green tea extract (GTE), co-consumption of GTE and WSP with wheat starch was investigated using in vitro digestion coupled with Caco-2 cells. The mechanism of the intestinal glucose transport was elucidated throughout the gene expression of the intestinal glucose transporters, which included sodium dependent glucose transporter (SGLT1 ) and glucose transporter 2 (GLUT2 ), using quantitative real-time polymerase chain reaction (qRT-PCR).

Results: The co-digestion of wheat starch with GTE during the small intestinal phase was the most rapidly digested into reducing sugar (73.96 g L−1) compared to itself (48.44 g L−1), WSP (60.35 g L−1), and GTE + WSP (61.81 g L−1). intestinal glucose transport was 11.82, 7.59, 4.49, and 2.40% for wheat starch, wheat starch with GTE, WSP, and GTE + WSP, respectively. The highest decreased expression pattern in SGLT1 was observed when cells treated with wheat starch + GTE + WSP (0.66-fold) compared to GTE or WSP treatment.

Conclusion: The results suggested that co-consumption of green tea derived products with wheat starch could delay the intestinal absorption of glucose. Results from the current study suggested that GTE and WSP could be the useful supplements of dietary therapy for hyperglycemia to delay glucose absorption.

epicatechin

Unraveling the inhibition of intestinal glucose Transport by Dietary Phenolics: A Review

Background: glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium – dependent glucose transporter (SGLT1 ) and the facilitated-transporter glucose transporter (GLUT2 ). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2.

Results: Phenolic concentrations above 100 μM has been proved to successfully inhibit the glucose transport. Generally, the aglycones quercetin, myricetin, fisetin or apigenin have been reported to strongly inhibit GLUT2 , while quercetin-3-O-glycoside has been demonstrated to be more effective in SGLT1. Additionally, epigallocatechin as well as epicatechin and epigallocatechin gallates were observed to be inhibited on both SGLT1 and GLUT2 .

Conclusion: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and a glycones exert significant, inhibition, and also the inhibition of phenolic acids remains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters. A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interactions is also included.

epigallocatechin

Unraveling the inhibition of intestinal glucose Transport by Dietary Phenolics: A Review

Background: glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium – dependent glucose transporter (SGLT1 ) and the facilitated-transporter glucose transporter (GLUT2 ). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2 .

Methods: Phenolic inhibition of intestinal glucose transport has been examined using brush border membrane vesicles from rats, pigs or rabbits, Xenopus oocytes and more recently Caco-2 cells, which are the most promising for harmonizing in vitro experiments.

Results: Phenolic concentrations above 100 μM has been proved to successfully inhibit the glucose transport. Generally, the aglycones quercetin, myricetin, fisetin or apigenin have been reported to strongly inhibit GLUT2 , while quercetin-3-O-glycoside has been demonstrated to be more effective in SGLT1 . Additionally, epigallocatechin as well as epicatechin and epigallocatechin gallates were observed to be inhibited on both SGLT1 and GLUT2 .

Conclusion: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and aglycones exert significant inhibition , and also the inhibition of phenolic acids sremains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters . A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interaction s is also included.

Eriobotrya japonica

Hypoglycemic effects of a sesquiterpene glycoside isolated from leaves of loquat (Eriobotrya japonica (Thunb.) Lindl.)

Sesquiterpene glycoside, nerolidol-3-O-α-l-rhamnopyranosyl(1→4)-α-l-rhamnopyranosyl(1→2)-[α-l-rhamnopyranosyl(1→6)]-β-d-glucopyranoside was isolated from dried leaves of loquat [Eriobotrya japonica (Thunb.) Lindl., Rosaceae].

Hypoglycemic effects of this natural product were assessed in normal and alloxan-diabetic mice model. Animals received orally administration of the sesquiterpene glycoside in dose of 25 and 75 mg/kg. The anti-hyperglycemic effect was compared with gliclazide’s. The dose of 25 and 75 mg/kg both exerted a significant () hypoglycemic effect in alloxan-diabetic mice throughout the test and a slight effect in normal mice.

Euonymus alatus (Thunb.) Sieb.extract

inhibitory activity of Euonymus alatus against alpha-glucosidase in vitro and in vivo

The major goal in the treatment of diabetes mellitus is to achieve near-normal glycemic control. To optimize both fasting blood glucose and postprandial glucose levels is important in keeping blood glucose levels as close to normal as possible. α-glucosidase is the enzyme that digests dietary carbohydrate, and inhibition of this enzyme could suppress postprandial hyperglycemia .

The purpose of this study was to test the inhibitory activity of methanol extract of Euonymus alatus on α-glucosidase in vitro and in vivo to evaluate its possible use as an anti-diabetic agent. Yeast α-glucosidase inhibitory activities of methanol extract of E. alatus were measured at concentrations of 0.50, 0.25, 0.10, and 0.05 mg/ml. The ability of E. alatus to lower postprandial glucose was studied in streptozotocin-induced diabetic rats. A starch solution (1 g/kg) with and without E. alatus extract (500 mg/kg) was administered to diabetic rats by gastric intubation after an overnight fast.

Plasma glucose levels were measured at 30, 60, 90, 120, 180, and 240 min. plasma glucose levels were expressed in increments from baseline, and incremental areas under the response curve were calculated. Extract of E. alatus,which had an IC₅₀ value of 0.272 mg/ml, inhibited yeast α-glucosidase activity in a concentration-dependent manner. A single oral dose of E. alatus extract significantly inhibited increases in blood glucose levels at 60 and 90 min (p<0.05) and significantly decreased incremental response areas under the glycemic response curve (p<0.05).

These results suggest that E. alatus has an antihyperglycemic effect by inhibiting α-glucosidase activity in this animal model of diabetes mellitus.

Euphorbia humifusa extract

Tannins and related Polyphenols of Euphorbiaceous Plants. XI.Three New Hydrolyzable Tannins and a Polyphenol Glucoside from Euphorbia humifusa

Three new hydrolyzable tannins, euphormisins M₁, M₂ and M₃, were isolated from Euphorbia hymifusa WILLD., and respectively characterized as 1, 3, 6-tri-O-galloyl-4-O-bravifolincarboxyl-β-D-glucose (19), an oxidative metabolite (23) of geraniin, and 1, 3, 6-tri-O-galloyl-α-D-glucose (18), by spectroscopic and chemical methods. A new ellagic acid glucoside (16) and fifteen known tannins, including geraniin (8) and four dimers [euphorbins A (13), B (14), excoecarianin (15) and eumaculin A (12)], were also isolated.

Fenugreek

In Vitro Effect of Fenugreek Extracts on intestinal sodium-dependent glucose uptake and Hepatic Glycogen Phosphorylase A

Fenugreek (Trigonella foenum-graecum L. seed) is a food with traditional medicinal use in diabetes. Beneficial effects have been demonstrated in diabetic animals and both insulin -dependent and non-insulin-dependent diabetic subjects. Effects of a lipid extract A, crude ethanolic extract B, further sub-fractions of B (saponin-free C, saponin D and sapogenin E) and a gum fibre fraction F on intestinal sodium-dependent glucose uptake were investigated in vitro using rabbit intestinal brush border membrane vesicles. All fraction s except A inhibited glucose–uptake at 0.33 and/or 3.3mg/mL (p < 0.001).

Greatest inhibition was observed with fractions D and E. Diosgenin and trigonelline (compounds reported in fenugreek)also inhibited glucose –uptake (IC50 values approximately 3mg/ml, equivalent to 8mM and 19mM respectively) but did not account for the activity of the crude extracts. Fenugreek extracts had no effect on basal levels of glycogen phosphorylase a (HGPa) activity in rat hepatocyte suspensions. However fractions C and E caused a marginal but statistically significant inhibition (18.9 and 15.1% respectively, p < 0.05) of glucagon induction of this enzyme suggesting a glucagon-antagonist effect. Diosgenin (1.65mg/ml; 4mM) inhibited glucagon-induced HGPa activity by 20% (p < 0.05), and was more effective than trigonelline (non significant inhibition of 9.4% at 1.65mg/ml, 10mM).

Ficus carica Linn extract

Protective effects of Ficus carica leaves on glucose and lipids levels, carbohydrate metabolism enzymes and β-cells in type 2 diabetic rats

Context: The decoctions of Ficus carica Linn. (Moraceae) leaves are used in the folklore treatment of diabetes .

Objective: To evaluate the effect of F. carica on glucose and lipids levels , carbohydrate metabolism enzymes and β-cells protective effects in type 2 diabetes .

Material and methods: diabetes was induced in 15 days high-fat diet (HFD)-fed Wistar rats by intraperitoneal injection of streptozotocin (STZ) (40 mg/kg). The ethyl acetate extract (250 and 500 mg/kg) of F. carica leaves was administered for 28 days. Oral glucose tolerance (OGTT) and intraperitoneal insulin tolerance tests (ITT) were evaluated on 15th and 25th days, respectively.

Results: The ethyl acetate extract (250 and 500 mg/kg) of n F. carica leaves showed significant effect (p < 0.005) in the levels of blood glucose , total cholesterol (TC), triglycerides (TG), body weight and hepatic glycogen. In OGTT, F. carica (250 and 500 mg/kg) significantly (p < 0.005) detained the increase in blood glucose levels at 60 and 120 min and in ITT, F. carica enhanced the glucose utilization significantly (p < 0.005) over 30 and 60 min compared to diabetic control. Further, the altered activities of key carbohydrate metabolizing enzymes such as glucose -6-phosphatase, fructose-1,6-bisphosphatase and hexokinase in the liver tissue of diabetic rats were significantly (p < 0.005) reverted to near normal levels upon treatment with F. carica. Immumohistochemical studies of islets substantiated the cytoprotective effect on pancreatic β-cells.

Discussion and conclusions: F. carica leaves exerted significant effect on carbohydrate metabolism enzymes with promising hypoglycemic and hypolipidemic activities in type 2 diabetic rats.

fisetin

The actions of fisetin on glucose metabolism in the rat liver

Fisetin is a flavonoid dietary ingredient found in the smoke tree (Cotinus coggyria) and in several fruits and vegetables. The effects of fisetin on glucose metabolism in the isolated perfused rat liver and some glucose -regulating enzymatic activities were investigated. Fisetin inhibited glucose , lactate, and pyruvate release from endogenous glycogen. Maximal inhibitions of glycogenolysis (49%) and glycolysis (59%) were obtained with the concentration of 200 µM.

The glycogenolytic effects of glucagon and dinitrophenol were suppressed by fisetin 300 µM. No significant changes in the cellular contents of AMP, ADP, and ATP were found. Fisetin increased the cellular content of glucose 6-phosphate and inhibited the glucose 6-phosphatase activity . Gluconeogenesis from lactate and pyruvate or fructose was inhibited by fisetin 300 µM. Pyruvate carboxylation in isolated intact mitochondria was inhibited (IC₅₀ = 163.10 ± 12.28 µM); no such effect was observed in freeze-thawing disrupted mitochondria.

It was concluded that fisetin inhibits glucose release from the livers in both fed and fasted conditions. The inhibition of pyruvate transport into the mitochondria and the reduction of the cytosolic NADH-NAD⁺ potential redox could be the causes of the gluconeogenesis inhibition . Fisetin could also prevent hyperglycemia by decreasing glycogen breakdown or blocking the glycogenolytic action of hormones.

Fructus Ligustri Lucidi extract

Hypoglycemic Effect of Fructus Ligustri Lucidi

The decoction of Fructus Ligustri Lucidi (FLL) 15.30 g/kg ig for 10 days significantly decreased the blood glucose level in normal mice. FLL 30 g/kg before or after the treatment of alloxan also decreased the blood glucose level in alloxan diabetic mice. The elevation of blood glucose level induced by adrenaline or glucose was antagonized by FLL.

Fucoxanthin

Transcriptomic analysis reveals effects of fucoxanthin on intestinal glucose transport

Fucoxanthin, one of carotenoid pigments from plants and algae, is known to regulate blood glucose and insulin levels. The mechanism of its hypoglycemic activity has drawn a lot of scientific interest in recent years. In this study, we investigated the effects of fucoxanthin on intestinal glucose transport using a murine model.

Our data demonstrated that fucoxanthin was able to decrease blood glucose level and alleviate insulin resistance significantly. The results from RNA-seq based transcriptomic analysis, suggested that fucoxanthin acted as a key regulator in insulin /PI3K/AKT/mTOR signaling and PKA/AMPK /mTOR signaling pathways. Moreover, fucoxanthin ingestion resulted in a significant reduction in the protein expression of intestinal glucose transporters, such as SGLT-1, and led to decreased translocation of GLUT-2, which contributed to the regulation of blood glucose level.

Together, our findings provided a mechanistic insight into the regulatory effect of fucoxanthin on blood glucose.

Ganoderma lucidum（Leyss. ex Fr.）Karst.extract

Hypoglycemic effect of Ganoderma lucidum polysaccharides

Aim of study: To investigate the hypoglycemic effect of Ganoderma lucidum polysaccharides (Gl-PS) in the normal fastedmice and its possible mechanism.

Methods: Normal fasted mice were given a single dose of Gl-PS 25, 50, and100 mg/kg by ip and the serum glucose was measured at 0, 3, and 6 h after administration. Gl-PS 100 mg/kg werealso given by ip and the serum glucose and insulin levels were measured at 0 min, 30 min, 1 h, 3 h, 6 h, and 12 h.Pancreatic islets were isolated and incubated with glucose 5.6 mmol/L and different concentration of Gl-PS, theinsulin content of islets and insulin release were examined. The islets fluorescent intensity of [Ca2+]i was alsostudied with a confocal microscope. Verapamil and egtazic acid were used to testify whether the insulin -releasingeffect of Gl-PS was mediated by its ability to raise the Ca2+ influx.

Results: Gl-PS dose-dependently lowered the serum glucose levels at 3 h and 6 h after administration. Gl-PS 100 mg/kg raised the circulating insulin levels at1 h after administration. In vitro, Gl-PS had no effect on islets insulin content, but it stimulated the insulin releaseafter incubation with glucose 5.6 mmol/L. Confocal microscope showed that Gl-PS 100 mg/L had the capacity toraise the [Ca2+] i. The insulin-releasing effect of Gl-PS was inhibited by verapamil/egtazic acid .

Conclusion: Gl-PS possesses the hypoglycemic effect on normal mice; one mechanism is through its insulin-releasing activity due to a facilitation of Ca2+ inflow to the pancreatic β cells.

Effects of the Extracts of Ganoderma lucidum on blood glucose level in Rats

The water extract of Ganoderma lucidum was found, by the oral glucose tolerance test (OGTT), to reduce blood glucose and insulin 10 min after oral glucose infusion as compared to control rats. In addition, the water extract increased blood insulin 30 min and 60 min after oral glucose infusion without affecting blood glucose level as compared to control rats. Intravenous infusion of adrenaline with the oral glucose tolerance test (OGTT) caused an increase of blood glucose without elevating blood insulin level, as found by the oral glucose tolerance test (OGTT). The water extract of G. lucidum reduced the elevation of blood glucose without elevating blood insulin by the intravenous infusion of adrenaline and oral infusion of glucose.

Gaultheria phillyreifolia

Iridoids and polyphenols from chilean Gaultheria spp. berries decrease the glucose uptake in Caco-2 cells after simulated gastrointestinal digestion

Berries are rich food sources of potentially health-beneficial (poly)phenols. However, they may undergo chemical modifications during gastrointestinal digestion. The effect of simulated gastrointestinal digestion on the content and composition of secondary metabolites from Gaultheria phillyreifolia and G. poeppigii berries was studied. The influence of the digested extracts on the in vitro metabolism and absorption of carbohydrates was evaluated. After simulated digestion, 31 compounds were detected by UHPLC-DAD-MS.

The total content of anthocyanins decreased by 98–100%, flavonols by 44–56%, phenylpropanoids by 49–75% and iridoids by 33–45%, the latter showing the highest stability during digestion. Digested extracts inhibited α-glucosidase (IC₅₀ 2.8–24.9 μg/mL) and decreased the glucose uptake in Caco-2 cells by 17–28%. Moreover, a decrease in the mRNA expression of glucose transporters SGLT1 (38–92%), GLUT2 (45–96%), GLUT5 (28–89%) and the enzyme sucrase-isomaltase (82–97%) was observed.

These results show the effect of simulated gastrointestinal digestion on the content and composition of Gaultheria berries.

genistein

Genistein Is a natural inhibitor of Hexose and Dehydroascorbic acid Transport through the glucose transporter, GLUT1

Genistein is a dietary-derived plant product that inhibits the activity of protein-tyrosine kinases. We show here that it is a potent inhibitor of the mammalian facilitative hexose transporter GLUT1. In human HL-60 cells, which express GLUT1, genistein inhibited the transport of dehydroascorbic acid , deoxyglucose , and methylglucose in a dose-dependent manner. Transport was not affected by daidzein, an inactive genistein analog that does not inhibit protein-tyrosine kinase activity , or by the general protein kinase inhibitor staurosporine. Genistein inhibited the uptake of deoxyglucose and dehydroascorbic acid in Chinese hamster ovary (CHO) cells overexpressing GLUT1 in a similar dose-dependent manner. Genistein also inhibited the uptake of deoxyglucose in human erythrocytes indicating that its effect on glucose transporter function is cell-independent. The inhibitory action of genistein on transport was instantaneous, with no additional effect observed in cells preincubated with it for various periods of time. Genistein did not alter the uptake of leucine by HL-60 cells, indicating that its inhibitory effect was specific for the glucose transporters .

The inhibitory effect of genistein was of the competitive type, with a K of approximately 12 μM for inhibition of the transport of both methyl-glucose and deoxy-glucose. Binding studies showed that genistein inhibited glucose-displaceable binding of cytochalasin B to GLUT1 in erythrocyte ghosts in a competitive manner, with a K of 7 μM. These data indicate that genistein inhibits the transport of dehydroascorbic acid and hexoses by directly interacting with the hexose transporter GLUT1 and interfering with its transport activity, rather than as a consequence of its known ability to inhibit protein-tyrosine kinases.

These observations indicate that some of the many effects of genistein on cellular physiology may be related to its ability to disrupt the normal cellular flux of substrates through GLUT1, a hexose transporter universally expressed in cells, and is responsible for the basal uptake of glucose.

Genistein directly inhibits GLUT4-mediated glucose uptake in 3T3-L1 adipocytes

The isoflavone-derivative genistein is commonly applied as an inhibitor of tyrosine kinases. In this report we analyze the effect of genistein on insulin -stimulated glucose uptake in 3T3-L1 adipocytes. In these cells insulin -induced glucose uptake is primarily mediated by the GLUT4 glucose transporter.

We observed that pre-treatment with genistein did not affect insulin -induced tyrosine kinase activity of the insulin receptor or activation of protein kinase B. On the other hand, genistein acted as a direct inhibitor of insulin-induced glucose uptake in 3T3-L1 adipocytes with an IC50 of 20 μM. We conclude that apart from acting as a general tyrosine kinase inhibitor, genistein also affects the function of other proteins such as the GLUT4 transporter.

These data suggest that caution must be applied when interpreting data on the involvement of tyrosine kinase activity in glucose uptake in 3T3-L1 adipocytes.

glycyrrhiza inflata

Chemical structure and inhibition on α-glucosidase of polysaccharide with alkaline-extracted from glycyrrhiza inflata residue

A new neutral polysaccharide, named AGP, was extracted from glycyrrhiza residue by 5% NaOH alkaline solution and purified by DEAE-cellulose and Sephadex G-150. A single and symmetrical peak was shown by HPLC, indicating that AGP is a homogeneous polysaccharide with a molecular weight of 2.89 × 103 KDa. The specific rotation of AGP was detected by a polarimeter and it was +45°. Monosaccharide composition analysis indicated that AGP was consisted of l-rhamnose: l-arabinose: d-xylose: d-mannose: d-glucose and d-galactose with a molar ratio of 1:2.33:2.85:0.69:3.05:1.54. The structure of AGP was analyzed by GC–MS, periodate oxidation, Smith degradation, FT-IR, methylation and NMR, which indicated that the AGP was composed of → 6)-β-d-Glcp-( → backbone and the →4)-α-d-Xylp-(1→, →5)-α-l-Araf-(1→, →3)-α-l-Rhap-(1→, →6)-α-d-Galp-(1→, →3,6)-α-Manp-(1→ and →1)-β-d-Glcp as branches.

The results of Congo red experiment and circular dichroism (CD) showed that there was triple helix conformation in AGP. The micro-structure of AGP were detected by scanning electron microscopy (SEM), which concluded that the shape of AGP was a “thin slice” and its structure is not regular. The crystal configuration was identified by X-ray diffraction (XRD), showing that there is no crystal structure. Furthermore, the AGP exhibited certain inhibition activity on α-glucosidase.

Gnetum gnemonoides

Gneyulins A and B, Stilbene Trimers, and Noidesols A and B, Dihydroflavonol-C-Glucosides, from the Bark of Gnetum gnemonoides

Gneyulins A (1) and B (2), two new stilbene trimers consisting of oxyresveratrol constituent units, and noidesols A (3) and B (4), two new dihydroflavonol-C-glucosides, were isolated from the bark of Gnetum gnemonoides. The structures and configurations of 1−4 were elucidated on the basis of 2D NMR correlations and X-ray analysis. Gneyulins A (1) and B (2) showed inhibition of Na⁺–glucose transporters (SGLT-1 and SGLT-2).

Gossypol

Endofacial competitive inhibition of the glucose transporter 1 activity by gossypol

Gossypol inhibits the transport of hexoses in HL-60 and CHO cells.

We determined the dose dependence from the effect of gossypol on the transport of methylglucose and deoxyglucose in HL-60 cells. We have previously shown that HL-60 cells express the glucose transporter GLUT1 and efficiently transport hexoses (53). We used a 30-s uptake assay to determine the kinetic constants of transport. When gossypol was added at the beginning of the uptake assay, it inhibited the uptake of deoxyglucose and methylglucose by HL-60 cells in a dose-dependent manner (Fig. 1, A and B). Fifty percent inhibition was observed at ∼30 μM.

Graviola (Annona muricata)

Possible anti-diabetic potentials of Annona muricata (soursop): inhibition of α-amylase and α-glucosidase activities

Background: Annona muricata has been used in folklore in the management of diabetes . A major strategy in decreasing postprandial hyperglycemia in diabetes involves the inhibition of carbohydrate-hydrolyzing enzymes – α-amylase and α-glucosidase . Thus, this study evaluated the in vivo and in vitro inhibitory potentials of the different parts (fruit-pulp, leaf, stem-bark and root-bark) of Annona muricata.

Methods: A total of 120 Wistar rats were treated with methanol extracts for 28 days after which blood and tissue samples were collected for α-amylase assay. In vitro inhibitory properties of methanol, ethyl acetate and dichloromethane extracts of the various parts of the plant on α-amylase and α-glucosidase activities were performed using standard procedures. The mode and mechanism of interaction s between the enzymes and extracts (and isolated acetogenin) were determined using various kinetic interpolations and in silico experiments.

Result: The fruit-pulp and root-bark methanolic extracts better -inhibited plasma and tissue amylase in vivo. The in vitro studies revealed that the stem-bark methanolic, fruit-pulp ethyl acetate, and leaf dichloromethane extracts, better inhibited α-amylase activity compared with the standard acarbose. Also, the leaf methanol, fruit-pulp ethyl acetate, and root-bark dichloromethane extract better inhibited α-glucosidase activity . These observations were corroborated with their higher Bmax and Vmax and lower Kd values. All the extracts exhibited an “uncompetitive” type of inhibition pattern. Also, the isolated acetogenin (15-acetyl guanacone) from the fruit-pulp showed a better binding affinity compared to the standard drug, Metformin.

Conclusion: Better natural remedy for diabetic s can be obtained from Annona muricata with minimal or no adverse side effects.

Effect of Annona Muricata L. on metabolic Parameters in diabetes mellitus: A Systematic Review

In recent decades, numerous scientific investigations have been conducted to study the antidiabetic effects of Annona muricata L. However, no comprehensive evidence-based systematic review regarding this topic is available. Hence, this study was conducted to systematically evaluate the studies of the efficacy of A. muricata in diabetes management. Six online databases used to search for the related articles.

The search terms used were A. muricata/ soursop in combination with diabetes, glucose, and insulin. Seventeen studies were identified that fit the inclusion criteria (1 clinical, 10 in vivo, 4 in vitro, 1 in vivo/ in vitro and 1 in silico). A clinical study showed the positive adjuvant effect of A. muricata to glibenclamide in type 2 diabetes patients. In vivo studies reported beneficial effects of A. muricata in murine models to include decreasing fasting blood glucose level, attenuating diabetes -associated weight loss, increasing serum insulin , improving the lipid profile, normalizing the activity of antioxidant enzymes, and exerting pancreas-protective and hepatoprotective effects. In vitro studies of A. muricata demonstrated its potential for reducing post-prandial glucose level by inhibiting pancreatic α-amylase, lipase, and α-glucosidase and lowering oxidative stress by inhibiting glycation and lipid peroxidation. Additionally, the in-silico study suggested a positive effect of A. muricata in enhancing insulin sensitivity. A. muricata showed a promising effect on the metabolic parameters in diabetes mellitus.

Considering that A. muricata is widely consumed worldwide, further exploration of its therapeutic potential is worthwhile.

guava (Psidium guajava)

In Vitro and In Vivo inhibition of intestinal glucose Transport by Guava (Psidium Guajava) Extracts

Scope: Known pharmacological activities of guava (Psidium guajava) include modulation of blood glucose level s . However, mechanistic details remain unclear in many cases.

Methods and results: This study investigated the effects of different guava leaf and fruit extracts on intestinal glucose transport in vitro and on postprandial glucose levels in vivo. Substantial dose- and time-dependent glucose transport inhibition (up to 80%) was observed for both guava fruit and leaf extracts, at conceivable physiological concentrations in Caco-2 cells. Using sodium -containing (both glucose transporters , sodium -dependent glucose transporter 1 [SGLT1 ] and glucose transporter 2 [GLUT2 ], are active) and sodium -free (only GLUT2 is active) conditions, we show that inhibition of GLUT2 was greater than that of SGLT1 . inhibitory properties of guava extracts also remained stable after digestive juice treatment , indicating a good chemical stability of the active substances. Furthermore, we could unequivocally show that guava extracts significantly reduced blood glucose levels (≈fourfold reduction) in a time-dependent manner in vivo (C57BL/6N mice). Extracts were characterized with respect to their main putative bioactive compounds (polyphenols) using HPLC and LC-MS.

Conclusion: The data demonstrated that guava leaf and fruit extracts can potentially contribute to the regulation of blood glucose levels.

Gymnema sylvestre

Gymnemic acids sInhibit sodium-Dependent glucose transporter

To evaluate the activity of botanicals used in Chinese traditional medicine as hypoglycemic agents for diabetes type II prevention and/or treatment , extracts prepared from 26 medicinal herbs were screened for their inhibitory activity on sodium -dependent glucose transporter 1 (SGLT1 ) by using two-electrode voltage-clamp recording of glucose uptake in Xenopus laevis oocytes microinjected with cRNA for SGLT1 . Showing by far the strongest SGLT1 inhibitory effect, the phytochemicals extracted from Gymnema sylvestre (Retz.) Schult were located by means of activity -guided fraction ation and identified as 3-O-β-d-glucuronopyranosyl-21-O-2-tigloyl-22-O-2-tigloyl gymnemagenin (1) and 3-O-β-d-glucuronopyranosyl-21-O-2-methylbutyryl-22-O-2-tigloyl gymnemagenin (2) by means of LC-MS/MS, UPLC-TOF/MS, and 1D/2D-NMR experiments.

Both saponins exhibited low IC₅₀ values of 5.97 (1) and 0.17 μM (2), the latter of which was in the same range as found for the high-affinity inhibitor phlorizin (0.21 μM). As SGLT1 is found in high levels in brush-border membranes of intestinal epithelial cells, these findings demonstrate for the first time the potential of these saponins for inhibiting electrogenic glucose uptake in the gastrointestinal tract.

Gynostemma Pentaphyllum

Anti-diabetic activity evaluation of a polysaccharide extracted from Gynostemma pentaphyllum

In current study, a polysaccharide (GPP) was successfully extracted from Gynostemma pentaphyllum herb. Monosaccharide composition of GPP was rhamnose, arabinose, galactose, glucose , xylose, mannose, galacturonic acid and glucuronic acid in a molar ratio of 4.11: 7.34: 13.31: 20.99: 1.07: 0.91: 4.75: 0.36. Molecular weight and polydispersity (Mw/Mn) of GPP were 4.070 × 104 Da and 1.037, respectively. Primary structure features of GPP were determined to be a polysaccharide by FT-IR and NMR.

Fasting blood sugar of diabetic mice decreased from 17.56 mmol/L to 7.42 mmol/L by orally administration of 0.5 mL GPP (1 mg/mL) for 30 days. GPP exhibited a dose-dependent inhibition effect on α-glucosidase activity. Moreover, GPP could inhibit the glucose absorption and affect the protein expression of GLUT2, but not the protein expression of SGLT1 . These results indicated GPP could be used as an effective ingredient to prevent and cure diabetes.

helichrysum (Helichrysum italicum)

Helichrysum and Grapefruit Extracts Inhibit Carbohydrate Digestion and absorption, Improving Postprandial glucose levels and Hyperinsulinemia in Rats

Several plant extracts rich in flavonoids have been reported to improve hyperglycemia by inhibiting digestive enzyme activities and SGLT1 -mediated glucose uptake. In this study, helichrysum (Helichrysum italicum) and grapefruit (Citrus × paradisi) extracts inhibited in vitro enzyme activities. The helichrysum extract showed higher inhibitory activity of α-glucosidase (IC₅₀ = 0.19 mg/mL) than α-amylase (IC₅₀ = 0.83 mg/mL), whereas the grapefruit extract presented similar α-amylase and α-glucosidase inhibitory activities (IC₅₀ = 0.42 mg/mL and IC₅₀ = 0.41 mg/mL, respectively).

Both extracts reduced maltose digestion in noneverted intestinal sacs (57% with helichrysum and 46% with grapefruit). Likewise, both extracts inhibited SGLT1 -mediated methylglucoside uptake in Caco-2 cells in the presence of Na⁺ (56% of inhibition with helichrysum and 54% with grapefruit). In vivo studies demonstrated that helichrysum decreased blood glucose level s after an oral maltose tolerance test (OMTT), and both extracts reduced postprandial glucose levels after the oral starch tolerance test (OSTT). Finally, both extracts improved hyper-insulin emia (31% with helichrysum and 50% with grapefruit) and HOMA index (47% with helichrysum and 54% with grapefruit) in a dietary model of insulin resistance in rats. In summary, helichrysum and grapefruit extracts improve postprandial glycemic control in rats, possibly by inhibiting α-glucosidase and α-amylase enzyme activities and decreasing SGLT1-mediated glucose uptake.

Herba fumariae

Antioxidant and alpha amylase inhibitory activities of Fumaria officinalis and its antidiabetic potential against alloxan induced diabetes

Fumaria officinalis belongs to family papaveraceae and is traditionally used to treat hypertension, hepatitis and diabetes. The current study was conducted to evaluate in vitro and in vivo antidiabetic activity of Fumaria officinalis. Aerial parts of the plant were sequentially extracted with n-hexane, chloro form, methanol and water. Phytochemical analysis was carried out on all extracts. Antioxidant activity was determined by 2,2-diphenyl-1-picryl hydrazyl (DPPH) inhibition method. In vitro alpha-amylase inhibitory activity was performed on all extracts by using dinitrosalicylic acid . Effect of aqueous and methanolic extracts of F. officinalis on blood glucose was evaluated in normo-glycaemic rats and alloxan induced diabetic rats. Glimepiride 0.2 mg/kg was used as standard therapy in diabetic rats.

Results showed that methanolic extract exhibited the maximum percentage inhibition of DPPH (86.30%) and alpha-amylase inhibition (94.01%) at 500 µg/ml and 16 mg/ml concentration respectively. Administration in normo-glycaemic rats did not show any significant decrease in blood glucose level at 500 and 750 mg/kg dosage. Aqueous and methanolic extracts exhibited a significant hypoglycaemic effect (p˂0.05) at all doses. A significant increase in the body weight and an improvement in liver and kidney function tests of diabetic rats were observed. These extracts also reduced the damage to the cells of glomeruli, interstitial inflammation, necrosis of tubular cells and thrombosis in the kidney, the enlargement of sinusoids and steatosis in the liver of diabetic rats.

This study concludes that F. officinalis may have antidiabetic potential possibly due to its antioxidant and alpha-amylase inhibitory activities.

Hordeurn vulgare L. extract

Assessment of the Phenolic Profiles, Hypoglycemic activity, and Molecular Mechanism of Different Highland Barley (Hordeum vulgare L.) Varieties

The phenolic profiles, hypoglycemic activity , and molecular mechanism of the effect on type 2 diabetes mellitus (T2DM) of four highland barley varieties were investigated in the present study. The fundamental phenolics in highland barley were ferulic acid , naringin, and catechin, which mainly existed in bound form. These varieties showed favorable hypoglycemic activity via inhibition of α-glucosidase and α-amylase activities, enhancement of glucose consumption, glycogen accumulation and glycogen synthase 2 (GYS2) activity , and down-regulation of glucose -6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities. Specifically, ZQ320 variety exhibited the strongest hypoglycemic activity compared to the other varieties. Highland barley phenolics could inhibit gluconeogenesis and motivate glycogen synthesis via down-regulating the gene expression of G6Pase, PEPCK, and glycogen synthase kinase 3β (GSK3β), while activating the expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3 kinase (PI3K), serine/threonine kinase (Akt), GYS2, and glucose transporter type 4 (GLUT4 ).

Therefore, phenolics from highland barley could be served as suitable candidates for therapeutic agent in T2DM to improve human health.

honeybush (Cyclopia genistoides)

In vitro α-glucosidase inhibition by honeybush (Cyclopia genistoides) food ingredient extract—potential for dose reduction of acarbose through synergism

Extracts of Cyclopia species are used as food ingredients. In vitro α-glucosidase (AG) inhibition by ultrafiltered C. genistoides extract, fraction s enriched in xanthones (XEF) and benzophenones (BEF), as well as mangiferin, isomangiferin, 3-β-D-glucopyranosyliriflophenone (I3G) and 3-β-D-glucopyranosyl-4-O-β-D-glucopyranosyliriflophenone (IDG) was determined with acarbose as positive control. XEF was more potent than the extract and BEF (IC₅₀ = 43.3, 95.5 and 205.7 μg mL⁻¹, respectively). Compounds demonstrated potency in the descending order: acarbose (IC₅₀ = 44.3 μM) > mangiferin (102.2 μM) > isomangiferin (119.8 μM) > I3G (237.5 μM) > IDG (299.4 μM). The combination index (CI) was used to determine synergism (CI < 0.7) as demonstrated for combinations of acarbose with XEF, BEF or the respective compounds at 50% and 75% effect levels.

The greatest potential acarbose dose reductions (>six-fold) across all effect levels were calculated for combinations of acarbose with mangiferin or isomangiferin, explaining the greater acarbose dose reduction potential of XEF vs. BEF. The effect of batch-to-batch variation (n = 10) of raw plant material on AG inhibition was quantified at a fixed concentration (160 μg mL⁻¹). XEFs (xanthone content = 223–481 g kg⁻¹) achieved AG inhibition of 63–72%, whereas BEFs (benzophenone content = 114–251 g kg⁻¹) achieved AG inhibition of 26–34%, with weak linear correlation (R² < 0.43) between target compound content of the fractions and their achieved AG inhibition.

Thus, extract fraction s of C. genistoides, enriched in xanthones and benzophenones, show potential in reducing the effective dose of acarbose required to prevent postprandial hyperglycaemia.

isoquercitrin

Hypoglycemic effect and mechanism of isoquercitrin as an inhibitor of dipeptidyl peptidase-4 in type 2 diabetic mice

Glucagon-like peptide (GLP)-1 is a potent glucose -dependent insulin otropic gut hormone released from intestinal L cells. The aim of this study was to investigate isoquercitrin as an inhibitor of dipeptidyl peptidase IV (DPP-IV) and determine whether it affects GLP-1 release in normal mice and NCI-H716 cells. In vitro, we used chromogenic substrate method detection methods to measure DPP-IV. We found that isoquercitrin was a competitive inhibitor , with IC₅₀ and K_i values of 96.8 and 236 μM, respectively.

Isoquercitrin and sitagliptin also stimulated GLP-1 release in NCI-H716 cells. In vivo, a type 2 diabetic mouse model was established, and oral treatment with different concentration of isoquercitrin and sitagliptin for 8 weeks significantly decreased the fasting blood glucose level . The weight and the levels of serum GLP-1 and insulin of the mice in the isoquercitrin group were higher than those in the model group (P < 0.001). An oral glucose tolerance test showed that the isoquercitrin significantly inhibited postprandial blood glucose changes in a dose-dependent manner.

These findings demonstrated the hypoglycemic effects of isoquercitrin and indicated that isoquercitrin improved insulin sensitivity by targeting DPP-IV.

Isoquercitrin protects HUVECs against high glucose‑induced apoptosis through regulating p53 proteasomal degradation

High glucose (HG)‑induced endothelial apoptosis serves an important role in the vascular dysfunction associated with diabetes mellitus (DM). It has been reported that isoquercitrin (IQC), a flavonoid glucoside, possesses an anti‑DM effect, but the mechanism requires further investigation. The present study investigated the effect of IQC against HG‑induced apoptosis in human umbilical vein endothelial cells (HUVECs) and explored its molecular mechanism. HUVECs were treated with 5 or 30 mM glucose for 48 h. Endothelial cell viability was monitored using the Cell Counting Kit‑8 assay. mitochondrial membrane potential was detected by JC‑1 staining.

Apoptosis was observed by TUNEL staining and flow cytometry. Western blotting was used for the analysis of apoptosis‑associated proteins Bax, Bcl‑2, cleaved (C)‑caspase3, total‑caspase3, p53 and phosphorylated p53. Reverse transcription‑quantitative PCR was used to analyze the mRNA expression levels of Bax, Bcl‑2 and p53. Immunofluorescence staining was utilized to detect the expression levels and distribution of p53 and ubiquitin specific peptidase 10 (USP10) in HUVECs.

The results revealed that IQC significantly attenuate d HG‑induced endothelial apoptosis, as shown by decreased apoptotic cells observed by TUNEL, JC‑1 staining and flow cytometry. Moreover, under HG stress , IQC treatment markedly inhibited the increased expression levels of the pro‑apoptotic proteins p53, Bax and C‑caspase3, and increased the expression levels of the anti‑apoptotic protein Bcl‑2 in HUVECs. However, the anti‑apoptotic effect of IQC against HG was partially blunted by increasing p53 protein levels in vitro. IQC influenced the mRNA expression levels of Bax and Bcl‑2 in response to HG, but it did not affect the transcription of p53. Notably, IQC inhibited the HG‑induced phosphorylation of p53 at Ser15 and the nuclear transport of USP10, destabilizing p53 and increasing the proteasomal degradation of the p53 protein.

The current findings revealed that IQC exerted a protective effect against the HG‑induced apoptosis of endothelial cells by regulating the proteasomal degradation of the p53 protein, suggesting that IQC may be used as a novel therapeutic compound to ameliorate DM‑induced vascular complications .

Quercetin and Isoquercitrin Inhibiting Hepatic Gluconeogenesis Through LKB1-AMPK α Pathway

Objective: To observe the impact of quercetin and isoquercitrin on gluconeogenesis in hepatocytes.

Methods: Mouse primary hepatocytes were cultured with lactic acid and pyruvic acid . After treatment with quercetin and isoquercitrin for 24 hours, the glucose concentration in the culture supernatant was determined. RT-PCR was used to detect the mRNAs of PEPCK, G6Pase, LKB1, and AMPK α. Protein levels of LKB1, AMPK α, and Thr172 phosphorylation were evaluated by Western blot.

Results: The glucose concentration in the gluconeogenesis group (GN) was significantly higher than in the control group (C), but the glucose concentrations in the high level quercetin(group 80Q) and high level isoquercitrin (group 80I) were significantly lower than in the group GN, P<0.01. In the group 80Q, and group 80I, the mRNA levels of PEPCK and LKB1were significantly lower than in the group GN (P<0.01), and the G6Pase mRNA were significantly lower than in the group GN (P<0.05). The protein levels of LKB1 and the phosphorylation of AMPK α Thr172 in the group 80Q, group 40I, and group 80I were higher than in the group GN. The effects of quercetin and isoquercitrin on LKB1 and AMPK α were similar to those of metformin.

Kaempferol

The Chemopreventive Effect of the Dietary Compound Kaempferol on the MCF-7 Human Breast Cancer Cell Line Is Dependent on inhibition of glucose Cellular uptake

Our aim was to investigate the effect of several dietary polyphenols on glucose uptake by breast cancer cells. Uptake of ³H-deoxy-D-glucose (³H-DG) by MCF-7 cells was time-dependent, saturable, and inhibited by cytochalasin B plus phloridzin. In the short-term (26 min), myricetin, chrysin, genistein, resveratrol, kaempferol, and xanthohumol (10–100 µM) inhibited ³H-DG uptake. Kaempferol was found to be the most potent inhibitor of ³H-DG uptake [IC₅₀ of 4 µM (1.6–9.8)], behaving as a mixed-type inhibitor.

In the long-term (24 h), kaempferol (30 µM) was also able to inhibit ³H-DG uptake , associated with a 40% decrease in GLUT1 mRNA levels. Interestingly enough, kaempferol (100 µM) revealed antiproliferative (sulforhodamine B and ³H-thymidine incorporation assays) and cytotoxic (extracellular lactate dehydrogenase activity determination) properties, which were mimicked by low extracellular (1 mM) glucose conditions and reversed by high extracellular (20 mM) glucose conditions. Finally, exposure of cells to kaempferol (30 µM) induced an increase in extracellular lactate levels over time (to 731 ± 32% of control after a 24 h exposure), due to inhibition of MCT1-mediated lactate cellular uptake.

In conclusion, kaempferol potently inhibits glucose uptake by MCF-7 cells, apparently by decreasing GLUT1-mediated glucose uptake. The antiproliferative and cytotoxic effect of kaempferol in these cells appears to be dependent on this effect.

The flavonoid Kaempferol Ameliorates Streptozotocin-Induced diabetes by Suppressing Hepatic glucose Production

In diabetes mellitus, the excessive rate of glucose production from the liver is considered a primary contributor for the development of hyperglycemia , in particular, fasting hyperglycemia . In this study, we investigated whether kaempferol, a flavonol present in several medicinal herbs and foods, can be used to ameliorate diabetes in an animal model of insulin deficiency and further explored the mechanism underlying the anti-diabetic effect of this flavonol. We demonstrate that oral administration of kaempferol (50 mg/kg/day) to streptozotocin-induced diabetic mice significantly improve d hyperglycemia and reduced the incidence of overt diabetes from 100% to 77.8%.

This outcome was accompanied by a reduction in hepatic glucose production and an increase in glucose oxidation in the muscle of the diabetic mice, whereas body weight, calorie intake, body composition, and plasma insulin and glucagon levels were not altered. Consistently, treatment with kaempferol restored hexokinase activity in the liver and skeletal muscle of diabetic mice while suppressed hepatic pyruvate carboxylase activity and gluconeogenesis.

These results suggest that kaempferol may exert antidiabetic action via promoting glucose metabolism in skeletal muscle and inhibiting gluconeogenesis in the liver.

Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice

Obesity-associated insulin resistance (IR) is a major risk factor for developing type 2 diabetes and an array of other metabolic disorders. In particular, hepatic IR contributes to the increase in hepatic glucose production and consequently the development of fasting hyperglycemia. In this study, we explored whether kaempferol, a flavonoid isolated from Gink go biloba, is able to regulate hepatic gluconeogenesis and blood glucose homeostasis in high-fat diet-fed obese mice and further explored the underlying mechanism by which it elicits such effects.

Oral administration of kaempferol (50 mg/kg/day), which is the human equivalent dose of 240 mg/day for an average 60 kg human, significantly improved blood glucose control in obese mice, which was associated with reduced hepatic glucose production and improved whole-body insulin sensitivity without altering body weight gain, food consumption or adiposity. In addition, kaempferol treatment increased Akt and hexokinase activity, but decreased pyruvate carboxylase (PC) and glucose-6 phosphatase activity in the liver without altering their protein expression.

Consistently, kaempferol decreased PC activity and suppressed gluconeogenesis in HepG2 cells as well as primary hepatocytes isolated from the livers of obese mice. Furthermore, we found that kaempferol is a direct inhibitor of PC. These findings suggest that kaempferol may be a naturally occurring antidiabetic compound that acts by suppressing glucose production and improving insulin sensitivity. Kaempferol suppression of hepatic gluconeogenesis is due to its direct inhibitory action on the enzymatic activity of PC.

kurarinone

Na+-glucose cotransporter (SGLT) inhibitory flavonoid s from the roots of Sophora flavescens

The methanol extract of Sophora flavescens, which is used in traditional Chinese medicine (sophorae radix), showed potent Na⁺–glucose cotransporter (SGLT) inhibitory activity . Our search for active components identified many well-known flavonoid antioxidants: kurarinone, sophoraflavanone G, kushenol K, and kushenol N.

natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes

Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes , many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney . SGLT2 inhibition reduce s glucose reabsorption by the kidney and ameliorates plasma glucose concentration. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2.

Some phlorizin -derived synthetic compounds, including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clinical trials investigation. In addition, other natural product-derived compounds have been investigated for their ability to improve blood glucose control.

The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compounds obtained from them, and discusses their application for the treatment of diabetes.

Lagerstroemia speciosa

Active Compounds from Lagerstroemia speciosa, insulin–like glucose uptake -Stimulatory/inhibitory and Adipocyte Differentiation-inhibitory Activities in 3T3-L1 Cells

Seven ellagitannins, lagerstroemin (1), flosin B (2), stachyurin (3), casuarinin (4), casuariin (5), epipunicacortein A (6), and 2, 3-(S)-hexahydroxydiphenoyl-α/β-d–glucose (7), together with one ellagic acid sulfate, 3-O-methyl-ellagic acid 4′-sulfate (8), ellagic acid (9), and four methyl ellagic acid derivatives, 3-O-methylellagic acid (10), 3,3′-di-O-methylellagic acid (11), 3,4,3′-tri-O-methylellagic acid (12), and 3,4,8,9,10-pentahydroxydibenzo[b,d]pyran-6-one (13), were identified by the bioassay-directed isolation from the leaves of Lagerstroemia speciosa (L.) Pers. The chemical structures of these components were established on the basis of one- and two-dimensional NMR and high-resolution mass spectroscopic analyses.

Other known compounds, including corosolic acid , gallic acid , 4-hydroxybenzoic acid , 3-O-methylprotocatechuic acid , caffeic acid , p-coumaric acid , kaempferol, quercetin, and isoquercitrin, were also isolated from the same plant. The obtained ellagitannins exhibited strong activities in both stimulating insulin -like glucose uptake (1−5 and 7) and inhibiting adipocyte differentiation (1 and 4) in 3T3-L1 cells. Meanwhile, ellagic acid derivatives (10−13) showed an inhibitory effect on glucose transport assay. This study is the first to report an inhibitory effect for methyl ellagic acid derivatives.

Effect and mode of action of banaba (Lagerstroemia speciosa L.) leaf extracts on postprandial blood glucose in rats [2001]

Banaba (Lagerstroemia speciosa L.) has been recognized as a folk medicine for diabetes in the Philippines. A hot water extract (HWE) of banaba leaves dose-dependently suppressed the elevation of blood glucose after oral administration of starch, but had no such effect after ingestion of glucose . The HWE was fraction ated using HP-20 column chromatography, and its methanol fraction (HPME) was found to suppress the elevation of blood glucose after oral administration of starch.

The inhibitory action of the HWE on activities of alpha-amylase and alpha-glucosidases was then examined in vitro. The HWE inhibited the activities of alpha-amylase, maltase, glucoamylase, sucrase and isomaltase, with estimated IC50 values of 0.53, 0.89, 1.24, 2.85 and 4.95mg/mL, respectively. The HPME also inhibited alpha-amylase and glucoamylase with IC50 values of 0.44 and 0.83 mg/mL, respectively.

These results suggest that the inhibitory effect of banaba on postprandial hyperglycemia is due to inhibition of alpha-amylase and alpha-glucosidases. Banaba may be a useful natural material for the prevention and therapy of diabetes.

Antidiabetes and Anti-obesity activity of Lagerstroemia speciosa

The leaves of Lagerstroemia speciosa (Lythraceae), a Southeast Asian tree more commonly known as banaba, have been traditional ly consumed in various forms by Philippinos for treatment of diabetes and kidney related diseases . In the 1990s, the popularity of this herbal medicine began to attract the attention of scientists worldwide. Since then, researchers have conducted numerous in vitro and in vivo studies that consistently confirmed the antidiabetic activity of banaba. Scientists have identified different components of banaba to be responsible for its activity . Using tumor cells as a cell model, corosolic acid was isolated from the methanol extract of banaba and shown to be an active compound. More recently, a different cell model and the focus on the water soluble fraction of the extract led to the discovery of other compounds. The ellagitannin Lagerstroemin was identified as an effective component of the banaba extract responsible for the activity.

In a different approach, using 3T3-L1 adipocytes as a cell model and a glucose uptake assay as the functional screening method, Chen et al. showed that the banaba water extract exhibited an insulin-like glucose transport inducing activity. Coupling HPLC fraction ation with a glucose uptake assay, gallotannins were identified in the banaba extract as components responsible for the activity , not corosolic acid . Penta-O-galloyl-glucopyranose (PGG) was identified as the most potent gallotannin. A comparison of published data with results obtained for PGG indicates that PGG has a significantly higher glucose transport stimulatory activity than Lagerstroemin. Chen et al. have also shown that PGG exhibits anti-adipogenic properties in addition to stimulating the glucose uptake in adipocytes.

The combination of glucose uptake and anti-adipogenesis activity is not found in the current insulin mimetic drugs and may indicate a great therapeutic potential of PGG.

Laminaria japonica extract

α-glucosidase inhibition and the in vivo hypoglycemic effect of butyl-isobutyl-phthalate derived from the Laminaria japonica rhizoid

he rhizoid of Laminaria japonica is widely used in Chinese medicine as a treatment for diabetes. Therefore, a bioactivity-tailored isolation and detailed chemical characterization was used to identify the antidiabetes compounds found in the L. japonica rhizoid. Liquid chromatography/mass spectrometry (LC/MS), proton NMR and carbon NMR spectra analyses demonstrated that the active compound was butyl-isobutyl-phthalate (BIP). BIP demonstrated a significant concentration-dependent, non-competitive inhibitory activity against α-glucosidase in vitro, with an IC₅₀ of 38 μm.

In vivo, the ethyl acetate fraction (EAF) and purified BIP displayed a significant hypo-glycemic effect in streptozocin-induced diabetic mice. The present study indicates BIP could be considered as an α-glucosidase inhibitor and developed as an important anti-diabetes agent for type II diabetes therapy.

Anti-diabetic Effects and Anti-Inflammatory Effects of Laminaria japonica and Hizikia fusiforme in Skeletal Muscle: In Vitro and In Vivo Model

Laminaria japonica (LJ) and Hizikia fusiforme (HF) are brown seaweeds known to have various health-promoting effects. In this study, we investigated the anti-diabetic effects and possible mechanism(s) of LJ and HF by using both in vitro and in vivo models. C2C12 myotubes, mouse-derived skeletal muscle cells, treated with LF or HF extracts were used for the in vitro model, and muscle tissues from C57BL/6N mice fed a high-fat diet supplemented with 5% LF or HF for 16 weeks were used for the in vivo model. Although both the LF and HF extracts significantly inhibited α-glucosidase activity in a dose-dependent manner, the HF extract had a superior α-glucosidase inhibition than the LF extract. In addition, glucose uptake was significantly increased by LJ– and HF-treated groups when compared to the control group.

Phosphorylation of protein kinase B and AMP-activated protein kinase was induced by LJ and HF in both the vivo and in vitro skeletal muscle models. Furthermore, LJ and HF significantly decreased tumor necrosis factor-α whereas both extracts increased interleukin (IL)-6 and IL-10 production in lipopolysaccharide-stimulated C2C12 myotubes. Taken together, these findings imply that the brown seaweeds LJ and HF could be useful therapeutic agents to attenuate muscle insulin resistance due to diet-induced obesity and its associated inflammation .

Lavandula stoechas

Ameliorative potential of Lavandula stoechas in metabolic syndrome via multitarget interaction s

Ethnopharmacological importance: Decoction and infusion prepared from aerial parts of Lavandula stoechas L. (L. stoechas) have been traditionallyused as remedy against several components of metabolic syndrome (MetS) and associated disorders including type II diabetes and cardiovascular diseases by Anatolian people.

Aim of the study: The aim is to elucidate the potential ameliorative effects of L. stoechas aqueous extracts on insulin resistance and inflammation models through multitarget in vitro approaches and also to elucidate mechanism of action by analyzing transcriptional and metabolic responses.

Materials and methods: An aqueous extract was prepared and fraction ated to give rise to ethyl acetate (EE) and butanol (BE) extracts. The anti-insulin resistance effects of BE and EE were evaluated on palmitate induced insulin resistance model of H4IIE, C2C12 and 3T3L1 cells by using several metabolic parameters. Specifically, whole genome transcriptome analysis was performed by using microarray over 55.000 genes in control, insulin resistant and EE (25 µg/mL) treated insulin resistant H4IIE cells. Anti-inflammatory effects of both extracts were analyzed in LPS-stimulated RAW264.7 macrophages.

Results: Both EE and BE at low doses (25–50 µg/mL) significantly decreased hepatic gluconeogenesis in H4IIE cell line by suppressing the expression of PEPCK and G6Pase. In C2C12 myotubes, both extracts increased the insulin stimulated glucose uptake more effective ly than metformin. Both extracts decreased the isoproterenol induced lipolysis in 3T3L1 cell line. Moreover, they also effective ly increased the expression of lipoprotein lipase protein level in insulin resistant myotubes at low doses. EE increased the protein level of PPARγ and stimulated the activation AKT in insulin resistant H4IIE and C2C12 cell lines. The results obtained from biochemical assays, mRNA/protein studies and whole genome transcriptome analyses were found to be complementary and provided support for the hypothesis that EE might be biologically active against insulin resistance and act through the inhibition of liver gluconeogenesis and AKT activation. Besides, LPS induced inflammation in RAW264.7 macrophages was mainly inhibited by EE through suppression of iNOS/NO signaling, IL1β and COX-2 genes. HPLC-TOF/MS analysis of EE of L. stoechas mainly resulted in caffeic acid, apigenin, luteolin, rosmarinic acid and its methyl ester, 4-hydroxybenzoic acid, vanillic acid, ferrulic acid and salicylic acid.

Conclusion: Data suggest that EE of L. stoechas contains phytochemicals that can be effective in the treatment /prevention of insulin resistance and inflammation. These results validate the traditional use of L. stoechas in Anatolia against several metabolic disorders including metabolic syndrome.

Lavender (Lavandula stoechas L.) essential oils attenuate hyperglycemia and protect against oxidative stress in alloxan-induced diabetic rats

Background: The present study described the phytochemical profile of Lavandula stoechas essential oils, collected in the area of Ain-Draham (North-West of Tunisia), as well as their protective effects against alloxan-induced diabetes and oxidative stress in rat.

Methods: Essential oils samples were obtained from the aerial parts of the plant by hydrodistillation and analyzed by GC–MS. Rats were divided into four groups: Healthy Control (HC); diabetic Control (DC); Healthy + Essential Oils (H + EO) and diabetic + Essential Oils (D + EO).

antidiabetic and antioxidant activities were evaluated after subacute intraperitoneally injection of Lavandula stoechas essential oils (50 mg/kg b.w., i.p.) to rats during 15 days.

Results: The principal compounds detected are: D-Fenchone (29.28%), α-pinene (23.18%), Camphor (15.97%), Camphene (7.83%), Eucapur (3.29%), Limonene, (2.71%) Linalool, (2.01%) Endobornyl Acetate (1.03%). The essential oils also contained smaller percentages of Tricyclene, Cymene, Delta-Cadinene, Selina-3,7(11)-diene. Furthermore, we found that Lavandula stoechas essential oils significantly protected against the increase of blood glucose as well as the decrease of antioxidant enzyme activities induced by aloxan treatment. Subacute essential oils treatment induced a decrease of lipoperoxidation as well as an increase of antioxidant enzyme activities.

Conclusions: These findings suggested that lavandula stoechas essential oils protected against diabetes and oxidative stress induced by alloxan treatment. These effects are in partly due to its potent antioxidant properties.

Medicinal properties of Mediterranean plants against glucose and lipid disorders

There are several components isolated from plants grown in Mediterranean environment exhibiting significant beneficial properties against a variety of disorders related to lipid or glucose metabolism. In this context, plant species (e.g. Salvia officinalis, Rosmarinus officinalis, Lavandula stoechas, Melissa officinalis, Mentha piperita, Thymus vulgaris,Origanum majorana, Sideritis raeseri, Ocimum basilicum, Pistacia lentiscus, Crocus sativus, Daucus carota) may act against lipid or carbohydrate metabolic disorders through their antioxidant, anti-inflammatory or other properties, or due to the beneficial action s of their compounds.

New horizons are very promising, since these plant species have been used both in traditional medicine and in current clinical practice.

Levisticum officinale

antidiabetic Properties of Hydroalcoholic Leaf and Stem Extract of Levisticum officinale: An implication for α-amylase inhibitory activity of Extract Ingredients through Molecular Docking

Levisticum officinale (Apiaceae) is a favorite food spice. Iranian folk medicine claims that it has a prominent antidyslipidemic property but this is not documented scientifically so far. This study evaluated antidyslipidemic and the other antidiabetic aspects of the stem and leaf hydroalcoholic extract of it (LOE). Regarding oral glucose tolerance test results, LOE (500 mg/kg) administration 30 min before glucose loading significantly decreased the blood glucose level (13%) at 90 min in male rats.

Additionally, LOE treatment (500 mg/kg, orally, once a day) for 14 days significantly reduced the serum glucose level (24.97%) and markedly improve d the lipid profile and the insulin , creatinine, alanine aminotransferase and aspartate aminotransferase serum levels in diabetic rats. Moreover, LOE effective ly amended the impaired antioxidant status and ameliorated lipid peroxidation in the plasma and pancreas and liver tissues of diabetics. Also, 14 days LOE treatment, significantly decreased the renal sodium –glucose cotransporter 2 and facilitated glucose transporter 2 (GLUT₂) mRNA levels and GLUT₂ gene expression in the enterocytes of jejunum tissue in comparison with diabetic untreated rats.

HPLC method revealed the presence of chlorogenic acid, rosmarinic acid, caffeic acid, quercetin and luteolin and GC-MS analysis detected bioactive compounds like phthalides, thymol, phytol, hexanoic acid , carene and menthofuran. LOE showed α-amylase (αΑ) inhibitory activity and in silico studies predicted that among extract ingredients luteolin, quercetin, rosmarinic, caffeic, and hexanoic acids shave the greatest αΑ inhibition potecy. Thus, current results justify antidyslipidemic value of L. officinale and shed light on more antidiabetic health benefits of it.

Litchi chinensis Sonn.seed extract

Effects of phenolic-rich litchi (Litchi chinensis Sonn.) pulp extracts on glucose consumption in human HepG2 cells

Phenolic composition of litchi (Litchi chinensis Sonn.) pulp from three cultivars was tentatively characterized and quantified by HPLC–MS. Pulp from hemaoli, a wild litchi cultivar, showed the highest content of total phenolics, flavonoids and procyanidins, the latter accounting for the majority of phenolic compounds identified. In hemaoli, (−)-epicatechin was the predominant compound, whereas flavone glycosides accounted for the majority of the phenolic compounds identified in Feizixiao and Lanzhu cultivars, with quercetin rhammosyl-rutinoside being predominant.

Hemaoli pulp caused the highest enhancement of glucose consumption rate in HepG2 cells, followed by Feizixiao pulp. This bioactivity was significantly correlated with antioxidant capacity, and total content of phenolics, flavonoids, and procyanidins of different cultivars. (−)-Epicatechin, but not quercetin rhammosyl-rutinoside, also resulted in a significant rise in glucose consumption activity.

These results showed that litchi cultivars with high (−)-epicatechin content or high procyanidin content may have great potential as hypoglycaemic foods.

Isolation and structural characterization of a non-competitive α-glucosidase inhibitory polysaccharide from the seeds of Litchi chinensis Sonn

In this study, a novel homogeneous polysaccharide (LSP-W-4, MW = 6.70 kDa) was isolated and purified from the seeds of Litchi chinensis Sonn. Monosaccharide composition analysis indicated that LSP-W-4 is a heteropolysaccharide consisting of arabinose, mannose, glucose and galactose in a molar ratio of 6.33:3.88:10.35:1.00. A detailed structural analysis revealed that LSP-W-4 has a backbone consisting of 1,4-α-Glcp and 1,4-β-Manp, as well as four branched chains including of T-α-Galp, T-α-Araf, α-Araf-(1 → 5)-α-Araf-(1 → and α-Araf-(1 → 5)-α-Araf-(1 → 5)-α-Araf-(1 → attached to O6 of 1,4-β-Manp and 1,4-α-Glcp. LSP-W-4 exhibited significant inhibitory activity both against yeast (Saccharomyces cerevisiae) and mammalian (rat-intestinal acetone powder) α-glucosidase , with IC50 values of 75.24 μM and 66.97 μM, respectively, with both such inhibitory activities being more powerful than those of acarbose.

A kinetic analysis revealed that LSP-W-4 inhibited the activities of both yeast and mammalian α-glucosidase in a typical non-competitive manner, with KM values of 0.43 mmol/L and 0.53 mmol/L, respectively.

Lonicera japonica Thunb. extract

Hypoglycemic and hypolipidemic effects of a polysaccharide from flower buds of Lonicera japonica in streptozotocin-induced diabetic rats

hyperglycemia and dyslipidemia are classic features for diabetes mellitus (DM). In this study, one fraction of the crude polysaccharides extracted from Lonicera japonica flower buds (LJP) were investigated for its hypolipidaemic and hypoglycaemic activities by means of streptozotocin (STZ)-induced diabetic rats. Interestingly, after orally administrated with 800 mg/kg body weight (B.W.) LJP for 42 days, the food and water intake and the levels of sugar and insulin in blood for the diabetic rats were drastically decreased, while the contents of liver and skeletal muscle glycogen and the concentrations of hepatic pyruvate kinase and hexokinase were obviously increased (p < 0.01 or p < 0.05). The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterin (LDL-C) and very-low-density lipoprotein-cholesterin (VLDL-C) were significantly descended, while high-density lipoprotein-cholesterin (HDL-C) was significantly ascended (p < 0.01 or p < 0.05). In addition, the oxidant stress in liver was restored as well.

The results suggested that LJP could be considered as an ingredient of functional foods for diabetes, and this is the first report about the hypo-glycemic and hypolipidemic effects of the polysaccharides extracted from Lonicera japonica.

Lycium chinense Mill. extract

Study on Anti-obesity and Hypoglycemic Effects of Lycium chinense Mill Extracts

This study was designed to evaluate the anti-obesity and hypoglycemic effects of Gugija (Lycium chinense Mill) extracts in 3T3-L1 adipocytes. We investigated the $α$ -amylase and $α$ -glucosidase inhibitory activities of extracts from Gugija. Gugija was extracted by 70% EtOH and 80% MeOH and aqueous, respectively. A single oral dose of Gugija extract inhibited the increase of blood glucose levels significantly at 0, 30, 60, 90 and 120 min and decreased incremental response areas under the glycemic response curve. These results suggest that Gugija 70% EtOH extracts may delay carbohydrate digestion and reduce postprandial hyperglycemia.

In addition, triglyceride content in 3T3-L1 adipocytes decreased at higher concentrations of Gugija 70% EtOH extract. Free fatty acid content in 3T3-L1 adipocytes was increased at higher concentrations of Gugija 70% EtOH extract. Also, glucose transporter 4 (GLUT4 ), the key insulin signaling pathway transcription factor, was remarkably increased by the Gugija 70% EtOH extract when compared to those of control cells in protein expression levels. Therefore, Gugija can be developed as an effective anti-obesity and hypo-glycemic agent.

maqui berries (Aristotelia chilensis)

Delphinol® standardized maqui berry extract reduce s postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition

Aim. The impetus of our study was to investigate the effects of a nutritional supplement Delphinol®, an extract of maqui berries (Aristotelia chilensis) standardised to ≥25% delphi-nidins and ≥35% total anthocyanins, on postprandial blood glucose and insulin levels and identify the physiologic mecha-nism involved.Methods. Postprandial blood glucose and insulin were investi-gated in double-blind, placebo-controlled, cross-over fashion in ten volunteers with moderate glucose intolerance. Longer term effects on blood sugar levels were investigated in strep-tozotocin-diabetic rats over a four months period. Effects of maqui berry delphinidins on sodium –glucose symport were examined in rodent jejenum of the small intestine.Results. Delphinol® intake prior to rice consumption statisti-cal signi”cantly lowered post prandial blood glucose and in-sulin as compared to placebo.

We identified an inhibition of Na+-dependant glucose transport by delphinidin, the princi-pal polyphenol to which Delphinol® is standardised. In a dia-betic rat model the daily oral application of Delphinol® over a period of four months signi”cantly lowered fasting blood glu-cose levels and reached values indistinguishable from healthy non-diabetic rats.Conclusion.

Our results suggest a potential use of Delphinol®for natural ly controlling post-prandial blood glucose owed to inhibition of sodium glucose co-transporter in small intestine.

Momordica charantia L. extract

Hypoglycaemic effect of Momordica charantia extracts in normoglycaemic or cyproheptadine-induced hyperglycaemic mice

The hypoglycaemie effect of orally administered extracts of Momordica charantia L. fruits was examined in normoglycaemic or cyproheptadine-induced hyperglycaemic mice. The aqueous extract reduced the fasting glucose levels of hyperglycaemic or normoglycaemic mice. However, the ethanol extract did not affect the fasting or nonfasting glucose levels significantly in both groups of mice. There was no significant difference between the glucose-loaded and glucose-loaded plus aqueous extract given group. On the other hand, oral glucose-loading of the cyproheptadine-induced hyperglycaemic animals reduced the fasting glucose levels significantly.

These results showed that aqueous extract of M. charantia fruits has a hypoglyeaemic activity without improving the tolerance to glucose in cyproheptadine-induced diabetic mice.

Effect of Momordica charantia (Karolla) extracts on fasting and postprandial serum glucose level s in NIDDM patients.

Effect of Momordica charantia, a bitter vegetable popularly known as Karolla, on fasting and post prandial (2 hours after 75 gm oral glucose intake) serum glucose levels were studied in 100 cases of moderate non-insulin dependent diabetic subjects. Drinking of the aqueous homogenized suspension of the vegetable pulp led to significant reduction (p < 0.001) of both fasting and post-prandial serum glucose levels. This hypoglycaemic action was observed in 86 (86%) cases. Five cases (5%) showed lowering of fasting serum glucose only.

Anti-diabetic properties and phytochemistry of Momordica charantia L. (Cucurbitaceae)

Unripe fruit, seeds and aerial parts of Momordica charantia Linn. (Cucurbitaceae) have been used in various parts of the world to treat diabetes. Oral administration of the fruit juice or seed powder causes a reduction in fasting blood glucose and improves glucose tolerance in normal and diabetic animals and in humans. Animal and in vitro data support both insulin secretagogue and insulin omimetic activity of the fruit. However, enhanced insulin levels in vivo in response to its administration have not been observed. Although a wide range of compounds have been isolated from Momordica charantia, notably steroidal compounds and proteins, the orally active antidiabetic principle has not been adequately identified. A polypeptide, p-insulin, produces hypoglycaemic effects in humans and animals on subcutaneous injection, but oral activity is questionable.

Other reported hypoglycaemic principles from Momordica charantia include the sterol glucoside mixture charantin (fruit) and the pyrimidine nucleoside vicine (seeds). However these are only effective at doses too high to account for all the activity of the plant extract. Principal toxicity of Momordica charantia in animals is to the liver and reproductive system. These effects have not been reported in humans despite widespread use of the fruit medicinally and as a vegetable.

antihyperglycemic effects of three extracts from Momordica charantia

Momordica charantia (L.) (Cucurbitaceae) commonly known as bitter gourd or karela is a medicinal plant, used in Ayurveda for treating various diseases, one of which is diabetes mellitus. In this study, various extract powders of the fresh and dried whole fruits were prepared and their blood glucose lowering effect compared by administrating them orally to diabetic rats. The aqueous extract powder of fresh unripe whole fruits at a dose of 20 mg/kg body weight was found to reduce fasting blood glucose by 48%, an effect comparable to that of glibenclamide, a known synthetic drug.

This extract was tested for nephrotoxicity, hepatotoxicity and biochemical parameters such as SGOT, SGPT and lipid profile. The extract did not show any signs of nephrotoxicity and hepatotoxicity as judged by histological and biochemical parameters. Thus the aqueous extract powder of Momordica charantia, an edible vegetable, appears to be a safe alternative to reducing blood glucose.

Suppressive activity of the Fruit of Momordica charantia with Exercise on blood glucose in type 2 diabetic Mice

The antidiabetic activity of Momordica charantia L. (Cucurbitaceae) with exercise was investigated in KK-Ay mice, an animal model with type 2 diabetes with hyperinsulin emia. The water extract of the fruit of Momordica charantia L. (MC) with exercise reduced the blood glucose of KK-Ay mice 5 weeks after oral administration (p<0.001), and also significantly lowered the plasma insulin of KK-Ay mice under similar conditions (p<0.01). The blood glucose of MC with exercise is lower than that of MC only or exercise only 5 weeks after the administration. MC with exercise decreased blood glucose in a glucose tolerance test. These results suggest that MC with exercise is useful for type 2 diabetic cure.

Systematic review and meta-analysis protocol for efficacy and safe ty of Momordica charantia L. on animal models of type 2 diabetes mellitus

Background: Studies on several preclinical models of type 2 diabetes mellitus have been conducted to establish the hypoglycemic activity of Momordica charantia L. Concerned with appropriateness of these models, we designed a systematic review to establish the efficacy and safe ty of M. charantia L. in preclinical models of type 2 diabetes mellitus .

Methods: Review authors will search without language restriction in MEDLINE/PubMed, Web of Science, Embase, Scopus, and CINAHL databases through April 2019. Search filters will be applied to enhance search efficiency. The authors will search for gray literature in Google and Google Scholar, OpenGrey, and ProQuest Dissertations & Theses. Two authors will evaluate full texts, extract data, and asses risk of bias independently. The review will include randomized or non-randomized studies that assessed the efficacy or safe ty of M. charantia L. with vehicle control group. The primary endpoint will be fasting blood glucose level. We will use Egger’s test to assess publication biases. Chi-square test and I² will be used to assess heterogeneity in effect size of the primary outcome. Using RevMan software version 5.3, the authors will perform a meta-analysis of quantitative data.

Discussion: The strength of evidence will be rated as high, moderate, low, or very low using GRADE framework for animal studies. This systematic review will potentially improve research practice by identifying risks of bias and design features that compromise translatability and contribute to evidence-based clinical trial design.

Extracts of Momordica charantia Suppress Postprandial hyperglycemia in Rats

Momordica charantia (bitter melon) is commonly known as vegetable insulin, but the mechanisms underlying its hypo-glycemic effect remain unclear. To address this issue, the effects of bitter melon extracts on postprandial glycemic responses have been investigated in rats. An aqueous extract (AE), methanol fraction (MF) and methanol insoluble fraction (MIF) were prepared from bitter melon. An oral sucrose tolerance test revealed that administration of AE, MF or MIF each significantly suppressed plasma glucose level s at 30 min as compared with the control. In addition, the plasma insulin level at 30 min was also significantly lower after MF administration than in the control in the oral sucrose tolerance test.

By contrast, these effects of bitter melon extracts were not observed in the oral glucose tolerance test. In terms of mechanism, bitter melon extracts dose-dependently inhibited the sucrase activity of intestinal mucosa with IC₅₀ values of 8.3, 3.7 and 12.0 mg/mL for AE, MF and MIF, respectively. The fraction with a molecular weight of less than 1,300 (LT 1,300) obtained from MF inhibited the sucrase activity most strongly in an uncompetitive manner with an IC₅₀ value of 2.6 mg/mL.

Taken together, these results demonstrated that bitter melon suppressed postprandial hyperglycemia by inhibition of α-glucosidase activity and that the most beneficial component is present in the LT 1,300 fraction obtained from MF.

Morus alba L root and peel extract

Polyphenols-Rich natural products for treatment of diabetes

Currently, experimental and clinical evidences showed that polyphenols-rich natural products, like nutraceuticals and food supplements, may offer unique treatment modalities in type 2 diabetes mellitus (DM), due to their biological properties. natural products modulate the carbohydrate metabolism by various mechanisms, such as restoring beta-cells integrity and physiology, enhancing insulin releasing activity, and the glucose using. Sea buckthorn berries, red grapes, bilberries, chokeberries and popular drinks like cocoa, coffee and green tea are all rich in polyphenols and may decrease the insulin response, offering a natural alternative of treatment in diabetes.

Therefore, researches are now focused on potential efficacies of different types of polyphenols, including flavonoids, phenolic acids, lignans, anthocyans and stilbenes. Animal and human studies showed that polyphenols modulate carbohydrate and lipid metabolism, decrease glycemia and insulin resistance, increase lipid metabolism and optimize oxidative stress and inflammatory processes. It is important to understand the proper dose and duration of supplementation with polyphenols-rich extracts in order to guide effective therapeutic interventions in diabetic patients.

Mulberry Leaf extract

Effect of Buan Mulberry on metabolic improve ment in Streptozotocin-Induced diabetic Rats

This study was designed to evaluate the anti-diabetic effects of Buan mulberries by using an insulin -dependent diabetes mellitus animal model. Several studies have shown that mulberries have metabolism -improving, antioxidant, and lipid-lowering properties in rats with streptozotocin (STZ)-induced diabetes.

In this study, Sprague-Dawley male rats were randomly assigned to 1 normal control group and 5 STZ-induced diabetes groups: rats that had STZ-induced diabetes and did not receive any agents (diabetic group; negative control), rats that had STZ-induced diabetes and received insulin (insulin group; positive control), rats that had STZ-induced diabetes and received 0.5% mulberry extract (0.5% mulberry group), rats that had STZ-induced diabetes and received 1.0% mulberry extract (1.0% mulberry group), and rats that had STZ-induced diabetes and received 2.0% mulberry extract (2.0% mulberry group).

Mulberry extracts were administered to the diabetic animals for 4 weeks. The rats that received mulberry extracts showed lower body weights and insulin levels, as well as higher kidney weights, blood glucose levels, urine quantities, and water intake in comparison with the normal controls. Further, the insulin concentrations in the mulberry-fed animals were higher than those in the diabetic group, and the kidney weights, blood glucose levels , urine quantities, and water intake in the mulberry-fed animals were lower than the corresponding values in the diabetic controls.

These results suggest that mulberry may be an effective function al food to prevent diabetes–related complications.

myricetin

Unraveling the inhibition of intestinal glucose Transport by Dietary Phenolics: A Review

Background: Glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium– dependent glucose transporter (SGLT1 ) and the facilitated-transporter glucose transporter (GLUT2). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2.

Conclusion: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and aglycones exert significant inhibition, and also the inhibition of phenolic acids remains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters. A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interaction s is also included.

Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes

The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function.

In the present study, we show that three flavonoids , quercetin, myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10–100 μM. These three flavonoids show a competitive pattern of inhibition, with K_i=16, 33.5 and 90 μM respectively. In contrast, neither catechin nor gallic acid inhibit methyl glucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction.

On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells.

Naringenin

The citrus fruit flavonoid naringenin suppresses hepatic glucose production from Fao hepatoma cells

Hepatic gluconeogenesis is the major source of fasting hyperglycemia. Here, we investigated the role of the citrus fruit flavonoid naringenin, in the attenuation of hepatic glucose production from hepatoma (Fao) cells. We show that naringenin, but not its glucoside naringin, suppresses hepatic glucose production. Furthermore, unlike insulin-mediated suppression of hepatic glucose production, incubation of hepatocytes with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor Ly294002 had no effect on the ability of naringenin to suppress hepatic glucose production. Further, naringenin did not increase phosphorylation of Akt at Ser473 or, Thr308, indicating this down-stream target of PI3-kinase is also not a player in naringenin-mediated suppression of hepatic glucose production.

Importantly, like the dimethylbiguanide, metformin, naringenin significantly decreased cellular ATP levels without increasing cell cytotoxicity. Together, these results suggest that the aglycone, naringenin, has a role in the attenuation of hyperglycemia and may exert this effect in a manner similar to the drug, metformin.

Naringenin Inhibits glucose uptake in MCF-7 Breast cancer cells: A Mechanism for impaired Cellular Proliferation

Certain flavonoids inhibit glucose uptake in cultured cells. In this report, we show that the grapefruit flavanone naringenin inhibited insulin-stimulated glucose uptake in proliferating and growth-arrested MCF-7 breast cancer cells. Our findings indicate that naringenin inhibits the activity of phosphoinositide 3-kinase (PI3K), a key regulator of insulin-induced GLUT4 translocation, as shown by impaired phosphorylation of the downstream signaling molecule Akt. Naringenin also inhibited the phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK). inhibition of the MAPK pathway with PD98059, a MAPK kinase inhibitor, reduced insulin-stimulated glucose uptake by approximately 60%. The MAPK pathway therefore appears to contribute significantly to insulin-stimulated glucose uptake in breast cancer cells.

Importantly, decreasing the availability of glucose by lowering the glucose concentration of the culture medium inhibited proliferation, as did treatment with naringenin. Collectively, our findings suggest that naringenin inhibits the proliferation of MCF-7 cells via impaired glucose uptake. Because a physiologically attainable dose of 10 µM naringenin reduced insulin-stimulated glucose uptake by nearly 25% and also reduced cell proliferation, naringenin may possess therapeutic potential as an anti-proliferative agent.

inhibition of intestinal and renal Na+-glucose cotransporter by naringenin

Reduction in glucose uptake constitutes a possible means of controlling diabetic hyperglycemia . Using purified intestinal brush border membrane vesicles and everted intestinal sleeves, we have demonstrated that naringenin, a flavonoid present in citrus fruits and juices, significantly inhibited glucose uptake in the intestine. In addition, naringenin also elicited inhibitory action s towards glucose uptake in renal brush border membrane vesicles. Naringin, a glycoside of naringenin, was totally inactive in these aspects. Naringenin exhibited moderate inhibitory action on glucose uptake in rabbit intestinal brush border membrane vesicles, and showed strong inhibitory action in rat everted intestinal sleeves. The IC₅₀ values were 205.9 and 2.4 μmol/l, respectively. Lineweaver–Burk analysis demonstrated that naringenin inhibited glucose uptake in rat everted intestinal sleeves in a competitive manner with a K_i value of 1.1 μmol/l. Glucose uptake activities in both the intestinal and renal brush border membrane vesicles of diabetic rats were significantly higher than in normal rats.

Naringenin (500 μM) reduced glucose uptake by more than 60% in both the intestinal and renal brush border membrane vesicles of diabetic rats to a level similar to that of the normal rats. The IC₅₀ values of naringenin in the renal brush border membrane vesicles of normal and diabetic rats were 323.9 and 166.1 μmol/l, respectively. These results suggest that inhibition of intestinal glucose uptake and renal glucose reabsorption explains, in part at least, the in vivo antihyperglycemic action of naringenin and its derivatives. The possible application of these natural compounds in controlling hyperglycemia warrants further investigations.

Metformin-like antidiabetic , cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights

Metformin is a widely used drug for the treatment of type 2 diabetes (T2D). Its blood glucose-lowering effects are initially due to inhibition of hepatic glucose production and increased peripheral glucose utilization. Metformin has also been shown to have several beneficial effects on cardio vascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular complications in patients with diabetes.

Adenosine Monophosphate Activated-Protein Kinase (AMPK ) is a major cellular regulator of lipid and glucose metabolism. Recent evidence shows that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profiles, blood pressure and insulin-resistance making it a novel therapeutic target in the treatment of T2D. Naringenin a flavonoid found in high concentrations as its glycone naringin in citrus fruits, has been reported to have antioxidant, antiatherogenic, anti- dyslipidemic and anti-diabetic effects. It has been shown that naringenin exerts its anti-diabetic effects by inhibition of gluconeogenesis through upregulations of AMPK hence metformin-like effects. Naringin has further been shown to have non-glycemic affects like metformin that mitigate inflammation and cell proliferation. This review evaluates the potential of naringenin as anti-diabetic , anti-dyslipidemic anti-inflammatory and antineoplastic agent similar to metformin and proposes its further development for therapeutic use in clinical practice.

Naringenin inhibits α-glucosidase activity: A promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats

Obesity and the onset of diabetes are two closely linked medical complications prevalent globally. Postprandial hyperglycemia is one of the earliest abnormalities of glucose homeostasis associated with type 2 diabetes (T2D). Postprandial glucose levels can be regulated through α-glucosidase inhibition. The present study aims to demonstrate the potent inhibitory role of naringenin against α-glucosidase activit.

The mode of inhibition of naringenin was examined by measuring enzyme activity in vitro with different concentrations of substrate using Lineweaver–Burk plot analysis. It shows competitive inhibition towards mammalian α-glucosidase thereby competing with α-limit dextrins and oligosaccharide residues for binding in the active site. Similar results have been obtained from the molecular docking analyses, where naringenin shows preferential binding for the active sites in each of the evaluated human intestinal α-glucosidase enzymes. Post-docking intramolecular hydrogen bonding analysis shows water molecule mediated hydrogen bonding for N-terminal maltase glucoamylase and N-terminal sucrase isomaltase. Naringenin’s docked pose in the C-terminal maltase glucoamylase active site does not show any particular water mediated interaction similar to the co-crystallized acarbose. Further, our results suggest that naringenin (25 mg/kg) exerts significant inhibition of intestinal α-glucosidase activity in vivo thereby delaying the absorption of carbohydrates in T2D rats, thus resulting in significant lowering of postprandial blood glucose levels.

Both in vitro and in vivo results were compared to the commercially available α-glucosidase inhibitor acarbose. Our findings clearly indicate that naringenin dampens postprandial glycemic response and offers a potential complementary approach in the management of T2D.

Effect of Citrus flavonoid s, Naringin and Naringenin, on metabolic syndrome and Their Mechanisms of action

flavonoids are important natural compounds with diverse biologic activities. Citrus flavonoids constitute an important series of flavonoids . Naringin and its aglycone naringenin belong to this series of flavonoids and were found to display strong anti-inflammatory and antioxidant activities. Several lines of investigation suggest that naringin supplementation is beneficial for the treatment of obesity , diabetes , hypertension, and metabolic syndrome . A number of molecular mechanisms underlying its beneficial activities have been elucidated. However, their effect on obesity and metabolic disorder remains to be fully established. Moreover, the therapeutic uses of these flavonoids are significantly limited by the lack of adequate clinical evidence.

This review aims to explore the biologic activities of these compounds, particularly on lipid metabolism in obesity, oxidative stress, and inflammation in context of metabolic syndrome.

antihyperglycemic and antioxidant effects of a flavanone,naringenin, in streptozotocin–nicotinamide-inducedexperimental diabetic rats

In the present study, the putative antihyper-glycemic and antioxidant effects of a flavanone, narin-genin, were evaluated in comparison with those of glyclazide, a standard drug for therapy of diabetes mel-litus. diabetes was induced experimentally in 12-h-fasted rats by intraperitoneal injections of first strepto-zotocin(50mg/kgb.w.) and then of nicotinamide (110 mg/kg b.w.) after a 15-min interval. Untreated diabetic rats revealed the following in comparison with normal rats: significantly higher mean levels of blood glucose and glycosylated hemoglobin, significantlylower mean levels of serum insulin , significantly lower mean activities of pancreatic antioxidant enzymes(superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase), significantly lower mean levels of plasma non-enzymatic antioxidants (reduced glutathione, vitamin C , vitamin E), significantly elevated mean levels of pancreatic malondialdehyde (MDA) and significantly elevated mean activities of serum alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase(ALP) and lactate dehydro-genase (LDH).

Following oral administration of naringe-nin (50 mg/kg b.w./day) to diabetic rats for 21 days, the following observations were made in comparison withuntreated diabetic rats: significantly lower mean levels offasting blood glucose and glycosylated hemoglobin, sig-nificantly elevated serum insulin levels, significantly higher mean activities of pancreatic enzymatic antioxi-dants, significantly higher mean levels of plasma non-enzymatic antioxidants, lower mean pancreatic tissuelevels of MDA and lower mean activities of ALT, AST,ALP and LDH in serum. The values obtained in thenaringenin-treated animals approximated those observedin glyclazide-treated animals. Histopathological studiesappeared to suggest a protective effect of naringenin onthe pancreatic tissue in diabetic rats.

These results suggestthat naringenin exhibits antihyperglycemic and antioxi-dant effects in experimental diabetic rats.

Purification of naringin and neohesperidin from Huyou (Citrus changshanensis) fruit and their effects on glucose consumption in human HepG2 cells

Huyou (Citrus changshanensis) is rich in naringin and neohesperidin, which are natural flavanone glycosides with a range of biological activities. Among the different fruit parts, i.e. flavedo, albedo, segment membrane (SM), and juice sacs (JS), albedo showed the highest contents of both compounds, with 27.00 and 19.09 mg/g DW for naringin and neohesperidin, respectively. Efficient simultaneous purification of naringin and neohesperidin from Huyou albedo was established by the combination of macroporous D101 resin chromatography and high-speed counter-current chromatography (HSCCC). Purified naringin and neohesperidin were identified by both HPLC and LC–MS, and their effects on glucose consumption were investigated in HepG2 cells. Cells treated with naringin and neohesperidin showed increased consumption of glucose, and this was associated with increased phosphorylation of AMP-activated protein kinase (AMPK ).

Therefore, naringin and neohesperidin from Huyou may act as potential hypoglycaemic agents through regulation of glucose metabolism.

antidiabetic effects of hesperidin and naringin in type 2 diabetic rats

This study was designed to investigate the effect of hesperidin and naringin on serum glucose , blood glycosylated hemoglobin and serum insulin levels in high fat fed (HFD)/streptozotocin (STZ)-induced type 2 diabetic rats. In addition, the effect on serum lipid profile, adiponectin and resistin levels, cardiac function parameters and liver and muscle glycogen contents was assessed.

Hesperidin and naringin were orally and daily administered at a dose level of 50 mg/kg b.w. for 30 days to HFD/STZ type 2 diabetic rats. Both hesperidin and naringin supplementation potentially ameliorated the elevated levels of glucose , glycosylated hemoglobin, AST, LDH and CK-MB and the lowered serum insulin level and hepatic and muscle glycogen content of insulin resistant diabetic rats. Both compounds were also found to alleviate lipid profile and serum adiponectin and resistin levels.

These results showed that hesperidin and naringin have potential antihyperglycemic and antidyslipidemic efficacies as well as cardiac function improving action in HFD/STZ-induced type 2 diabetic rats.

Nelumbo nucifera Gaertn extract

Effect of Nelumbo nucifera rhizome extract on blood sugar level in rats

Oral administration of the ethanolic extract of rhizomes of Nelumbo nucifera markedly reduced the blood sugar level of normal, glucose -fed hyperglycemic and streptozotocin-induced diabetic rats, when compared with control animals. The extract improve d glucose tolerance and potentiated the action of exogenously injected insulin in normal rats. When compared with tolbutamide, the extract exhibited activity of 73 and 67% of that of tolbutamide in normal and diabetic rats, respectively.

Evaluation of Hypoglycemic activity of Inorganic Constituents in Nelumbo nucifera Seeds on Streptozotocin-Induced diabetes in Rats

The seeds of Nelumbo nucifera (Lotus) have been used in the traditional system of medicine for various ailments including diabetes. The present study was aimed at analyzing the levels of biologically important trace elements in the lotus seeds by atomic absorption spectroscopy and evaluating the hypoglycemic properties of seed ash on streptozotocin-induced diabetes in rats. diabetic rats treated with lotus seed ash at a concentration of 200 mg/kg body weight orally for 30 days exhibited significant hypoglycemic activity.

The presence of trace elements in appreciable amounts in the seeds may play a direct or indirect role on insulin secretion or its action in a synergetic manner. The hypo-glycemic activity of the ash was comparable with glyclazide. The role of trace elements in disorders related to diabetes is also discussed briefly.

Effects of Flower Extract from Lotus (Nelumbo nucifera) on Hypoglycemic and Hypolipidemic in Streptozotocin-induced diabetic Rats

This study was aimed to investigate an acute toxicity and effects of Nelumbo nuciferaflower extract (NNFE) on hyperglycemic and hypolipidemic effects in streptozytocin-induced diabetic rats. In vivo acute toxicity study of NNFE was carried out by once oral admin-istration various doses (0, 500, 1000, 1500 and 2000 mg/kg) of the extract to healthy male adult W istar rats. Sign or symptom of toxicity and mortality were examined within 24 h and further period of 14 days. The studies of effects of the extract on hypoglycemic and hypolipidemic activities were performed by given the extract at a dose of 250 mg/g b.w. to STZ-induced diabetic rats orally and daily for 8 weeks.

The results revealed that the extract did not produce any signs or symptoms of toxicity and the mortal rats were not found during the period of ob-servation. Furthermore, the extract at a dose of 250 mg/kg significantly (p<0.05) decreased the levels of fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), and blood urea nitrogen (BUN) but increased high density lipoprotein (HDL) in the NNFE– treated diabetic rats compared to diabetic controls. However, the extract did not alter creatinine in diabetic treated rats compared to diabetic controls.

These findings indicate that NNFE had non acute toxicity but possesses hypoglycemic and hypolipidemic ac-tivities. NNFE is one of alternative beneficial products in a treatment of diabetes.

Hypoglycemic and hypolipidemic effects of Nelumbo nucifera flower in Long-Evans rats

The study was conducted to assess the hypolipidemic and hypoglycemic effects of Nelumbo nucifera flowers powder in Long-Evans rats.

Methods: Experimental rats were made hyperlipidemic and diabetic (type 2 ) by feeding high fat diet (Lab diet, Dalda and Coconut oil = 4: 3: 1) and injecting alloxan respectively. N. nucifera flowers powder in different percentages was mixed with the regular Lab Diet for 21 days feeding. Serum total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and blood glucose levels were evaluated in various groups.

Results: Feeding with N. nucifera flowers powder at different percentages to hyperlipidemic groups showed diverse but a significant (P<0.05) decrease in serum total cholesterol, triglyceride and LDL-cholesterol levels when compared to control group while HDL-cholesterol level was increased significantly (P<0.05). Routine feeding with N. nucifera flowers powder for 21 days resulted in significant decrease in the blood glucose levels of alloxan-induced diabetic rats. Both 20% and 10% of N. nucifera flower powders with Lab Diet significantly (P<0.05) decreased blood glucose level up to 48% and 34%, respectively in comparison to the drug control group treated with glibenclamide which was found with the decreasing capability up to 66% where the higher percentage of N. nucifera flower powder was found to exert more prominent effect in lowering blood glucose level.

During comparison to the control group, the above mentioned percentages of N. nucifera flowers powder was found to reduce the blood glucose level around 32.05% and 47.92% respectively. Although not prominent, but the data revealed that the sample was endowed with the body weight declining capability.

Conclusion: Results of the experiments affirm that the flower of N. nucifera has potent hypoglycemic and hypolipidemic properties and might be useful in these patients.

Ophiopogon japonicus（L.f.）KerGawl extract

Effects of polysaccharide in Ophiopogon japonicus on blood glucose in gestational diabetic rats

Aim: To investigate the effects of polysaccharide in Ophiopogon japonicus on blood glucose in gestational diabetic rats.Methods: The models of gestational diabetic rats were established with alloxan by intraperitoneal injection administration.Polysaccharide in Ophiopogon japonicus was given by intragastric administration on 14 days.The blood glucose levels of rats at the day 0,7,14 were detected respectively, their body weight and serum insulin levels detected by the method of radioimmunoassay at the day 0,14 were analyzed.

Results: The blood glucose levels were significantly decreased in gestational diabetic rats treated by polysaccharide in Ophiopogon japonicus at the day 7,14 compared with model group(P0.01),and it showed no effects on the levels of blood insulin and the body weight of rats.

Conclusion: Polysaccharide in Ophiopogon japonicus could decrease the levels of blood glucose in gestational diabetic rats. It maybe relate to increase the hepatic cell intakeing the amylaceum, and increase the composition of the hepatic glycogen.

Oridonin

Plant‐derived glucose transport inhibitors with potential antitumor activity

Glucose, a key nutrient utilized by human cells to provide cellular energy and a carbon source for biomass synthesis, is internalized in cells via glucose transporters that regulate glucose homeostasis throughout the human body. Glucose transporters have been used as important targets for the discovery of new drugs to treat cancer, diabetes , and heart disease, owing to their abnormal expression during these disease conditions. Thus far, several glucose transport inhibitors have been used in clinical trials, and increasing numbers of natural products have been characterized as potential anticancer agents targeting glucose transport.

Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells

The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells. Then miRNA profiling of SW480 cells revealed those intracellular signaling related to energy supply was affected by oridonin, suggesting that glucose metabolism is a potential target for CRC therapy. Moreover, our results indicated that oridonin induced metabolic imbalances by significantly inhibiting glucose uptake and reducing lactate export through significantly downregulating the protein levels of GLUT1 and MCT1 in vitro and vivo.

However, the ATP level in oridonin-treated CRC cells was not decreased when oridonin block ed the glucose supply, indicating that oridonin induced autophagy process, an important ATP source in cancer cells . The observation was then supported by the results of LC3-II detection and transmission electron microscopy analysis, which confirmed the presence of autophagy. Furthermore, p-AMPK was rapidly deactivated following oridonin treatment , resulting in downregulation of GLUT1 and induction of autophagy in the cancer cells.

Thus our finding helped to clarify the anticancer mechanisms of oridonin and suggested it could be applied as a glucose metabolism –targeting agent for cancer treatment.

Oroxylum indicum seed

Combination of flavonoids from Oroxylum indicum seed extracts and acarbose improves the inhibition of postprandial blood glucose: In vivo and in vitro study

The combined effect of Oroxylum indicum seed extracts (OISE) or major flavonoids from OISE and acarbose on reducing postprandial blood glucose (PBG) levels was investigated in vitro and in vivo. In vitro, the IC₅₀ values of OISE and baicalein against α-glucosidase were 43.4 ± 0.731 μg mL⁻¹ and 25.9 ± 0.412 μg mL⁻¹ respectively. A combination of acarbose with OISE or baicalein synergistically inhibited rat intestinal α-glucosidase . The combination index (CI) values for acarbose with OISE ranged from 0.33 to 0.75, suggesting a synergistic but not additive effect. OISE was determined to be a non-competitive inhibitor of maltose-hydrolyzing activity. In vivo, OISE were administered to normoglycemic and diabetic mice, either alone or in combination with acarbose.

At doses between 50 and 200 mg kg⁻¹, OISE enhanced the efficacy of acarbose by up to 5-fold. These results demonstrated that OISE enhances the efficacy of acarbose in vivo, and that the combination of OISE and acarbose displayed a synergistic effect in vitro. Therefore, OISE can be used to design dietary supplements to treat diabetes.

Paeonia lactiflora Pall extract

antihyperglycemic Effects of Paeoniflorin and 8-Debenzoylpaeoniflorin, Glucosides from the Root of Paeonia lactiflora

Paeoniflorin and 8-debenzoylpaeoniflorin were isolated from the dried root of Paeonia lactiflora Pall. (Ranunculaceae). They produced a significant blood sugar lowering effect in streptozotocin-treated rats and had a maximum effect at 25 min after treatment.

This hypoglycemic action was also observed in normo-glycemic rats only at 1 mg/kg. The antihyperglycemic activity of 8-debenzoylpaeoniflorin seems lower than that of paeoniflorin. plasma insulin was not changed in paeoniflorin-treated normoglycemic rats indicating an insulin-independent action. Also, this glucoside reduced the elevation of blood sugar in glucose challenged rats. Increase of glucose utilization by paeoniflorin can thus be considered. There are no previous data showing the hypo-glycemic activity of paeoniflorin and/or 8-debenzoylpaeoniflorin in rats.

Pelargonidin-3-O-glucoside

Plant‐derived glucose transport inhibitors with potential antitumor activity

Thus far, several glucose transport inhibitors have been used in clinical trials, and increasing numbers of natural products have been characterized as potential anticancer agents targeting glucose transport.

Panax ginseng C. A. Meye extract

Ginsenosides, ingredients of the root ofPanax ginseng, arenot substrates but inhibitors of sodium-glucose transporter

AbstractRecent pharmacokinetic studies have revealedthat ginsenosides, the major ingredients of ginseng (theroots ofPanax ginseng), are present in the plasma collectedfrom subjects receiving ginseng, and speculated that gin-senosides might be actively transported via glucose trans-porters. We evaluated whether ginsenosides Rb1and Rg1,and their metabolites from enteric bacteria act as substratesof sodium–glucose cotransporter (SGLT) 1, the major glucose transporter expressed on the apical side ofintestinal epithelial cells. First, we evaluated the competingeffects of ginseng extract and ginsenosides on the uptake of[14C]methyl-glucose, a substrate of SGLT1 , by SGLT1–overexpressing HEK293 cells. A boiling water extract ofginseng inhibited SGLT1 in a concentration-dependentmanner with an IC50value of 0.85 mg/ml. By activity–guided fraction ation, we determined that the fraction con-taining ginsenosides displayed an inhibitory effect onSGLT1.

Of the ginsenosides evaluated, protopanaxatriol-type ginsenosides were not found to inhibit SGLT1 ,whereas protopanaxadiol-type ginsenosides, includingginsenosides Rd, Rg3,Rh2,F2and compound K, exhibitedsignificant inhibitory effects on SGLT1, with ginsenosideF2having the highest activity with an IC50value of23.0lM. Next, we measured the uptake of ginsenoside F2and compound K into Caco-2 cells, a cell line frequentlyused to evaluate the intestinal absorption of drugs. The uptake of ginsenoside F2and compound K into Caco-2cells was not competitively inhibited by glucose.

Furthermore, the uptake of ginsenoside F2and compound K into SGLT1-overexpressing HEK293 cells was not significantlyhigher than into mock cells. Ginsenoside F2and compoundK did not appear to be substrates of SGLT1, although thesecompounds could inhibit SGLT1. Ginsenosides might beabsorbed by passive diffusion through the intestinal membrane or actively transported via unknown transporters other than SGLT1.

Anti-diabetic effects of Panax notoginseng saponins and its major anti-hyperglycemic components

Ethnopharmacological relevance: Panax notoginseng (Burk) F.H. Chen (Araliaceae) is a well-known and commonly used traditional Chinese herb for treatment of various diseases , such as hemostasis, edema and odynolysis.

Aim of study: Our aim was to investigate the mechanisms of anti-hyper glycemic and anti-obese effects of Panax notoginseng saponins (PNS) in KK-Ay mice, and explore the components in PNS for such effects.

Materials and methods: KK-Ay mice received daily intraperitoneal injections of PNS 200 mg/kg or vehicle for 30 days while ginsenoside Re 14 mg/kg, Rd 15 mg/kg, Rg1 40 mg/kg, Rb1 60 mg/kg and notoginsenoside R1 6 mg/kg for 12 days. Fasting blood glucose levels (FBGL), glucose tolerance (GT), serum insulin , leptin levels , body weight changes, food intake, adipose tissues and blood fat levels were measured at different time points.

Results: The PNS group had significantly lower FBGL, improve d GT and smaller body weight incremental percentage after the 30-day treatment . Additionally, Rb1 exhibited significant reduction of FBGL on day 12, and Re also exhibited a decreasing trend after the 12-day treatment .

Conclusions: PNS possess anti-hyperglycemic and anti-obese activities by improving insulin-and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice.

Dammarane-type triterpene extracts of Panax notoginseng root ameliorates hyperglycemia and insulin sensitivity by enhancing glucose uptake in skeletal muscle

Skeletal muscle is an important organ for controlling the development of type 2 diabetes. We discovered Panax notoginseng roots as a candidate to improve hyperglycemia through in vitro muscle cells screening test. Saponins are considered as the active ingredients of ginseng. However, in the body, saponins are converted to dammarane-type triterpenes, which may account for the anti-hyperglycemic activity. We developed a method for producing a dammarane-type triterpene extract (DTE) from Panax notoginseng roots and investigated the extract’s potential anti-hyperglycemic activity. We found that DTE had stronger suppressive activity on blood glucose levels than the saponin extract (SE) did in KK-A^y mice.

Additionally, DTE improved oral glucose tolerance, insulin sensitivity, glucose uptake, and Akt phosphorylation in skeletal muscle. These results suggest that DTE is a promising agent for controlling hyperglycemia by enhancing glucose uptake in skeletal muscle.

Anti-diabetic Potential of Panax Notoginseng Saponins (PNS): A Review

herbal medicines have traditionally played a major role in the management of diabetes in Asian countries for centuries. Panax notoginseng (Burk) F. H. Chen (Araliaceae) known as Tiánqī or san qi is a well-known medicinal herb in Asia for its long history of use in Chinese medicine. Qualified as ‘the miracle root for the preservation of life’, it has been used in China for 600 years, for treatment of various diseases. Panax notoginseng saponins (PNS) are the key active components. PNS have been widely used in China for treatment of cardio-vascular diseases. However, scientific studies have shown a wide range of other pharmacological applications including anti-cancer, neuroprotective and anti-inflammatory agents, immunologic adjuvant and prevention of diabetes complications.

Recently, hypoglycemic and anti-obesity properties of PNS have also been demonstrated. The present review highlights the effects of PNS on glucose production and absorption, and on inflammatory processes that seem to play an important role in the development of diabetes.

Saponins Isolated from the Root of Panax notoginseng Showed Significant Anti-diabetic Effects in KK-Ay Mice

Panax notoginseng, a well-known and commonly used traditional Chinese herb, has been used in China for six hundred years. Panax notoginseng Saponins (PNS) were extracted from the root of the plant. This is the first study on anti-hyperglycemic and anti-obese effects of PNS in genetic model mice. Additionally, the preventive effect on diabetic nephropathy was investigated. Animals received intraperitoneal injections of PNS 50 or 200 mg/kg daily. On day 12, 22 and 30, PNS-treated groups had significantly lower fasting blood glucose levels and smaller body weight incremental percentage. After a 12-day treatment, glucose tolerance of PNS groups were significantly improved; these indices in PNS-treated mice exhibited a dose-dependent improvement.

Furthermore, on day 30, the serum insulin resistance index and triglyceride levels of PNS-treated groups decreased significantly, and the development of the mice glomerular lesions was prevented significantly. The results in this present paper indicate that PNS possesses anti-diabetes and anti-obese activities and may prove to be of clinical importance in improving the management of type 2 diabetes.

Panaxnotoginseng(Burk.)F.H.Chen extract

The Effects and Mechanism of Saponins of Panax notoginseng on glucose metabolism in 3T3-L1 Cells

This study was carried out to determine the effect of saponins of Panax notoginseng (SPN), a naturally occurring cardiovascular agent, on: (1) glucose uptake , (2) GLUT4 translocation and (3) glycogen synthesis in 3T3-L1 adipocytes. Electrospray ionization-Mass spectrometry (ESI-MS) was used to determine the structural characterization of the major active components of SPN. 3T3-L1 adipocytes were cultured and treated with 100 nM insulin alone or with 10, 50 and 100 μg/ml of SPN. [³H]2-deoxyglucose glucose uptake, GLUT4 immunofluorescence imaging and glycogen synthesis assay were carried out to determine the effects of SPN on glucose metabolism.

Under insulin stimulation, SPN significantly increased glucose uptake in a dose-dependent manner; 50 μg/ml of SPN increased glucose uptake by 64% (p < 0.001). Immunofluorescence imaging and analysis have revealed that 50 and 100 μg/ml of SPN increased GLUT4 in the plasma membrane by 3-fold and 6-fold respectively (p < 0.001). Furthermore, the incorporation of D-[U-¹⁴C] glucose into glycogen was enhanced by 53% in 3T3-L1 cells treated with 100 μg/ml of SPN (p < 0.01 vs. insulin stimulation alone). SPN, a naturally occurring agent used to treat ischemic cardio-cerebral vascular disease in China, enhanced insulin -stimulated glucose uptake and glycogen synthesis in adipocytes.

The results of this study indicate that SPN may have a therapeutic potential for hyperglycaemia in type 2 diabetes.

persimmon tannin

Persimmon Tannin Decreased the glycemic Response through Decreasing the Digestibility of Starch and Inhibiting α-amylase, α-glucosidase, and intestinal glucose uptake

Regulation of postprandial blood glucose levels is an effective therapeutic proposal for type 2 diabetes treatment . In this study, the effect of persimmon tannin on starch digestion with different amylose levels was investigated both in vitro and in vivo. Oral administration of persimmon tannin–starch complexes significantly suppressed the increase of blood glucose levels and the area under the curve (AUC) in a dose-dependent manner compared with starch treatment alone in an in vivo rat model. Further study proved that persimmon tannin could not only interact with starch directly but also inhibit α-amylase and α-glucosidase strongly, with IC₅₀ values of 0.35 and 0.24 mg/mL, separately. In addition, 20 μg/mL of persimmon tannin significantly decreased glucose uptake and transport in Caco-2 cells model.

Overall, our data suggested that persimmon tannin may alleviate postprandial hyperglycemia through limiting the digestion of starch as well as inhibiting the uptake and transport of glucose .

Phloretin

Phloretin inhibits Zika virus infection by interfering with cellular glucose utilisation

Zika virus (ZIKV) is a re-emerging Flavivirus that has been linked to microcephaly and other neurological pathologies. In this study, phloretin, a glucose transporter inhibitor natural ly derived from plants, was used to investigate the glucose dependence of ZIKV replication in host cells. The results showed that phloretin significantly decreased infectious titres of two ZIKV strains, namely MR766 (African genotype) and PRVABC59 (Puerto Rico genotype). The 50% effective concentration (EC50) of phloretin against MR766 and PRVABC59 was 22.85 µM and 9.31 µM, respectively. Further analyses demonstrated that decreased viral production was due to host-targeted inhibition , including decreased apoptotic caspase-3 and -7 activities and reduced phosphorylation of Akt/mTOR pathways . In addition, upon disruption of cellular glucose availability within host cells using 2-deoxy-d-glucose , ZIKV propagation was inhibited.

Collectively, we demonstrate phloretin inhibition of ZIKV propagation and provide evidence of glucose utilization pathways as being important for ZIKV propagation. The activity of phloretin and its role in inhibiting glucose uptake could provide a useful foundation for the development of ZIKV antivirals.

Phloretin-induced apoptosis in B16 melanoma 4A5 cells by inhibition of glucose transmembrane transport

Phloretin, a naturally occurring dihydrochalcone, is known to inhibit tumor cell growth in vitro and in vivo. To clarify the anti-tumor effects of phloretin, its apoptosis-inducing effects in B16 melanoma 4A5 cells were examined. Phloretin induced the internucleosomal DNA fragmentation typical of apoptosis in B16 melanoma cells. The addition of extracellular glucose remarkably inhibited the phloretin-induced apoptosis in the cells. When apoptosis was strongly induced in the B16 cells by phloretin, protein kinase C activity was inhibited in the cells.

Our results suggest that phloretin induced apoptosis in B16 melanoma 4A5 cells mainly through the inhibition of glucose transmembrane transport. inhibition of protein kinase C activity by phloretin probably promote s the ratio of apoptotic cells in the cells.

In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter

Phloretin (Ph), a natural product found in apples and pears with glucose transporter (GLUT) inhibitory activity, exerts antitumor effects. However, little is known about its effects on human liver cancer. The purpose of this study is to test the cytotoxic effects of Ph on HepG2 cells and to identify the underlying molecular pathways. Human hepatocellular carcinoma specimens and HepG2 show a high level of GLUT2 transporter activity in the cell membrane. Real-time PCR and MTT assays demonstrate that Ph-induced cytotoxicity correlates with the expression of GLUT2. Flow cytometry and DNA fragmentation studies show that 200 μM Ph induces apoptosis in HepG2, which was reversed by glucose pretreatment. GLUT2 siRNA knockdown induced HepG2 apoptosis, which was not reversed by glucose. Western blot analysis demonstrates that both intrinsic and extrinsic apoptotic pathways in addition to Akt and Bcl-2 family signaling pathways are involved in Ph-induced cell death in HepG2 cells. Furthermore, using flow cytometry analysis, a mitochondrial membrane potential assay and Western blot analysis, we show that cytochalasin B, a glucose transport inhibitor, enhances the Ph-induced apoptotic effect on HepG2 cells, which was reversed by pretreatment with glucose.

Furthermore, we found significant antitumor effects in vivo by administering Ph at 10 mg/kg intraperitoneally to severe combined immune deficiency mice carrying a HepG2 xenograft. A microPET study in the HepG2 tumor-bearing mice showed a 10-fold decrease in ¹⁸F-FDG uptake in Ph-treated tumors compared to controls. Taken together, these results suggest that Ph-induced apoptosis in HepG2 cells involves inhibition of GLUT2 glucose transport mechanisms.

inhibition of glucose transport into brain by phlorizin, phloretin and glucose analogues

An indicator dilution technique with ²²Na⁺ as the intravascular marker was used to measure unidirectional transport of d-[6-³H]glucose from blood into the isolated, perfused dog brain. 18 compounds which are structurally related to glucose were tested for their ability to inhibit glucose transport. The data suggest that no single hydroxyl group is absolutely required for glucose transport, but rather that glucose binding to the carrier probably occurs through hydrogen bonding at several sites (hydroxyls on carbons 1, 3, 4 and 6). In addition, α-d–glucose has higher affinity for the carrier than does β-d–glucose .

A separate series of experiments demonstrated that phlorizin and phloretin are competitive inhibitors of glucose transport into brain; however, phloretin is partially competitive and inhibits at lower concentrations than does phlorizin . inhibition by phlorizin and phloretin is mutually competitive, indicating that these compounds compete for binding to the glucose carrier.

Comparison with the results reported in the literature for similar studies using the human erythrocyte demonstrates a fundamental similarity between glucose transport systems in the blood -brain barrier and erythrocyte.

The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter

Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells.

Interestingly, we found that Ph (10–150 μM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10–150 μM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues.

In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.

Asymmetrical binding of phloretin to the glucose transport system of human erythrocytes

The sidedness of phloretin binding to the glucose carrier has been determined by comparing the type of inhibition produced in zerotrans entry and zerotrans exit experiments. Initial rates of zerotrans entry were measured by the method of R.D. Taverna and R.G. Langdon (Biochim. Biophys. Acta 298:412–421, 1973), which involves pink ghosts loaded with glucose oxidase; this obviates the problem of rapid substrate accumulation inside the cells. With phloretin equilibrated across the membrane, the inhibition of entry was competitive, and the inhibition of exit noncompetitive.

The experimental procedures were validated by showing that the inhibition by cytochalasin B, known to bind inside but not outside, was noncompetitive in entry and competitive in exit, as predicted. It was also demonstrated that even after pre-incubation of the cells with a relatively high concentration of phloretin, the phloretin adsorbed in the membrane did not significantly alter the rate of carrier reorientation.

The results show that the outward-facing form of the glucose carrier, but not the inward-facing form, bears a phloretin binding site; thus phloretin, as well as cytochalasin B, is bound asymmetrically, phloretin outside and cytochalasin B inside.

Apple Polyphenol Phloretin Inhibits Colorectal Cancer Cell Growth via inhibition of the type 2 glucose transporter and Activation of p53-Mediated Signaling

glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells.

The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (*, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22–26.54-fold; *, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0–100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0–100 μM, for 24 h).

The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.

phlorizin

Dual SGLT1 /SGLT2 inhibitor phlorizin Ameliorates Non-Alcoholic fatty Liver Disease and Hepatic glucose Production in type 2 diabetic Mice

Purpose: NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. inhibitors of sodium glucose transporter 2 (SGLT2 ) reduce glycemia and exert beneficial effects on diabetic complications . Recently, dual SGLT1 /2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1 /2 inhibition could be accompanied by beneficial effects on NAFLD progression.

Methods: Glycemic homeostasis , hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1 /2 inhibitor phlorizin for 1 week.

Results: T2D increased glycemia; insulin emia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose -6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P<0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered .

Conclusion: NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1 /2 inhibitor . This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.

Pharmacokinetic and Pharmacodynamic Modeling of the Effect of an sodium–glucose cotransporter inhibitor , phlorizin , on Renal glucose Transport in Rats

A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium –glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy . First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2 . This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption . The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance.

The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption . The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2 , which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model.

The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor .

Effect of phlorizin on SGLT2 expression in the kidney of diabetic rats.

Background: The purpose of our study was to determine whether increased SGLT2 expression in the kidney of diabetic rats was associated with the development of hypertension and to investigate the effect of phlorizin (P) on blood pressure and SGLT2 expression in diabetic rats.

Methods: The animals were divided into two groups: Control (C) and streptozotocin-induced diabetic (D) rats were used to evaluate SGLT2 activity in brush border membrane vesicles (BBMV) using a rapid filtration technique. Others animals were divided into two groups: Normal (NSD) or high salt diet (4%)(HSD), and subdivided in four groups: C, C+P, D, D+P. Systolic blood pressure (SBP) was recorded for 30 days by the use of a telemetric system and at day 30 urine samples (24 h) were collected to evaluate renal function and SGLT2 expression in the renal cortex.

Results: At day 30, diabetic animals with NSD or HSD exhibited hyperglycemia , lower body weight, glycosuria , diuresis, decrease natriuresis, increased SBP values and SGLT2 expression. In diabetic rats, phlorizin treatment decreased hyperglycemia and prevented development of hypertension, decreased SGLT2 activity in BBMV but did not modify SGLT2 expression.

Conclusions: In conclusion, SGLT2 inhibition prevented the development of hypertension in diabetic rats as well as hyperglycemia , suggesting a hypertensive mechanism associated with SGLT2 activity and the likelihood that increased SGLT2 expression may be associated with progression of diabetic renal complications .

Identification of phlorizin binding domains in sodium–glucose cotransporter family: SGLT1 as a unique model system

The sodium glucose cotransporter SGLT1 expressed mainly in the intestine and kidney has been explored extensively for understanding the mechanism of sugar cotransport and its inhibition by a classical competitive inhibitor , phlorizin (Pz). It has been shown that inhibition of SGLT1 by Pz involves its interaction followed by major conformational changes in the Pz binding domain (PBD) in C-terminal loop 13. However, the mechanism of Pz inhibition and its interaction with other members of SGLT is not known.

In this hypothesis, we performed molecular modeling of SGLT1 -loop 13 with Pz and carried out primary sequence analyses and secondary structure predictions to determine qualitatively similar PBDs in C-termini of human SGLT2 -4, except for vSGLT, which contains an unstructured short C-terminus. The ranking of predictions of Pz interaction strongly agrees with the following ranking of previously reported Pz inhibition : SGLT2 >SGLT1 >SGLT4>SGLT3>>vSGLT. In addition, the sugar binding residues were found to be quite conserved among all SGLT members investigated here.

Based on these preliminary analyses, we propose that other Pz-sensitive SGLTs are also inhibited via mechanism similar to SGLT1 where an aglucone of Pz, phloretin, interacts with PBD and glucoside moiety with sugar binding residues. Our hypothesis sets the stage for future analyses on investigation of Pz interaction with SGLT family and further suggests that Pz modeling may be explored to design novel inhibitors targeting several SGLT members.

Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats

Phloridzin is the specific and competitive inhibition of sodium / glucose cotransporter s in the intestine (SGLT1 ) and kidney (SGLT2 ). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products . The effect of phloridzin orally doses 5, 10, 20 and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic , urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.

Apple Trees to sodium glucose Co-transporter inhibitors: A Review of SGLT2 inhibition

The kidney plays a key role in glucose homeostasis . The delineation of the role of SGLTs throughout the body has been a major advancement in our understanding of the kinetics of glucose in the body . Our better understanding of the physiology of renal glucose homeostasis and recent pharmacological advances have brought us to a point where pharmacological modulation of this system is possible. Although diabetes management is an obvious candidate to benefit from these advances, other medical conditions such as obesity may also eventually be targeted via methods to modulate either SGLT1 or SGLT2 .

Currently, a host of studies are underway evaluating the effects of the SGLT2 inhibitor dapagliflozin. Although the published studies offer a great deal of promise, there is still some concern regarding potential side effects, namely urinary tract and genital infections. As data from phase 3 trials develop, many of these unanswered questions will be resolved.

In addition to dapagliflozin, several other SGLT2 inhibitors , an SGLT anti-sense molecule, and SGLT1 inhibitors are being developed. Eventually, pharmacological or biological modulation of these transporters will almost certainly offer us a useful method of disease intervention.

Dietary Phloridzin reduces blood glucose levels and Reverses SGLT1 Expression in the Small Intestine in Streptozotocin-Induced diabetic Mice

Phloridzin is a dihydrochalcone typically contained in apples. In this study, it is shown that a diet containing 0.5% phloridzin significantly reduced the blood glucose levels in streptozotocin (STZ)-induced diabetic mice after 14 days. We detected phloridzin in the plasma of STZ-induced diabetic mice fed the phloridzin diet for 14 days, although its concentration was much lower than that of the phloridzin metabolites. A quantitative RT-PCR analysis showed a reversal of STZ induction of the sodium /glucose cotransporter gene SGLT1 and the drug-metabolizing enzyme genes Cyp2b10 and Ephx1 in the small intestine of mice fed a 0.5% phloridzin diet. These mice also showed a reversal of the STZ-mediated renal induction of the glucose -regulated facilitated glucose transporter gene GLUT2.

Dietary phloridzin improved the abnormal elevations in blood glucose levels and the overexpression of SGLT1, Cyp2b10, and Ephx1 in the small intestine of STZ-induced diabetic mice.

Dual SGLT1 /SGLT2 inhibitor phlorizin Ameliorates Non-Alcoholic fatty Liver Disease and Hepatic glucose Production in type 2 diabetic Mice

Methods: Glycemic homeostasis , hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1 /2 inhibitor phlorizin for 1 week.

Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia.

Individuals with non-insulin dependent or insulin-dependent diabetes mellitus present insulin resistance in peripheral tissues. This is reflected in a subnormal whole body insulin-dependent glucose utilization, largely dependent on skeletal muscle. Glucose transport across the cell membrane of this tissue is rate limiting in the utilization of the hexose. Therefore, it is possible that a defect exists in insulin-dependent glucose transport in skeletal muscle in diabetic states. This review focuses on two questions: is there a defect at the level of glucose transporters in skeletal muscle of diabetic animal models, and is this a consequence of abnormal insulin or glucose levels? The latter question arises from the fact that these parameters usually vary inversely to each other. glucose transport into skeletal muscle occurs by two membrane proteins, the GLUT1 and GLUT4 gene products. By subcellular fraction and Western blotting with isoform-specific antibodies, it was determined that isolated plasma membranes (PM) contain GLUT4 and GLUT1 proteins at a molar ratio of 3.5:1 and that an intracellular fraction (internal membranes; IM) different from sarcoplasmic reticulum contains only GLUT4 transporters.

The IM furnishes transporters to the PM in response to insulin. Both transporter isoforms bind cytochalasin B in a D-glucose -protectable fashion. In streptozocin-induced diabetes of the rat with normal fasting insulin levels and marked hyperglycemia , the number of cytochalasin B-binding sites and of GLUT4 proteins diminishes in the PM whereas the GLUT1 proteins increase to a new ratio of about 1.5:1 GLUT4 :GLUT1. In the IM, the levels of GLUT4 protein drop, as does the cellular GLUT4 mRNA. To investigate if these changes are associated with hyperglycemia, glucose levels were corrected back to normal values for a 24-h period with sc injections of phlorizin to block proximal tubule glucose reabsorption. This treatment restored cytochalasin B binding, restored GLUT4 and GLUT1 values back to normal levels in the PM, and partly restored cytochalasin B binding but not GLUT4 levels in the IM, consistent with only a partial recovery of GLUT4 mRNA. It is concluded that GLUT4 protein in the PM correlates inversely whereas GLUT1 protein correlates directly with glycemia.

It is proposed that the decrease in GLUT4 levels is a protective mechanism, sparing skeletal muscle from gaining glucose and experiencing diabetic complications, albeit at the expense of becoming insulin resistant.

Pharmacological investigations on efficacy of phlorizin a sodium–glucose co-transporter (SGLT) inhibitor in mouse model of intracerebroventricular streptozotocin induced dementia of AD type

Objectives: The study has been commenced to discover the potential of phlorizin (dual SGLT inhibitor ) in streptozotocin induced dementia of Alzheimer’s disease (AD) type.

Material and methods: Injection of Streptozotocin (STZ) was given via i.c.v. route (3 mg/kg) to induce dementia of Alzheimer’s type. In these animals learning and memory was evaluated using Morris water maze (MWM) test. Glutathione (GSH) and thiobarbituric acid reactive species (TBARS) level was quantified to evaluate the oxidative stress; cholinergic activity of brain was estimated in term of acetylcholinesterase (AChE) activity; and the levels of myeloperoxidase (MPO) were measured as inflammation marker.

Results: The mice model had decreased performance in MWM, representing impairment of cognitive functions. Biochemical evaluation showed rise in TBARS level, MPO and AChE activity, and fall in GSH level. The histopathological study revealed severe infiltration of neutrophils. In the study, phlorizin /Donepezil (serving as positive control) treatment mitigate streptozotocin induced cognitive decline, histopathological changes and biochemical alterations.

Conclusions: The results suggest that phlorizin decreased cognitive function via its anticholinesterase, antioxidative , antiinflammatory effects and probably through SGLT inhibitory action. It can be conferred that SGLTs can be an encouraging target for the treatment of dementia of AD.

Platycodon grandifloru extract

antihyperglycemic Effects of Platycodon grandiflorum (Jacq.) A. DC. Extract on Streptozotocin-induced diabetic Mice

The root of Platycodon grandiflorum (Jacq.) A. DC has been reported to have a wide range of health benefits in oriental food.

This study examined the hypoglycemic effects of Platycodon grandiflorum (Jacq.) A. DC aqueous-ethanol extract (PGE) in streptozotocin (STZ) -induced diabetic ICR mice (STZ diabetic mice) for the first time. The effects of PGE on blood glucose , plasma insulin levels and body weight were investigated. A significant decrease in blood glucose levels was observed after single administration of PGE. Furthermore, Glibenclamide and PGE significantly suppressed the rise in blood glucose after 30 min in the acute glucose tolerance test. treatment with glibenclamide and PGE resulted in a reduction in blood glucose levels from the 2nd week, and this reduction was maintained until the 4th week of treatment.

The body weight changed slightly in glibenclamide and PGE treated mice in comparison with the STZ control group. plasma insulin levels were increased with glibenclamide treatment in STZ diabetic mice, whereas such effect was not observed with PGE. These results indicated that PGE could induce hypoglycemic effects without stimulating insulin secretion.

Platycodon grandiflorum modifies adipokines and the glucose uptake in high-fat diet in mice and L6 muscle cells

Objectives: Obesity and diabetes have become the most common human health problems worldwide. obesity ‘s contribution to type 2 diabetes might be due to dysregulation of adipokines and glucose uptake .

Methods: In this study, we performed in-vivo and in-vitro studies to evaluate the effects of Platycodon grandiflorum extract (PGE) on adipokines and glucose uptake . Before study, platycodin D concentrations were analysed by HPLC in PGE prepared in water, in 50% ethanol and in 80% ethanol, and we selected the 80% ethanol extract as the PGE for this study based on the HPLC results.

Results: We found that inclusion of PGE in the high-fat diet (HFD) markedly attenuated food intake, body weight, epididymal fat weight, adipocyte size and blood glucose levels by the oral glucose tolerance test in mice, and maintained serum levels of adiponectin, resistin, leptin, fructosamine and triglycerides. Gene expression analysis revealed that PGE up-regulated adiponectin, and down-regulated TNF-α and leptin in fat tissue. In L6 muscle cells in vitro, PGE increased insulin -stimulated glucose uptake .

Conclusions: We conclude that PGE may improve obesity in mice fed an HFD and glucose uptake in L6 muscle cells by modifying adipokines, and could offer clinical benefits as a supplement to treat obesity and diabetes.

improve ment of blood glucose control in type 2 diabetic db/db mice using Platycodon grandiflorum seed extract

The biological activities of Platycodon grandiflorum (PG) root extracts have been studied intensively, whereas there are limited number of studies on PG seed extract (PGSE). PGSE was prepared by ethanol extraction , and its antidiabetic effect was evaluated in mice with type 2 diabetes (C57BLKS/J-db/db). Results indicated that the administration of high-dose PGSE (600 mg/kg, wb) significantly stabilized the blood glucose levels , as evidenced by the results of the oral glucose tolerance test. Mice treated with high-dose PGSE exhibited significantly lower serum hemoglobin A1c, insulin , and leptin levels after eight weeks of feeding trial (p<0.05). High-dose PGSE administration significantly improve d glucose uptake in the femoral muscle of db/db mice by activating both IRS-1/PI3K/AKT/AS160 and AMPK phosphorylation pathways . GLUT4 translocation from the cytosol to the plasma membrane increased 1.7-fold in the PGSE high-dose group. These results suggest that PGSE has potential for development as an antidiabetic agent.

Influence of Platycodon grandiflorum in blood glucose of Streptozotocin-induced DiabeticICR Mice

To study the hypoglycemic effect of Platycodon grandiflorum extract on diabetic ICR mice. Methods: diabetic models were induced by the i.v. (intravenous) injection of streptozotocin (STZ) in ICR mice, and were divided into different groups, which were given 8, 4g/kg PGE, glibenclamide or water respectively. The effects of PGE on 28d blood glucose level of the STZ-diabetic mice were studied. Food, water intake, body weight, blood glucose , TC, TG, LDL-C, HDL-C and insulin levels were respectively tested. Result: After 28d drug administration, symptoms of diabetic mice fed PGE are alleviated obviously. Water and food intake of diabetic mice are decreased by oral administrations of PGE, and their body weight is increased. High and low doses of PVE suppress the level of blood glucose by 11.42% and 6.86% resptectively, and both doses of PGE also suppresse the levels of TC, TG and LDL-C, but increase the level of HDL-C remarkably. insulin levels are also improve d by PGE. PGE has the potential hypoglycemic effect and alleviate the diabetic symptoms on diabetic mice.

Polygonatum odoratum (Mill.) Druce extract

Homoisoflavonoid s Are Potent glucose transporter 2 (GLUT2) inhibitors: A Potential Mechanism for the glucose -Lowering Properties of Polygonatum odoratum

Foods of high carbohydrate content such as sucrose or starch increase postprandial blood glucose concentrations . The glucose absorption system in the intestine comprises two components: sodium-dependent glucose transporter-1 (SGLT1 ) and glucose transporter 2 (GLUT2 ).

Here five sappanin-type (SAP) homoisoflavonoids were identified as novel potent GLUT2 inhibitors , with three of them isolated from the fibrous roots of Polygonatum odoratum (Mill.) Druce. SAP homoisolflavonoids had a stronger inhibitory effect on 25 mM glucose transport (41.6 ± 2.5, 50.5 ± 7.6, 47.5 ± 1.9, 42.6 ± 2.4, and 45.7 ± 4.1% for EA-1, EA-2, EA-3, MOA, and MOB) than flavonoids (19.3 ± 2.2, 11.5 ± 3.7, 16.4 ± 2.4, 5.3 ± 1.0, 3.7 ± 2.2, and 18.1 ± 2.4% for apigenin, luteolin, quercetin, naringenin, hesperetin, and genistein) and phloretin (28.1 ± 1.6%) at 15 μM. SAP homoiso flavonoids and SGLT1 inhibitors were found to synergistically inhibit the uptake of glucose using an in vitro model comprising Caco-2 cells.

This observed new mechanism of the glucose -lowering action of P. odoratum suggests that SAP homoisoflavonoids and their combination with flavonoid monoglucosides show promise as natural ly function al ingredients for inclusion in foods and drinks designed to control postprandial glucose levels.

Saponin rich fraction s from Polygonatum odoratum (Mill.) Druce with more potential hypoglycemic effects

Aim of the study: The root of Polygonatum odoratum (YuZhu), also a medicinal food has long been used for the treatment of diabetes . The objective of the study was to characterize the anti-diabetic active fraction s or compounds in this herb.

Materials and methods: Fraction s with a different polarity were prepared by solvent extraction and macroporous absorptive resin (D101) column and their anti-diabetic potentials were evaluated by glucose uptake in HepG2 cells and STZ-induced diabetic rats. In addition, α-glycosidase inhibitory activities of active fractions were measured in vitro and chemical compositions including saponin, total flavonoids and total sugar in the fraction s were determined.

Results: The n-buthanol fraction , a saponin-rich fraction obtained by partitioning the ethanol extract with n-buthanol after petroleum ether and acetic ether showed the highest anti-diabetic potential in glucose uptake in HepG2 cells followed by acetic ether fraction which was rich in flavonoids . Further fraction ation the saponin-rich fraction using macroporous resin column (D101), polysaccharide, flavonoid and saponin rich fraction s were obtained by elution with water, 40% and 60% ethanol, respectively and their anti-diabetic potentials proved by glucose uptake test in HepG2 cells and STZ-induced diabetic rats were in the order of saponin rich fraction > flavonoid rich fraction > polysaccharide rich fraction .

Long-term therapy test (60 d) in severe diabetic rats indicated that saponin-rich fraction significantly ameliorated clinical symptoms of diabetes including the elevated blood glucose , body weight loss as well as the increased food and water intake while flavonoid -rich fraction was more potential than saponin-rich fraction to increase superoxide dismutase (SOD) activity and decrease malondialdehyde (MDA) level in rat plasma . Additionally, saponin-rich fraction and flavonoid -rich fraction showed α-glycosidase inhibitory activity with IC₅₀ value of 2.05 ± 0.32 and 3.92 ± 0.65 mg/ml, respectively.

Conclusion: The results suggested that saponin in this herb was more important than flavonoid in exhibiting anti-diabetic activity and flavonoid contributed more to anti-oxidant activity in vivo.

antihyperglycemic effects of total flavonoid s from Polygonatum odoratum in STZ and alloxan-induced diabetic rats

Aim of the study: Total flavonids of Polygonatum(P) odoratum (TFP) were tested for anti-diabetic activity in streptozotocin (STZ)-induced diabetic mice and alloxan-induced diabetic rats.

Materials and methods: Rhizoma Polygonati Odorati, well-known Chinese traditional medicine, is widely used for treatment of diverse diseases for example diabetes. In our study, TFP was extracted by 70% ethanol and purified by macroreticular resin. The experiments were designed to detect the anti-diabetic activity of TFP by determination of blood glucose (BG) using one touch gluco-meter and insulin levels by using a radioimmunoassay kit in streptozotocin (STZ)-induced diabetic mice and alloxan-induced diabetic rats and alpha-amylase inhibitory activity by alpha-amylase inhibition assay in vitro.

Results: TFP had beneficial effects on regulation of blood glucose. Daily administration with 50–200 mg/kg body weight of TFP for 9 days can reduce significantly hyperglycemia in STZ-induced diabetic mice. Thirtieth day administration with TFP (50–200 mg/kg body weight) also decreased significantly fasting blood glucose in alloxan-induced diabetic rats. The hypoglycemic effect of TFP at 50 and 100 mg/kg is less than that of acarbose 20 mg/kg and gliclazide 15 mg/kg. The hypoglycemic effects of TFP at 200 mg/kg is similar to that of acarbose 20 mg/kg and gliclazide 15 mg/kg. TFP also could increase significantly the insulin level in alloxan-induced type 2 diabetic rats (P < 0.05) compared with control. Alpha-amylase inhibition assay in vitro showed that TFP inhibited significantly alpha-amylase activity in a dose-dependent manner.

Conclusions: TFP possess significant dose-dependent anti-diabetic activity. TFP is one of the primary hypoglycemic active compounds of Polygonatum odoratum which would worth further study and development.

A Steroidal Glycoside from Polygonatum odoratum (Mill.) Druce. improves insulin Resistance but does not Alter insulin Secretion in 90% Pancreatectomized Rats

The aim of this study was to investigate the effects of three steroidal glycosides (SG-100, SG-280, and SG-460) obtained from Polygonatum odoratum (Mill.) Druce. on insulin secretion, insulin action , and relative glucose uptake in various tissues of 90% pancreatectomized male Sprague-Dawley rats. One of the compounds (30 mg/kg body weight daily) with a 40%-fat diet was orally administered to a group of such rats for 13 weeks. On the day after a hyperglycemic clamp, euglycemic hyperinsulin emic clamp with 1 μCi of [1-¹⁴C]2-deoxyglucose per 100 g body weight was used. Serum glucose levels were lowest in the rats receiving SG-100. insulin secretion from pancreatic β-cells did not change with SG administration.

Whole-body glucose disposal rates increased with SG-100 administration by 39%. SG-100 increased the glycogen contents and glycogen synthase activity in the soleus muscle of pancreatectomized rats. uptake of [1-¹⁴C]2-deoxyglucose into the soleus muscle was higher in such rats receiving SG-100 than in rats receiving other compounds. In conclusion, SG-100 has an antihyperglycemic effect by promoting peripheral insulin sensitivity without changing insulin secretion.

Polygonum multiflorum (Fleeceflower Root)

Characterization of Proanthocyanidins in Stems of Polygonum multiflorum Thunb as Strong Starch Hydrolase inhibitors

Characterzation of polyphenolic compounds in the stems of P. multiflorum was conducted using HPLC, high resolution LC-MS and LC-MSⁿ. Proanthocyanidins in particular were isolated in 4.8% yield using solvent extraction followed by Sephadex LH-20 fraction ation. HPLC analysis using a diol column revealed oligomers (from dimer to nonamer) as minor components, with (epi)catechin monomeric units predominating, and oligomers with higher degree of polymerization being dominant. Thiolysis treatment of the proanthocyanidins using mercaptoacetic acid produced thioether derivatives of (epi)catechin as the major product and a mean value of the degree of polymerization of 32.6 was estimated from the ratio of terminal and extension units of the (epi)catechin.

The isolated proanthocyanidins were shown to strongly inhibit α-amylase with an acarbose equivalence (AE) value of 1,954.7 µmol AE/g and inhibit α-glucosidase with an AE value of 211.1 µmol AE/g

Polygonatum sibiricum Delar. ex Redoute extract

Effects of the polygonatum sibiricum polysaccharides on blood glucose in mice and their initial mechanical study

Objective: To explore the effects of the P.sibiricum polysaccharides (PSP) on the blood glucose of mice.

Methods: The normal mice and the hyperglycemic mice are divided into five groups: large, middle, small dose groups of PSP, positive control group, normal control group. Then we measure the blood glucose of all groups and hepatic adenosine-3′, 5′-cyclic monophosphate (camp) of the adrenalin mice model respectively.

Results: The polysaccharides have no significant effects on the blood glucose of normal mice, but could remarkably decrease it in those of the adrenalin mice model, and the best effect can be reached with the dose of 500 mg per kilogram. And the polysaccharides decrease the amount of hepatic cAMP in the adrenalin mice model at the same time.

Conclusion: The blood glucose ‘s lowering action of PSP closely correlates with its reducing the amount of hepatic cAMP.

Polygonatum sibiricum polysaccharide inhibits high glucose-induced oxidative stress, inflammatory response, and apoptosis in RPE cells

Diabetic retinopathy is one of the major diabetic complications and remains the most common cause of adult blindness among patients with diabetes mellitus . Polygonatum sibiricum polysaccharides (PSP) are a group important component of Polygonatum sibiricum (PS) with anti-diabetic activity. However, the effect and underlying mechanism of PSP on diabetic retinopathy remains unclear. We used high glucose (HG)-stimulated ARPE-19 cells to establish in vitro diabetic retinopathy model. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was performed to evaluate cell viability of ARPE-19 cells. The changes in the ROS production, malondialdehyde (MDA) content, and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were detected to indicate oxidative stress . The secretion levels of tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) were detected by ELISA. The protein levels of TNF-α, IL-8, bcl-2, bax, nuclear Nrf2, and anti-hemeoxygenase-1 (HO-1) were detected by western blot analysis.

Our results showed that HG treatment caused a significant reduction in cell viability of ARPE-19 cells. PSP treatment improve d the reduced cell viability of ARPE-19 cells. PSP also attenuate d HG-induced oxidative stress with decreased ROS production and MDA content, as well as increased the activities of SOD and GPx. In addition, HG significantly increased bax expression and caspase-3 activity , and decreased bcl-2 expression. However, these changes were mitigated by PSP treatment. Furthermore, PSP markedly induced the activation of Nrf2/HO-1 pathway in HG-induced ARPE-19 cells. Knockdown of Nrf2 reversed the protective effects of PSP on HG-induced ARPE-19 cells.

Taken together, these findings indicated that PSP protects ARPE-19 cells from HG-induced oxidative stress, inflammation, and cell apoptosis through regulation of Nrf2/HO-1 signaling pathway.

Poria cocos(Schw.)Wolf extract

Poria cocos Inhibits High glucose-Induced Proliferation of Rat Mesangial Cells

Mesangial cell proliferation is correlated with the progression of renal failure. The purpose of this study was to determine whether a water extract of Poria cocos Wolf (WPC), a well-known medicinal plant, regulates rat mesangial cell proliferation in the presence of high glucose (HG). HG significantly accelerated [³H]-thymidine incorporation, which was inhibited by WPC (1–50 μg/mL) in a dose-dependent manner. Cell migration and fibronectin mRNA expression data also supported the anti-proliferative effect of WPC. Western blot analysis revealed that pretreatment with WPC decreased the expression of cyclins and cyclin-dependent kinases (CDKs) and promoted the expression of p21^waf1/cip1 and p27^kip1. WPC also suppressed HG-induced p38 mitogen-activated protein kinase (p38 MAPK) and extracellular-signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Furthermore, WPC inhibited HG-induced production of dichlorofluorescein (DCF)-sensitive intracellular reactive oxygen species (ROS).

In conclusion, HG promoted mesangial cell proliferation, and WPC inhibited this activity, at least in part, via induction of cell cycle arrest and activation of anti-oxidant properties. Taken together, these results suggest that P. cocos may be a potent regulator of HG-induced proliferation.

Anti-Hyperglycemic Properties of Crude Extract and Triterpenes from Poria cocos

Poria cocos, Bai Fu Ling in Chinese, is used in traditional Chinese medicine to treat diabetes . However, its claimed benefits and mechanism are not fully understood. This study aimed to investigate the effect and action of P. cocos on type 2 diabetes . We first performed phytochemical analysis on the crude extract and factions of P. cocos. P. cocos crude extract at 50 mg/kg body weight or more significantly decreased blood glucose levels in db/db mice. Based on a bioactivity-directed fraction ation and isolation (BDFI) strategy, chloroform fraction and subfractions 4 and 6 of the P. cocos crude extract possessed a blood glucose-lowering effect. Dehydrotumulosic acid, dehydrotrametenolic acid, and pachymic acid were identified from the chloroform sub-fraction s 4, 3, and 2, respectively. Dehydrotumulosic acid had anti-hyperglycemic effect to a greater extent than dehydrotrametenolic acid and pachymic acid.

Mechanistic study on streptozocin- (STZ-) treated mice showed that the crude extract, dehydrotumulosic acid , dehydrotrametenolic acid , and pachymic acid of P. cocos exhibited different levels of insulin sensitizer activity. However, the P. cocos crude extract and triterpenes appeared not to activate PPAR- pathway. Overall, the data suggest that the P. cocos extract and its triterpenes reduce postprandial blood glucose levels in db/db mice via enhanced insulin sensitivity irrespective of PPAR.

An insoluble polysaccharide from the sclerotium of Poria cocos improves hyperglycemia , hyperlipidemia and hepatic steatosis in ob/ob mice via modulation of gut microbiota

Metabolic syndrome characterized by obesity , hyperglycemia and liver steatosis is becoming prevalent all over the world. Herein, a water insoluble polysaccharide (WIP) was isolated and identified from the sclerotium of Poria cocos, a widely used traditional Chinese medicine . WIP was confirmed to be a (1-3)-β-D-glucan with an average Mw of 4.486 × 10⁶ Da by NMR and SEC-RI-MALLS analyses. Furthermore, oral treatment with WIP from P. cocos significantly improved glucose and lipid metabolism and alleviated hepatic steatosis in ob/ob mice. 16S DNA sequencing analysis of cecum content from WIP-treated mice indicated the increase of butyrate-producing bacteria Lachnospiracea, Clostridium.

It was also observed that WIP treatment elevated the level of butyrate in gut, improve d the gut mucosal integrity and activated the intestinal PPAR-γ pathway. Fecal transplantation experiments definitely confirmed the causative role of gut microbiota in mediating the benefits of WIP. It is the first report that the water insoluble polysaccharide from the sclerotium of P. cocos modulates gut microbiota to improve hyperglycemia and hyperlipidemia. Thereby, WIP from P. cocos, as a prebiotic, has the potential for the prevention or cure of metabolic diseases and may elucidate new mechanism for the efficacies of this traditional herbal medicine on the regulation of lipid and glucose metabolism.

Portulaca oleracea L.extract

Anti-diabetic Effect of Portulaca oleracea L. Polysaccharideandits Mechanism in diabetic Rats

diabetes mellitus (DM) is a metabolic syndrome caused by multiple genetic and environmental factors. traditional Chinese medicine preparations have shown a comprehensive and function -regulating characteristic. Purslane (Portulaca oleracea L.) is an annual succulent herb. Currently, there have been some related reports on the treatment of diabetes with purslane.

The current study was designed to separate and purify the polysaccharide, a systematic study of its physical and chemical properties, antioxidant activity , and anti-diabetic mechanism, in order to provide a theoretical basis for the development of drugs of purslane. A crude water soluble polysaccharide extracted from purslane was named CPOP (crude Portulaca oleracea L. polysaccharide). Effects of CPOP on body weight, glucose tolerance test (GTT), fasting blood glucose (FBG), fasting serum insulin (FINS), insulin sensitivity index (ISI), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), methane dicarboxylic aldehyde (MDA), and superoxygen dehydrogenises (SOD) were investigated. The results indicate that the oral administration of CPOP could significantly increase the body weight and significantly improve the glucose tolerance in diabetic rats. Meanwhile, CPOP could significantly reduce the FBG level , and elevate the FINS level and ISI value in diabetic rats. In addition, CPOP could significantly reduce TNF-α and IL-6 levels in diabetic rats; CPOP could also reduce MDA and SOD activities in the liver tissue of diabetic rats. These results suggest that the anti-diabetic effect of CPOP may be associated with its antioxidant and anti-inflammatory effects.

Hypoglycemic and pancreatic protective effects of Portulaca oleracea extract in alloxan induced diabetic rats

Background: Diabetes is a major public health concern. In spite of continuous new drug development to treat diabetes , herbal remedies remain a potential adjunct therapy to maintain better glycemic control while also imparting few side-effects. Portulaca oleracea has been traditionally used to manage several diseases due to the anti-oxidant and anti-atherogenic effects it imparts. To better understand the mechanisms associated with potential protective effect of P. oleracea extract against diabetes , alloxan-induced diabetic rats were used in this study.

Methods: Forty Wistar rats (male, 7–8-wk-old, 140–160 g) were divided into four groups (n = 10/group): Group I (control), Group II (P. oleracea-treated; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks), Group III (diabetic control; daily IP injection of alloxan [at 75 mg/kg] for 5 days) and Group IV (P. oleracea-pre-treated diabetic ; gavaged with P. oleracea extract daily [at 250 mg/kg] for 4 weeks and then daily IP injection of alloxan [at 75 mg/kg] for 5 days). body weight, food consumption, blood (serum) levels of glucose , C peptide, Hb A1C, insulin , tumor necrosis factor (TNF)-α and interleukin (IL)-6 were determined for all groups.

Results: The results indicated that while Hb A1C, serum levels of glucose , TNF-α and IL-6 were all significantly decreased in the P. oleracea-pre-treated diabetic rats, these hosts also had significant increases in C peptide and insulin compared to levels in the counterpart diabetic rats. These results were confirmed by the histopathological assessments which showed marked improve ment of the destructive effect on pancreatic islet cells induced by alloxan.

Conclusion: P. oleracea extract is a general tissue protective and regeneartive agent, as evidenced by increasing β-cell mass and therefore improve d the glucose metabolism . Thus, stimulation of Portulaca oleracea signaling in β- cells may be a novel therapeutic strategy for diabetes prevention.

Prunella vulgaris L.

antihyperglycemic activity of Prunella vulgaris L. in streptozotocin-induced diabetic mice

Prunella vulgaris L. (Labiatae) has been reported to have a wide range of health benefits in oriental medicine , This study for the first time is to examine the antihyperglycemic effects of P, vulgaris in streptozotocin (STZ) – induced diabetic ICR mice (STZ diabetic mice). The effects of P. vulgaris L. aqueous-ethanol extract (PVEI on blood glucose , exogenous insulin sensitivity and plasma insulin levels were investigated. In four doses of extracts from the spikes of P. vulgaris, extract at dose of 100 mg/kg significantly suppressed the rise in blood glucose after 30 min in the acute glucose tolerance test. Furthermore, this dose was applied in the fellow experiments.

A significant decrease in blood glucose levels was observed after treatment of PVE. A combination of PVE and glibenclamide produced a greater effect in blood glucose level than using glibenclamide or PVE alone. PVE enhanced and prolonged the antihyperglycemic effects of exogenous insulin on STZ diabetic mice. plasma insulin levels were increased with glibenclamide treatment in STZ diabetic mice, whereas such effect was not observed with PVE.

These results indicated that P. vulgaris enhances the antihyperglycemic effects of exogenous insulin without stimulating insulin secretion, indicating that insulin sensitivity is increased in STZ diabetic mice.

Psidium guajava Linn. extract

Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats

This study investigated the effect of aqueous and ethanol soluble solid extracts of guava (Psidium guajava Linn.) leaves on hypoglycemia and glucose metabolism in type 2 diabetic rats. Low-dose streptozotocin (STZ) and nicotinamide were injected into Sprague-Dawley (SD) rats to induce type 2 diabetes . Acute and long-term feeding tests were carried out, and an oral glucose tolerance test (OGTT) to follow the changes in plasma glucose and insulin levels was performed to evaluate the antihyperglycemic effect of guava leaf extracts in diabetic rats.

The results of acute and long-term feeding tests showed a significant reduction in the blood sugar level in diabetic rats fed with either the aqueous or ethanol extract of guava leaves (p < 0.05). Long-term administration of guava leaf extracts increased the plasma insulin level and glucose utilization in diabetic rats. The results also indicated that the activities of hepatic hexokinase, phosphofructokinase and glucose -6-phosphate dehydrogenase in diabetic rats fed with aqueous extracts were higher than in the normal diabetic group (p < 0.05). On the other hand, diabetic rats treated with the ethanol extract raised the activities of hepatic hexokinase and glucose -6-phosphate dehydrogenase (p < 0.05) only. The experiments provided evidence to support the antihyperglycemic effect of guava leaf extract and the health function of guava leaves against type 2 diabetes .

Pterocarpus marsupium Roxb

Mechanistic understanding of PtyroneTM: A plant based natural anti diabetic product

Objective: To investigate the combinatorial effect of hydroalcoholic extracts of Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. plants prospective to diabetes management.

Methods: Taking a lead from the scientific literature, in silico studies have also been designed for the screening of anti-diabetic targets against andrographolide and pterostilbene compounds followed by in vivo studies from Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. Furthermore, the diabetes was induced by STZ model and the impact of Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. have been conformed by relative expression studies by qPCR.

Results: Our results have shown that andrographolide and pterostilbene are SGLT2 inhibitors and selective PPARγ agonists in in silico studies. Later, during in vivo mRNA expression studies confirming the same pattern. The findings of the study has shown to overcome the common knowledge of the only C–glycoside based molecules inhibiting the SGLT2.

Conclusions: The possible mechanism for PtyroneTM in the management of diabetes could be a selective PPARγ agonist, GLUT4 translocation and SGLT2 inhibition molecule.

quercetin

antidiabetic effects of quercetin in streptozocin-induced diabetic rats

Effects of the intraperitoneal injection of quercetin in streptozocin-induced diabetic and normal rats were investigated and compared. Although quercetin had no effect on plasma glucose level of normal animals, it significantly and dose-dependently decreased the plasma glucose level of streptozocin-induced diabetic rats. glucose tolerance tests of the diabetic animals approached those of normal rats, their plasma cholesterol and triglycerides were reduced significantly, while their hepatic glucokinase activity was significantly increased upon quercetin treatment . In normal rats, quercetin did not affect the glucose tolerance test, but resulted in an increase of plasma cholesterol and triglycerides and a decrease in hepatic glucokinase activity. No significant pathologic changes were noted in hepatocytes or kidney tubules and glomeruli, while the number of pancreatic islets significantly increased in both treated normal and diabetic groups.

It is concluded that quercetin, a flavonoid with antioxidant properties brings about the regeneration of the pancreatic islets and probably increases insulin release in streptozocin-induced diabetic rats; thus exerting its beneficial antidiabetic effects. However, it may be of little value in normoglycemic animals.

quercetin-3-O-glycoside

Unraveling the inhibition of intestinal glucose Transport by Dietary Phenolics: A Review

Background: glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium – dependent glucose transporter (SGLT1 ) and the facilitated-transporter glucose transporter (GLUT2 ). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2.

Results: Phenolic concentrations above 100 μM has been proved to successfully inhibit the glucose transport. Generally, the aglycones quercetin, myricetin, fisetin or apigenin have been reported to strongly inhibit GLUT2 , while quercetin-3-O-glycoside has been demonstrated to be more effective in SGLT1. Additionally, epigallocatechin as well as epicatechin and epigallocatechin gallates were observed to be inhibited on both SGLT1 and GLUT2.

Conclusion: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and aglycones exert significant inhibition , and also the inhibition of phenolic acids sremains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters . A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interactions is also included.

quercetin-4-O-glucoside (Q4′glc)

Extracts and flavonoid s from onion inhibit the intestinal sodium-coupled glucose transporter 1 (SGLT1 ) in vitro but show no anti-hyperglycaemic effects in vivo in normoglycaemic mice and human volunteers

Ranawara (Cassia auriculata)

α-glucosidase inhibitory activity of Some Sri Lanka Plant Extracts, One of Which, Cassiaauriculata, Exerts a Strong antihyperglycemic Effect in Rats Comparable to the therapeutic Drug Acarbose

Some Sri Lanka plant stuffs were examined regarding in vitro and in vivo α-glucosidase (AGH) inhibitory action s . According to the results, water extracts and methanol extracts of dried fruits of Nelli (Phylanthus embelica), methanol extracts of dried flowers of Ranawara (Cassiaauriculata), and water extracts of latex of Gammalu (Pterocarpus marsupium) were found to have a potential AGH inhibitory activity . In particular, Ranawara methanol extract showed the strongest AGH inhibitory activity in vitro preferably on maltase giving an IC₅₀ value of 0.023 mg/mL and inhibited the maltase activity competitively.

As a result of single oral administration of Ranawara (C.auriculata) methanol extract in Sprague−Dawley rats, a significant and potent lowering of blood glycemic response toward maltose ingestion was observed at 30 min after dosing of 5 mg/kg, thus, concurrently suppressed insulin activity. The ED₅₀ of the extract (4.9 mg/kg) clearly indicated that the antihyperglycemic effect was as potent as that of therapeutic drug, acarbose (ED₅₀ 3.1 mg/kg).

Resveratrol

Pilot Study of Resveratrol in Older Adults With impaired glucose Tolerance

Resveratrol, a plant-derived polyphenol, has shown promising effects on insulin sensitivity and glucose tolerance in animal models and is also reported to have cardioprotective properties, but human studies are limited. In a pilot study, we tested the hypothesis that resveratrol improves glucose metabolism and vascular function in older adults with impaired glucose tolerance (IGT).

Methods: Ten subjects aged 72 ± 3 years (M ± SD) with IGT were enrolled in a 4-week open-label study of resveratrol (daily dose 1, 1.5, or 2 g). Following a standard mixed meal (110 g carbohydrate, 20 g protein, 20 g fat), we measured 3-hour glucose and insulin area under the curve (AUC), insulin sensitivity (Matsuda index), and secretion (corrected insulin response at 30 minutes). Endothelial function was assessed by reactive hyperemia peripheral arterial tonometry (reactive hyperemia index) before and 90 minutes postmeal. Results did not differ by dose, so data were combined for analysis.

Results: At baseline, body mass index was 29 ± 5 kg/m², fasting plasma glucose 110 ± 13 mg/dL, and 2-hour glucose 183 ± 33 mg/dL. After 4 weeks of resveratrol, fasting plasma glucose was unchanged, but peak postmeal (185 ± 10 vs 166 ± 9 mg/dL, p = .003) and 3-hour glucose AUC (469 ± 23 vs 428 ± 19, p = .001) declined. Matsuda index improve d (3.1 ± 0.5 vs 3.8 ± 0.5, p = .03), and corrected insulin response at 30 minutes was unchanged (0.6 ± 0.1 vs 0.5 ± 0.5, p = .49). There was a trend toward improve d postmeal reactive hyperemia index (baseline vs resveratrol postmeal delta −0.4 ± 0.2 vs 0.2 ± 0.3, p = .06). Weight, blood pressure, and lipids were unchanged.

Conclusions: At doses between 1 and 2 g/day, resveratrol improves insulin sensitivity and postmeal plasma glucose in subjects with IGT. These preliminary findings support the conduct of larger studies to further investigate the effects of resveratrol on metabolism and vascular function .

improved glucose homeostasis in Obese Mice Treated With Resveratrol Is Associated With Alterations in the Gut Microbiome

Oral administration of resveratrol is able to improve glucose homeostasis in obese individuals. Herein we show that resveratrol ingestion produces taxonomic and predicted function al changes in the gut microbiome of obese mice. In particular, changes in the gut microbiome were characterized by a decreased relative abundance of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia and an increased relative abundance of Bacteroides and Parabacteroides.

Moreover, fecal transplantation from healthy resveratrol-fed donor mice is sufficient to improve glucose homeostasis in obese mice, suggesting that the resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol.

Resveratrol inhibits glucose metabolism in human ovarian cancer cells

Objectives: Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells . Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response.

Methods: Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. glucose uptake , lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment .

Results: We show here that epithelial ovarian cancer cells are highly sensitive to glucose -deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR , two signals that increase glucose uptake and the rate limiting steps in glycolysis .

Conclusions: Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer.

α-glucosidase inhibitory effect of resveratrol and piceatannol

Dietary polyphenols have been shown to inhibit α-glucosidase , an enzyme target of some antidiabetic drugs. Resveratrol, a polyphenol found in grapes and wine, has been reported to inhibit the activity of yeast α-glucosidase . This triggered our interest to synthesize analogs and determine their effect on mammalian α-glucosidase activity . Using either sucrose or maltose as substrate resveratrol, piceatannol and 3′-hydroxypterostilbene showed strong inhibition of mammalian α-glucosidase activity ; pinostilbene, cis-desoxyrhapontigenin and trans-desoxyrhapontigenin had moderate inhibition . Compared to acarbose (IC50 3–13 μg/ml), piceatannol and resveratrol inhibited mammalian α-glucosidase to a lesser extent (IC50 14–84 and 111–120 μg/ml, respectively). 3′-Hydroxypterostilbene (IC50 105–302 μg/ml) was 23–35-fold less potent than acarbose.

We investigated the effect of piceatannol and resveratrol on postprandial blood glucose response in high-fat-fed C57Bl/6 mice. Animals administered resveratrol (30 mg/kg body weight [BW]) or piceatannol (14 mg/kg BW) 60 min prior to sucrose or starch loading had a delayed absorption of carbohydrates, resulting in significant lowering of postprandial blood glucose concentrations , similar to the antidiabetic drug acarbose, while no significant effect was observed with the glucose-loaded animals. Our studies demonstrate that the dietary polyphenols resveratrol and piceatannol lower postprandial hyperglycemia and indicate that inhibition of intestinal α-glucosidase activity may be a potential mechanism contributing to their antidiabetic property.

Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis

Although the regular consumption of resveratrol has been known to improve glucose homeostasis and reverse insulin resistance in type 2 diabetes mellitus (T2DM), the reported results are inconsistent. Thus, we aimed to assess the effects of resveratrol on glycemic control and insulin sensitivity among patients with T2DM. We searched for relevant articles published until June 2017 on PubMed-Medline, Embase, Cochrane Library, and Web of Science. Randomized controlled trials in T2DM patients administered with resveratrol as intervention were included. After study selection, quality assessment and data extraction were performed independently by two authors, and STATA and RevMan software were used for statistical analysis. Nine randomized controlled trials involving 283 participants were included. Meta-analysis showed that resveratrol significantly improve d the fasting plasma glucose ( −0.29 mmol/l, 95% CI: −0.51, −0.06, p < 0.01) and insulin levels (−0.64 U/mL, 95% CI: −0.95, −0.32, p < 0.0001).

The drug also reduced homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, and diastolic blood pressure among participants with T2DM. The changes in hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were negligible. Subgroup analysis comparing the resveratrol supplementation doses of < 100 mg/d versus ≥ 100 mg/d revealed a significant difference in fasting plasma glucose . In particular, the latter dose presented more favorable results.

This meta-analysis provides evidence that supplementation of resveratrol may benefit management of T2DM.

Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials

Background: The results of human clinical trials investigating the effects of resveratrol on glucose control and insulin sensitivity are inconsistent.

Objective: We aimed to quantitatively evaluate the effects of resveratrol on glucose control and insulin sensitivity .

Design: We performed a strategic literature search of PubMed, Embase, MEDLINE, and the Cochrane Library (updated to March 2014) for randomized controlled trials that estimated the effects of resveratrol on glucose control and insulin sensitivity . Study quality was assessed by using the Jadad scale. Weighted mean differences were calculated for net changes in glycemic measures by using fixed-effects or random-effects models. We performed prespecified subgroup and sensitivity analyses to evaluate potential heterogeneity. Meta-regression analyses were conducted to investigate dose effects of resveratrol on fasting glucose and insulin concentrations in nondiabetic subjects.

Results: Eleven studies comprising a total of 388 subjects were included in this meta-analysis. Resveratrol consumption significantly reduced fasting glucose , insulin , glycated hemoglobin, and insulin resistance (measured by using the homeostatic model assessment) levels in participants with diabetes . No significant effect of resveratrol on glycemic measures of nondiabetic participants was found in the meta-analysis. Subgroup and sensitivity analyses indicated that the pooled effects of resveratrol on fasting glucose and insulin concentrations in nondiabetic participants were not affected by body mass index, study design, resveratrol dose, study duration, or Jadad score.

Conclusions: Resveratrol significantly improves glucose control and insulin sensitivity in persons with diabetes but does not affect glycemic measures in nondiabetic persons. Additional high-quality studies are needed to further evaluate the potential benefits of resveratrol in humans .

Rhodiola rosea L extract

antihyperglycemic action of rhodiola-aqeous extract in type1-like diabetic rats

Background: Rhodiola rosea (Rhodiola) is a plant in the Crassulaceae family that grows in cold regions of the world. It is mainly used in clinics as an adaptogen. Recently, it has been mentioned that Rhodiola increases plasma β-endorphin to lower blood pressure. Thus, the present study aims to investigate the antidiabetic action of Rhodiola in relation to opioids in streptozotocin-induced diabetic rats (STZ-diabetic rats).

Methods: In the present study, the plasma glucose was analyzed with glucose oxidase method, and the determination of plasma β-endorphin was carried out using a commercially available enzyme-linked immunosorbent assay. The adrenalectomy of STZ-diabetic rats was used to evaluate the role of β-endorphin. In addition, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to investigate mRNA and protein expressions.

Results: Rhodiola-water extract dose-dependently lowered the plasma glucose in STZ-diabetic rats and this action was reversed by block ade of opioid μ-receptors using cyprodime. An increase of plasma β-endorphin by rhodiola-water extract was also observed in same manner. The plasma glucose lowering action of rhodiola-water extract was attenuate d in bilateral adrenalectomized rats. In addition, continuous administration of rhodiola-water extract for 3 days in STZ-diabetic rats resulted in an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle and a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver. These effects were also reversed by block ade of opioid μ-receptors.

Conclusions: Taken together, rhodiola-water extract improves hyperglycemia via an increase of β-endorphin secretion from adrenal gland to activate opioid μ-receptors in STZ-diabetic rats.

Hypoglycemic and hypolipidaemic activities of polysaccharides from Rhodiola rosea in KKAy mice

Hyperglycaemia and hyperlipidaemia are major risk factors for developing coronary artery diseases and atherosclerosis; therefore, therapeutic drugs must be developed to prevent these conditions. Rhodiola rosea is widely used in traditional Chinese medicine . In this study, R. rosea polysaccharides (RPs) were prepared by hot water extraction , and their hypoglycaemic and hypolipidaemic activities were evaluated. KKAy mice were gavaged once daily with either distilled water (control) or RPs for 6 weeks. Intragastric RP administration improve d oral glucose tolerance, decreased serum insulin levels , serum triglycerides (TG), cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) and increased high-density lipoprotein cholesterol (HDL-c).

Results suggest that RPs exhibit high hypoglycaemic and hypolipidaemic activities and could be explored as possible therapeutic agents for diabetes mellitus .

Rhodiola crenulata extract suppresses hepatic gluconeogenesis via activation of the AMPK pathway

Background: Rhodiola, a popular herb, has been used for treating high altitude sicknesses, depression, fatigue, and diabetes . However, the detailed mechanisms by which Rhodiola crenulata function s in the liver need further clarification.

Purpose: The current study was designed to examine the effects of Rhodiola crenulata root extract (RCE) on hepatic glucose production.

Methods: Human hepatoma HepG2 cells were treated with RCE for 6 h. glucose production, the expression level of p-AMPK , and the expression of key gluconeogenic genes were measured. The effects of RCE were also studied in Sprague–Dawley (SD) rats. The efficacy and underlying mechanism of RCE in the liver were examined.

Results: RCE significantly suppressed glucose production and gluconeogenic gene expression in HepG2 cells while activating the AMPK signaling pathway. Interestingly, RCE-suppressed hepatic gluconeogenesis was eliminated by an AMPK -specific inhibitor , but not by the PI3K/AKT-specific inhibitor . In addition, oral administration of RCE significantly increased phosphorylated AMPK levels and inhibited gluconeogenic gene expression in the rat liver. Furthermore, RCE treatment also decreased plasma glucose concentration in rats.

Conclusion: We present in vitro and in vivo evidence that RCE might exert the glucose -lowering effect partly by inhibiting hepatic gluconeogenesis through activating the AMPK signaling pathway. These findings provide evidence that Rhodiola crenulata may be helpful for the management of type II diabetes .

Rosa laevigata Michx.extract

Fruits of Rosa laevigata and its bio-active principal sitostenone facilitate glucose uptake and insulin sensitivity in hepatic cells via AMPK /PPAR-γ activation

Background: Fruits of Rosa laevigata Michx is commonly used in traditional Chinese medicine for treating of spleen deficiency, chronic diarrhea, and chronic urinary tract infection. Recently, fruits of R. laevigate have been shown to have renal protective effects in diabetic rats. However, up to now, no studies have been reported on the anti-hyperglycemic or anti-diabetic effect of R. laevigata or its derived compounds.

Purpose: Therefore, this study investigated the anti-diabetic effect of ethanol extract of R. laevigata (EtRL) fruits, its derivate sub-fractions , and pure compounds in terms of glucose -lowering effect on hyperglycemia -induced hepatic cells in vitro.

Methods: We investigated the anti-hyperglycemic effect of EtRL and its derivate sub-fractions (water, n-butanol, ethyl acetate, and n-hexane), and its major bioactive compound, sitostenone, in normal and high glucose -induced insulin -resistant hepatic HepG2 cells using in vitro DNS glucose uptake and Western blotting assays.

Results: Treatment with EtRL and its derivate sub-fractions significantly increased glucose uptake by hepatic cells. Besides, co-treatment with insulin further improve d glucose uptake in insulin -resistant cells. Notably, compared with all soluble fraction s , the n-hexane sub-fraction displayed the strongest activity in the context of glucose consumption. Furthermore, sitostenone, a primary bioactive compound was isolated from n-hexane sub-fraction by bioactivity -guided fraction ation procedure. Sitostenone treatment significantly increased glucose uptake , whereas there was no further increase when co-treatment with insulin . Indeed, sitostenone significantly increased glucose uptake and promote insulin sensitivity in insulin -resistant cells. Further analysis revealed that sitostenone activates proteins involved in the insulin signal transduction pathway, including insulin receptor substrate-1 (IRS-1), AKT, and glycogen synthase kinase 3 β (GSK3β). It was also found that sitostenone provoked glucose uptake in insulin -resistant cells via peroxisome proliferator-activated receptor-γ (PPAR-γ) and AMP-activated protein kinase (AMPK ) activation, which facilitates up-regulation of glucose transporters , GLUT2 and GLUT4 in the cell membrane and down-regulation of Forkhead box protein O1 (FOXO1) in the nucleus.

Conclusion: This study demonstrating that sitostenone, a steroid-like compound from fruits of R. laevigata has a promising ability to promote glucose uptake and repairs insulin resistance in hepatic cells.

Salvia miltiorrhiza Bge extract

Hypoglycemic Effects of a Standardized Extract of Salvia miltiorrhiza Roots in Rats

Background and Aims: Salvia miltiorrhiza Bunge (Labiatae) is a Chinese medicinal plant, the dried roots of which (known as Dan-Shen) have been used for hundreds of years in the treatment of a series of ailments, including hyperglycemia . This study was designed to evaluate the hypoglycemic effect of a new, standardized extract of S. miltiorrhiza.

Materials and Methods: S. miltiorrhiza extract (containing 21% total tanshinones and 3.7% tanshinone IIA) was administered acutely and intragastrically at the doses of 0, 50, 100, and 200 mg/kg to male, healthy, fasted Wistar rats 60 min before the intragastric infusion of a bolus of starch (3 g/kg; a semi-naturalistic experimental condition) (Experiment 1) or glucose (2 g/kg) (Experiment 2).

Results: In both experiments, treatment with S. miltiorrhiza extract produced a dose-related decrease in glycemia, evidenced in terms of reduction of peak value and/or area under the curve of the time-course of glycemia. The effect of S. miltiorrhiza extract occurred at doses devoid of any behavioral toxicity in rats.

Conclusion: The results of this study suggest that the hypoglycemic effect of S. miltiorrhiza extract was likely secondary to an action on carbohydrate metabolism . These results are consistent with several preclinical and clinical data and add further support to the hypothesis that S. miltiorrhiza extracts may act as effective anti-hyperglycemic remedies.

Schisandrae chinensis Fructus

antidiabetic Effect of Schisandrae Chinensis Fructus Involves inhibition of the sodium glucose cotransporter

Schisandrae Chinensis Fructus (SCF), the fruit of Schisandra chinensis (Turcz.) Baill. (family Schisandraceae) is traditionally used as a tonic and antidiabetic agent in Asia. In this study, SCF was investigated for its effects on sodium glucose cotransporters 1 and 2 (SGLT 1 and 2) expressed in a COS-7 cell line for its specificity in inhibiting SGLT2, which is a novel mechanism to screen for potential antidiabetic agents . Using a bioassay-guided fraction, we then tried to isolate and identify the active fraction(s)/component(s). The ethanol extract of SCF at a concentration of 1 mg/mL significantly inhibited 89% of SGLT1 and 73% of SGLT2 activities in a [¹⁴C]-α-methyl-d-glucopyranoside ([¹⁴C]-AMG) uptake assay.

Fraction of the ethanol extract yielded nine fractions, of which F8, at a concentration of 1 mg/mL, was specific in inhibiting SGLT 2 (42% inhibition, P < 0.001), without inhibiting SGLT 1. Using LC/MS-MS, three compounds, deoxyschisandrin, schisandrin B (γ-schisandrin) and schisandrin were identified in F8 and their amounts quantified. However, subsequent evaluation in the [¹⁴C]-AMG uptake assay showed that these three compounds failed to inhibit SGLT 2 activity indicating that the SGLT active component(s) from SCF have yet to be identified.

silybin

Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins

Silybin, the major flavonoid of Silybum marianum, is widely used to treat liver diseases such as hepatocellular carcinoma and cirrhosis-associated insulin resistance. Research so far has focused on its anti-oxidant properties. Here, we demonstrate that silybin and its derivative dehydrosilybin inhibit glucose uptake in several model systems. Both flavonoids dose-dependently reduce basal and insulin-dependent glucose uptake of 3T3-L1 adipocytes, with dehydrosilybin showing significantly stronger inhibition. However, insulin signaling was not impaired, and immunofluorescence and subcellular fraction showed that insulin-induced translocation of GLUT4 to the plasma membrane is also unchanged.

Likewise, hexokinase activity was not affected suggesting that silybin and dehydrosilybin interfere directly with glucose transport across the PM. Expression of GLUT4 in CHO cells counteracted the inhibition of glucose uptake by both flavonoids. Moreover, treatment of CHO cells with silybin and dehydrosilybin reduced cell viability which was partially rescued by GLUT4 expression. Kinetic analysis revealed that silybin and dehydrosilybin inhibit GLUT4 -mediated glucose transport in a competitive manner with K_i = 60 and 116 µM, respectively.

We conclude that silybin and dehydrosilybin inhibit cellular glucose uptake by directly interacting with GLUT transporters. Glucose starvation offers a novel explanation for the anti-cancer effects of silybin.

Sophora flavescens

sodium–glucose cotransporter 2 (SGLT2 ) inhibitors from natural products: Discovery of Next-Generation antihyperglycemic agents

diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium–glucose cotransporter 2 (SGLT2 ) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes.

Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

sophoraflavanone

sodium–glucose cotransporter 2 (SGLT2 ) inhibitors from natural products: Discovery of Next-Generation antihyperglycemic agents

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin action s , leading to the development of life-threatening complications . Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safe r antidiabetic drugs. Since the important roles of the sodium –glucose cotransporter 2 (SGLT2 ) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes.

Syzygium aromaticum

Effects of Syzygium aromaticum-Derived Triterpenes on Postprandial blood glucose in Streptozotocin-Induced diabetic Rats Following Carbohydrate Challenge

Purpose: Recent reports suggest that the hypoglycaemic effects of the triterpenes involve inhibition of glucose transport in the small intestine. Therefore, the effects of Syzygium spp-derived triterpenes oleanolic acid (OA) and maslinic acid (MA) were evaluated on carbohydrate hydrolyzing enzymes in STZ-induced diabetic rats and consequences on postprandial hyperglycaemia after carbohydrate loading.

Methods: We determined using Western blot analysis the expressions of α-amylase and α-glucosidase and glucose transporters SGLT1 and GLUT2 in the small intestine intestines isolated from diabetic rats treated with OA/MA for 5 weeks. In vitro assays were used to assess the inhibitory activities of OA and MA against α-amylase , α-glucosidase and sucrase.

Results: OA and MA ameliorated postprandial hyperglycemia in carbohydrate loaded diabetic rats as indicated by the significantly small glucose area under the curve (AUC) in treated diabetic animals compared with that in untreated diabetic rats. Western blotting showed that OA and MA treatment not only down-regulated the increase of SGLT1 and GLUT2 expressions in the small intestine of STZ-induced diabetic rats, but also inhibited small intestine α-amylase , sucrase and α-glucosidase activity . IC50 values of OA against α-amylase (3.60 ± 0.18 mmol/L), α-glucosidase (12.40 ± 0.11 mmol/L) and sucrase (11.50 ± 0.13 mmol/L) did not significantly differ from those of OA and acarbose.

Conclusions: The results of suggest that OA and MA may be used as potential supplements for treating postprandial hyperglycemia.

Taraxacum mongolicum Hand.-Mazz.extract

Study on Combined Hypoglycemic Effect of Wild Taraxacum mongolicum and Rhodiola sachalinensis on diabetic Mice

Objective: The aim was to study the combined hypoglycemic effect of wild Taraxacum mongolicum and Rhodiola sachalinensis in Changbai Mountain on diabetic mice.

Method: Thirty kunming mice were selected,among which 24 became diabetes model by man-made methods.Thirty mice were divided into five groups,including blank control group,alloxan group,Rhodiola sachalinensis group,wild Taraxacum mongolicum group and combined dose group.The mice in Rhodiola sachalinensis group,wild Taraxacum mongolicum group and combined dose group received intragastric administration of self-made water decoction for five days continuously,one time per day,and then their blood glucose were detected.

Result: The blood glucose of diabetic mice in each group all lowered five days after the intragastric administration,which had an extremely significant difference from the alloxan group(P0.01).

Conclusion: Rhodiola sachalinensis, wild Taraxacum mongolicum as well as the combined treatment of Rhodiola sachalinensis and wild Taraxacum mongolicum all had significant hypoglycemic effect on diabetic mice.

tangeretin

inhibitory Effect of Tangeretin and Cardamonin on Human intestinal SGLT1 activity In Vitro and blood glucose levelS in Mice In Vivo

Rapid postprandial blood glucose elevation can cause lifestyle-related diseases , such as type II diabetes . The absorption of food-derived glucose is primarily mediated by sodium /glucose cotransporter 1 (SGLT1). Moderate SGLT1 inhibition can help attenuate postprandial blood glucose elevation and prevent lifestyle-related diseases. In this study, we established a CHO cell line stably expressing human SGLT1 and examined the effects of phytochemicals on SGLT1 activity. Among the 50 phytochemicals assessed, tangeretin and cardamonin inhibited SGLT1 activity. Tangeretin and cardamonin did not affect the uptake of L-leucine, L-glutamate, and glycyl-sarcosine. Tangeretin, but not cardamonin, inhibited fructose uptake , suggesting that the inhibitory effect of tangeretin was specific to the monosaccharide transporter , whereas that of cardamonin was specific to SGLT1.

Kinetic analysis suggested that the suppression of SGLT1 activity by tangeretin was associated with a reduction in V_max and an increase in K_m, whereas suppression by cardamonin was associated with a reduction in V_max and no change in K_m. Oral glucose tolerance tests in mice showed that tangeretin and cardamonin significantly suppressed the rapid increase in blood glucose levels.

In conclusion, tangeretin and cardamonin were shown to inhibit SGLT1 activity in vitro and lower blood glucose level in vivo.

Taurine

Characterization of Taurine as inhibitor of sodium glucose transporter

The most characterized roles of taurine include osmoregulator and membrane-stabilizing activities. However, much remains to be understood about its role in human physiology concerning its anti-hyperglycemic effect. Studies indicate that taurine-supplemented diet helps alleviate hyperglycemia or insulin resistance. This hypoglycemic effect has been postulated as taurine helping to increase the excretion of cholesterol.

Alternatively, this study investigated the effect of taurine on glucose transporter using heterologous expression of sodium –glucose transporter -1 (SGLT-1). SGLT-1 was expressed in Xenopus oocytes and the effect of taurine on the expressed SGLT-1 was analyzed utilizing 2-deoxy-D-glucose (2-DOG) uptake and voltage clamp studies. In the oocytes expressing SGLT-1, taurine was shown to inhibit SGLT-1 activity compared to the non-treated controls in a dose-dependent manner. In the presence of taurine, the glucose uptake was greatly inhibited and the glucose -generated current was significantly inhibited. Synthetic taurine analogs were also shown to be effective in inhibiting SGLT-1 activity in a manner comparable to taurine.

These effects might offer a promising opportunity in designing function al foods with anti-hyperglycemic potential by supplementing taurine and its analogs to the diet.

theaflavins

Theaflavins inhibit glucose transport across Caco-2 cells through the downregulation of the Ca2+/AMP-activated protein kinase-mediated glucose transporter SGLT1

The study investigated the effects of theaflavins, which are intestinal ly non-absorbable compounds, on intestinal glucose transport in Caco-2 cells. ¹³C₆–glucose transport experiments clearly revealed that glucose transport across Caco-2 cells was significantly (p < 0.01) inhibited by theaflavins. When Caco-2 cells were treated with 40 μM theaflavins for 24 h, the expression of SGLT1 expression was significantly (p < 0.05) suppressed , whereas no difference in GLUT2 expression was observed. The theaflavin-induced inhibition of glucose transport was reversed by the inhibition of influx routes mediated by OATP and MCT transporters . A Wes analysis established that theaflavin-induced phosphorylation of AMPK was significantly (p < 0.05) suppressed by the inhibition of endoplasmic reticulum Ca²⁺-release and CaMKK β.

These findings demonstrated for the first time that theaflavins can inhibit glucose transport across Caco-2 cell monolayers through the suppression of SGLT1 expression partly via the activation of the intracellular Ca²⁺/CaMKK β/AMPK signaling pathway.

Thymus praecox

The methanolic extract of Thymus praecox subsp. skorpilii var. skorpilii restores glucose homeostasis , ameliorates insulin resistance and improves pancreatic β-cell function on streptozotocin/nicotinamide-induced type 2 diabetic rats

Thymus praecox subsp. skorpilii var. skorpilii (syn. Thymus praecox subsp. jankae (Celak.) Jalas) is consumed as a Turkish folk medicine for the treatment of spasm, sore throat and shortness of breath, also having strong antioxidant activity and the leaves of the plant have been utilized for the treatment of diabetes as the decoction in Turkey.

Aim of the study: In the present study, we aimed to investigate the potential mechanism of antidiabetic action of Thymus praecox subsp. skorpilii var. skorpilii methanolic extract (TPSE) on streptozotocin (STZ)/nicotinamide (NA)-induced type 2 diabetic rats.

Materials and methods: Sprague Dawley rats were randomly divided into four groups; control, diabetes , TPSE (100 mg/kg b.w, p.o.) and metformin group (400 mg/kg b.w, p.o.). diabetes was established in all groups except control group by 55 mg/kg STZ (i.p.) for once 15 min after 100 mg/kg NA injection. 3 days after STZ/NA injection, treatments were administered for three weeks and then rats were decapitated; tissue and blood samples were obtained for measuring the level of glucose transporters (both GLUTs and sodium glucose co-transporters (SGLTs)), enzymes related to glucose (Hexokinase (HK), phosphoenolpyruvate carboxykinase (PEPCK), α-glucosidase ) and lipid metabolism (Acetyl-coenzyme carboxylase (ACC)), AST, ALT, creatinine, insulin , anti-inflammatory (IL-10) and inflammatory (TNF-α, IL-1β, IL-6) cytokines, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPAR-γ) and glucagon like peptide-1 (GLP-1). Histopathological alterations of the pancreas were examined.

Results: After three weeks of treatment , TPSE has exhibited a significant reduction of plasma levels of the proinflammatory cytokines. Besides, TPSE treatment elevated plasma insulin levels and normalized blood glucose levels . Moreover, it improve d the values of AMPK in liver and GLP-1 in pancreas. Increased α-glucosidase , PEPCK, GLUT-2 and SGLTs levels with the induction of diabetes considerably lowered with TPSE treatment . Especially on SGLT-2, TPSE achieved a more prominent decrease. After the atrophy in Langerhans islets due to diabetes induction, treatment was found to prevent the damage of islets.

Conclusions: Based on the findings presented here, it has been concluded that TPSE has marked antidiabetic effects through various pathways on STZ/NA-induced diabetic rats and it may potentially be used as an effective treatment for type 2 diabetes mellitus (T2DM). Further research on isolation of the bioactive components is underway.

Tiliroside

Tiliroside, a glycosidic flavonoid , inhibits carbohydrate digestion and glucose absorption in the gastrointestinal tract

Scope: Recent studies have reported that tiliroside, a glycosidic flavonoid , possesses anti-diabetic activities. In the present study, we investigated the effects of tiliroside on carbohydrate digestion and absorption in the gastro-intestinal tract.

Methods and results: This study showed that tiliroside inhibits pancreatic α-amylase (IC₅₀ = 0.28 mM) in vitro. Tiliroside was found as a noncompetitive inhibitor of α-amylase with K_i values of 84.2 μM. In male ICR mice, the increase in postprandial plasma glucose levels was significantly suppressed in the tiliroside-administered group. Tiliroside treatment also suppressed hyperinsulin emia after starch administration. Tiliroside administration inhibited the increase of plasma glucose levels in an oral glucose tolerance test, but not in an intraperitoneal glucose tolerance test. In human intestinal Caco-2 cells, the addition of tiliroside caused a significant dose-dependent inhibition of glucose uptake . The inhibitory effects of both sodium -dependent glucose transporter 1 (SGLT1 ) and glucose transporter 2 (GLUT2 ) inhibitors (phlorizin and phloretin, respectively) on glucose uptake were significantly inhibited in the presence of tiliroside, suggesting that tiliroside inhibited glucose uptake mediated by both SGLT1 and GLUT2 .

Conclusion: These findings indicate that the anti-diabetic effects of tiliroside are at least partially mediated through inhibitory effects on carbohydrate digestion and glucose uptake in the gastrointestinal tract.

Trichosanthes kirilowii Maxim.extract

Isolation and Hypoglycemic activity of Trichosans A, B, C, D, and E: Glycans of Trichosanthes kirilowii Roots1

The non-dialyzable portion of the water extract of the Oriental crude drug “karokon”, the roots of Trichosanthes kirilowii, was found to reduce the plasma glucose level in mice. activity -guided fractionation of this non-dialyzable portion led to the isolation of five glycans termed as trichosans A, B, C, D and E, showing hypoglycemic actions in normal mice. The main glycan, trichosan A, also exhibited activity in alloxan-induced hypoglycemic mice.

Hypoglycemic effects of Trichosanthes kirilowii and its protein constituent in diabetic mice: the involvement of insulin receptor pathway

Background: Diabetes is a serious chronic metabolic disorder. Trichosanthes kirilowii Maxim. (TK) is traditionally used for the treatment of diabetes in traditional Chinese medicine (TCM ). However, the clinical application of TK on diabetic patients and the hypoglycemic efficacies of TK are still unclear.

Methods: A retrospective cohort study was conducted to analyze the usage of Chinese herbs in patients with type 2 diabetes in Taiwan. glucose tolerance test was performed to analyze the hypoglycemic effect of TK. Proteomic approach was performed to identify the protein constituents of TK. insulin receptor (IR) kinase activity assay and glucose tolerance tests in diabetic mice were further used to elucidate the hypoglycemic mechanisms and efficacies of TK.

Results: By a retrospective cohort study, we found that TK was the most frequently used Chinese medicinal herb in type 2 diabetic patients in Taiwan. Oral administration of aqueous extract of TK displayed hypoglycemiceffects in a dose-dependent manner in mice. An abundant novel TK protein (TKP) was further identified by proteomic approach. TKP interacted with IR by docking analysis and activated the kinase activity of IR. In addition, TKP enhanced the clearance of glucose in diabetic mice in a dose-dependent manner.

Conclusions: In conclusion, this study applied a bed-to-bench approach to elucidate the hypoglycemic efficacies and mechanisms of TK on clinical usage. In addition, we newly identified a hypoglycemic protein TKP from TK. Our findings might provide a reasonable explanation of TK on the treatment of diabetes in TCM.

TKP, a Serine Protease from Trichosanthes kirilowii, Inhibits Cell Proliferation by blocking Aerobic glycolysis in Hepatocellular Carcinoma Cells

Aim of the study: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. TKP is a serine protease extracted from the fruit of Trichosanthes kirilowii. We investigated the impact of TKP on the proliferation of HCC cells and its underlying mechanisms.

Methods: Bel-7402 and HepG2 cell viability and colony formation capacity were evaluated using MTT and colony formation assays, respectively. glucose uptake and lactate production were determined using glucose and lactate assay kits. The mRNA expressions of GLUT1, PDK, LDHA, PKM2, β-catenin, c-Myc, and HnRNPA1 were assessed using real-time PCR analysis. Protein expression and the distribution of PKM2 were examined by western blot assay.

Results: TKP significantly inhibited Bel-7402 and HepG2 cell survival and colony formation capacity. The IC50 values of TKP against Bel-7402 and HepG2 cells were 31.37 ± 1.33 and 27.41 ± 0.81 μg/mL, respectively. TKP restrained aerobic glycolysis . TKP decreased the expression level , nuclear protein level and pyruvate kinase activity of PKM2, whereas overexpression PKM2 reversed the suppression of TKP on glycolysis . TKP inhibited the β-catenin/c-Myc/HnRNPA1 pathway. LiCl treatment partly rescued the inhibitory effects of TKP on PKM2, aerobic glycolysis , and cell viability.

Conclusion: TKP suppresses HCC cell proliferation via block ing PKM2-dependent glycolysis , which is regulated by inhibiting the β-catenin/c-Myc/HnRNPA1 pathway.

Structural characterization and hypoglycemic activity of Trichosanthes peel polysaccharide

Trichosanthes peel polysaccharide (TPP) was obtained from the aqueous extract of Trichosanthes peel by alcohol precipitation, deproteinization and decoloration. TPP was then separated and purified by Sephadex G-100 column to obtain the homogeneous component TPP-1 (1.2 × 105 Da). The compositions in monosaccharides were d-arabinose (Ara), d-mannose (Man), d-glucose (Glc) and d-galactose (Gal) with a molar ratio of 1.00:3.27:4.26:6.01. Its backbone was composed of 1,4,6-Galp, 1,4-Galp, 1,3,6-Manp and 1,4-Manp, while the branches comprised of 1,3-Araf, 1-Araf and 1-Glcp. diabetic mice experiments showed that the blood glucose levels in hyperglycemia mice reduced by 22.47%, 15.38% and 12.72% after administration of high, medium and low doses of TPP-1, respectively.

Compared with the negative control group, the contents of insulin and total superoxide dismutase of the hyperglycemia mice in groups treated with different doses of TPP-1 were increased significantly, while the contents of biochemical indexes including malondialdehyde, creatinine, triglyceride, total cholesterol low density lipoprotein cholesterin and blood urea nitrogen were decreased in different degrees. These results suggested that TPP-1 possessed strong hypoglycemic activity on streptozotocin-induced model mice.

Zea mays L.extract

Hypoglycemic action of Stigma of Zea mays L. in Normal and diabetic Mice

The hypoglycemic effect of Maydis Stigmata, i.e., “Nanbanmou” (stigma of Zea mays L.), was investigated in both normal and streptozotocin-induced diabetic mice. A water extract of Nanbanmou (NM) (100 mg/kg) reduced the blood glucose level of normal mice from 189±3 to 136±5 mg/100 ml, 4h after intraperitoneal administration (p<0.001), and also significantly lowered the blood glucose level of streptozotocin-induced diabetic mice from 500±26 to 361±41 mg/100 ml under similar conditions (7h:p<0.05). NM also suppressed the epinephrine-induced hyperglycemia in mice (p<0.01).

(+)-Cryptocaryone

Constituents of an Extract of Cryptocarya rubra Housed in a Repository with Cytotoxic and glucose Transport inhibitory Effects

A new alkylated chalcone (1), a new 1,16-hexadecanediol diester (2), and eight known compounds were isolated from a dichloromethane-soluble repository extract of the leaves and twigs of Cryptocarya rubra collected in Hawaii. The structures of the new compounds were determined by interpretation of their spectroscopic data, and the absolute configurations of the two known cryptocaryanone-type flavonoid dimers, (+)-bicaryanone A (3) and (+)-chalcocaryanone C (4), were ascertained by analysis of their electronic circular dichroism and NOESY NMR spectra. All compounds isolated were evaluated against HT-29 human colon cancer cells , and, of these, (+)-cryptocaryone (5) was found to be potently cytotoxic toward this cancer cell line, with an IC₅₀ value of 0.32 μM.

This compound also exhibited glucose transport inhibitory activity when tested in a glucose uptake assay.

Size	100g

14 reviews for GLUCOSE BLOCKER

Rated 5 out of 5

Rich Ryan – December 4, 2021

This blend right here is pretty much the cure for diabetes. I really tried to get this blend to fail. I really love my crap food, so I tried eating every possible high-carb thing to get my blood sugar to skyrocket. Pizza, ice cream, tons of rice and bread, cake, pie, fried chicken, quarts of grape, apple and orange juice, pounds and pounds of pasta, all the worst stuff. The highest my blood sugar EVER GOT WAS 95. That’s it! You couldn’t get your blood sugar to sky-rocket with this blend if you wanted to! Unreal!
Here are some examples:

3 pieces of Pizza and 1 quart of Java Chip Ice Cream : 1 tsp Glucose blend after eating. 1 hour later – Blood Sugar 95.

All the Pancakes I Could Cram Down : 1/2 tsp Glucose blend after eating. 1 hour later – Blood Sugar 88.

Brown Rice and Beans with fully loaded Baked Potato – 1/2 tsp Glucose blend after eating. 1 hour later – Blood Sugar 85.

Fried Chicken and Mashed Potatoes with 1 Quart Grape Juice – 1/2 tsp Glucose blend after eating. 1 hour later – Blood Sugar 92.

Giant Plate of Tuna Pasta (homemade) with 1/2 Gallon of Apple Cider. Ate so much I almost threw up! – 1/2 tsp Glucose blend after eating. 1 hour later – Blood Sugar 91.

Whatever your lowest blood sugar is during the day, that’s what this blend will return it to, no matter what you eat. Eating mostly keto, doing intermittent fasting and taking this blend will repair your pancreas function, lower your blood sugar slowly over time, and restore your body’s insulin sensitivity, until your blood sugar levels are back to normal. I would be really surprised if anyone with diabetes is not able to get off of insulin after taking this blend and following protocols for a year or so.
I played around with various doses and my favorite dose is 1/2 tsp. You don’t really need more than that with this blend as it’s super strong. So 1 bag should last for quite a while.
Amazing product!
Rated 5 out of 5

Tracy McCulloch – December 5, 2021

Glucose Blocker to the rescue. I am 51 years old, perimenopausal woman who felt she was no longer in her own body (increased belly fat). Prior to using this amazing blend, I was struggling to keep up with my fasting and not seeing the results as quickly as I wanted. Reading up on all the studies Gavin provided, helped me learn about my body and the reasons I felt so tired, had hot flashes, night sweats and weight gain without increasing my food intake. I was insulin resistant due to low oestrogen (which helps increase the tolerance to glucose). My body could no longer cope with the amount of carbohydrates I was consuming. In addition, getting older goes hand in hand with increased stress, activating the cortisol levels (fight or flight hormone), thus increasing the amount of glucose being released into my body and increasing all the adverse menopausal symptoms. It was a vicious circle, and I am so grateful for the amazing GLUCOSE BLOCKER BLEND. The studies also informed me to make huge changes within my life i.e., diet and exercise (Gavin’s 22/2 protocol). Learning about cortisol, insulin, and oxytocin and how they needed to be in Sync to keep me happy and energised without drugs or artificial hormones, is the reason I will never be without GLUCOSE BLOCKER and INTERSTELLAR BLENDS.
My 30-day trials of this blend highlighted how my blood sugar in the morning was particularly high, even when fasted (120 mg/dl). Normal levels would be approximately 90-115. I would take the glucose blocker 1/8th first thing on waking with plenty of water and within the hour it would be below 90. Due to my perimenopausal lack of oestrogen, my blood sugar also fluctuated throughout the day so I would take 1/8th every 4-6 hours, again like clockwork back to normal levels. In the evening when I had my one meal a day consisting of BROCOLLI, POTATOES AND 1 SLICE OF WHOLEMEAL BREAD and 2 gingersnap biscuits, my blood sugar levels went from 170 to 94 mg/dl (1 hour after meal). I have also been in fasted state first thing in the morning and for scientific purposes (lol) had toast with jam and a bar of chocolate (galaxy), resulting in going from 181 – 60 mg/dl an hour after eating. I like to try to keep my food intake down as I am trying to get used to the 22/2 protocol and having GLUCOSE BLOCKER has meant I can have family celebrations of CHINESE TAKEAWAY with glucose level spikes of 200 mg/dl, as it is back to my normal 90 within 2 hours.
I am going to continue trialling with the doses/times taking the blends and find my sweet spot. For the moment though 1/8th dose (3 times a day) is working for me. I would like to add the benefits of fasting (22/2 protocol) with the other blends incorporated makes it so much easier to sustain. Doing some research, which is already provided on the website for each blend, will show how these all work together to crush any ailment you have. Glucose blocker and Interstellar Blends are the way to go if you have Diabetes or want to lead a fasting focused lifestyle and be happy simultaneously (who would have thought that could happen!). Amazing service. Thank you, Gavin.
Rated 5 out of 5

Amanda – January 7, 2022

Had some Chinese chicken and other stuff this is an amazing product keeps sugar down went tova Chinese buffet twice with egg roll and chicken

Had tested sugar it helps your sugar stay good perfect product keeps you healthy.
This product is amazing
Having dinner take out Chinese this waa a life saver I love this product you can test sugar and have amazing result

I know having pizza cookies and other stuff this product is top notch great stuff thank you Gavin I I love this product
Rated 5 out of 5

Marie Rodger (verified owner) – January 28, 2022

Been using the blends for a while now, and recently tried the Glucose Blocker. Well, it’s fantastic. I do struggle with fasting for the full day and find I am hungry around 1pm as i don’t eat after 6 pm the night before.The glucose blocker helps keep my blood sugar down when do have the odd Chinese etc. NO! it’s not an excuse to binge eat but it certainly helps for those family get together or parties when you know salad ain’t on the menu lol. I highly recommend this in anyone’s daily routine.
The science that Gavin has to back up his products is second to none, so even for those who like to do a lot of research id say go at it because it’s all there.
I wouldn’t be without this now and along with the other blends really help keep me feeling great and balanced.
Rated 5 out of 5

Steve S – February 1, 2022

Glucose blocker has quickly become my absolute favorite product Interstellar offers. Not to take away from the others though, because I have tried at least 75% of them and I take at least 6 different blends per day and they are all FANTASTIC in their own right. This one, however, has made the most noticeable difference in my overall appearance and health. In just a month of using this product I have shed 12 pounds and I have not once felt bloated or gross after eating a meal, no matter how heavy. This was also accomplished with no exercise nor changes to my diet. At first I thought it was just water weight/retention being shed and that it will quickly come back. It never has come back, no matter what I eat. Sometimes after dinner I sit in regret of the carb heavy meal I ate and say that I surely will gain a few pounds this week (as I gain weight extremely easily). To my surprise, I have not, and that is a first in my life. For the record, I am not immensely obese. I am 33 years old, 5’8 and 190lbs, but I have been overweight for literally my entire life, and losing lots of weight has not been easy.

Prior to taking this I started noticing spikes in my blood sugar after certain meals, and I would feel heavy, bloated, retained lots of water, etc. Since taking glucose blocker, I have not felt like that ever. I’ll admit that having it has made it harder for me to eat healthier because I just take my glucose blocker after a carb heavy meal and my blood sugar doesn’t spike, which is ideal. For reference though, I do eat healthier than other folks. I don’t eat much junk food nor drink pop or any other sugary drinks for that matter. What I consider “bad” are carb heavy foods like pasta, rice, bread, etc, which I love and eat quite often. I do a solid 16-18 hour daily fast, but my next goal is to increase that to 20/4 and also start lowering my carb intake overall. Paired with glucose blocker and thermo, I believe I’ll shed another 10 pounds fairly easily. Add-in daily weight training and cardio and I’m sure that will be 20 pounds in no time.

I mix this blend evenly with my 2nd favorite blend, which is Thermo. I mix a few teaspoons of each at a time in a jar and shake it up so I can take 1/4 teaspoon of the new mixture. In another container I mix equal parts of Supernova, peel, spice, anti-adipo, and apigenin. I like to separate the thermo and glucose blocker so I have better control of the amounts, and because glucose blocker is more time sensitive than other blends. I typically take it fasted in the morning, and then shortly after each meal, whereas the other blends can be taken whenever (ideally fasted though). Thermo is an incredible fat burner, and it does not have any negative side effects that are induced by your typical junk fat burners that are laden with caffeine and other stimulants.

I have not missed a single dose of this blend in over a month, and I don’t plan on it. This will be a staple in my daily routine for a long time to come. I highly recommend to anyone who is overweight and/or diabetic. You really can not go wrong. On a side note, Gavin is an incredible person with a wealth of knowledge and I genuinely enjoy the science-based approach he takes to everything he creates. No BS “proprietary” secret ingredients or synthetics. Just natural ingredients with countless scientific studies to back them up. Thanks Gavin.
Rated 5 out of 5

Chloe M (verified owner) – March 13, 2022

Okay yes, the numbers went down, but I want to talk about how Glucose blocker is an appetite suppressant. I am 410-pound women, who thinks about food everyday all day. I have been following Gavin for over 8 years, about the time I felt I needed to fast so I went on YouTube searching “fasting blogs” so that it can motivate me. But nothing helped because my body demanded what it wanted each day. So for the last 8 years daily, weekly and monthly I would try again and again to fast. I have tried water fast, juicing and the Danial fast not only my body but my mind rejected those methods. I started following Gavin on facebook where I later discovered interstellar plan but I couldn’t afford it, I tried saving for it but things kept coming up that unfortunately felt more important then my health. This year has and is bring about so many miracles my job that I have been on for five years did a big economy raise. So now I can afford to purchase some interstellar so going on the website to narrow down to what I should try first I decided to try the glucose blocker because it sound the closes to the health issues I needed to focus on first. First day I took it I couldn’t believe the taste was easy to consume, then two I was not hungry I didn’t realize until the next morning I only ate breakfast yesterday, I didn’t think about food my mood was good and I was not hungry. So the next day I ate and made my drink. I was able to take my time and cook some breakfast and make good choices of what I wanted to eat. The same thing happen again I went to bed didn’t think about food all day as well as I was not having hungry pains. SO by the fourth day I decided to go with this no hungry feeling as well as not even thinking about food so I decided to water fast. I am on day 3 water fasting, me doing something I have not been able to do in 8 years. I am happily down 17 pounds. I have decided to ride this wave with the interstellar plan and looking forwarded to trying something else. I am so happy to be on the interstellar plan so that I can get all my years back then some. Thanks Gavin this is truly my year I can feel it.
Rated 5 out of 5

Martin Richling (verified owner) – March 16, 2022

My experience with Glucose Blocker has been nothing short of fantastic!
A lot of people out in this evil world will try to sell you a bunch of stuff (in any arena!) that are filled with things that do not work. Like I said, in any arena!
years back my sugar level was 599. I did not even know it: I just knew I felt like crap.
The doctor told me to start on the typical path of medication that they tell everyone. I told him that I was not taking anything. He whispered (literally!) to me to just lose weight then, and it would go down. My blood sugar that is.
I did lose weight and started eating a healthy keto diet.
After much research it became obvious to me that SUGAR was the enemy.
So, a friend of mine, Gen la Grange told me about Gavin.
The rest is HISTORY, as they say.
Being a former cop, as my friend was too, we can spot a crook easily. And I could tell that Gavin was an honest, truth speaking, direct speech man who did not tolerate fools at all and yet will help any honest person.
I will always take the Glucose Blocker, eat WISELY according to 22/2 DAILY and I reject the modern doctors who simply want to make money off of you and KEEP YOU SICK!
The Glucose Blocker has done so much for me and continues to do so much for me. I will take it always.
I have recommended Gavin’s site to several of those that I teach and my family and friends. Several are now customers as well!
I value greatly Gavin as a person and his SINCERELY HARD WORK in so much research to truly help others.
Take it from a US MARINE, a former cop, and now a REAL Bible teacher and pastor: Gavin and his blends are ONE IN THE SAME–EXCELLENT!
Thank you, Gavin, for literally, saving my health from total destruction!
Rated 5 out of 5

Kathy Ostrowski – April 18, 2022

I’m convinced everyone would benefit from this stuff! Glucose Blocker is the answer to my prayers. I am Kathy from Texas and I have had Insulin dependant type II diabetes for over 20 years. Before GB it was not uncommon for my fasting blood glucose to be off the chart (ie. Over 500) I prayed to find a way to change that and stop the shots. I believe Gavin has found the answer.
I have taken GB and Supernova (thanks for the samples!) for 3 weeks now and while I am still transitioning off the insulin shots, I have more hope to reach my goals than ever before. My glucose readings these days are 200-140 in the morning, much improved from the typical 500-400 I was getting before starting this journey. I intend to implement some dietary changes including a fasting schedule (also recommended by my nutritionist) and continue to transition into freedom from insulin. Supernova has been another wonderful blessing! My friends tell me I seem more alert and functional than they have ever seen me. I feel it too! I walk more upright than I used to and don’t need my walker as much. My energy levels are through the roof and it eliminates the foggy sleepiness I had come to just expect. Thanks for all your good works Gavin!
Rated 5 out of 5

Dan Austad – April 25, 2022

I stumbled on to this website by accident. Actually, I believe I was guided here because Glucose Blocker has been the answer to my prayers. I’ve had blood sugar issues for many years and I was diagnosed with prostate cancer about 3 years ago. I ordered your products because of a review showing how one man’s PSA was dramatically reduced from over 200 to under 1 in a very short amount of time. My PSA has been increasing lately and my doctor wants to put me on a Chemo drug with some potentially serious side effects. I already take Lupron shots every 3 months which has helped until now to keep my PSA count down. I added Glucose Blocker to Vital Force Combo and my blood sugar dropped without changing my diet. My glucose reading before starting on Glucose Blocker was 179, after the first day on the products it was 152 and after day two it was 133. This is truly amazing to drop 46 points in 2 days! I feel one part of my health puzzle has been found. My PSA is being tested every month but this time I’m excited to go to my appointment. I will do another review with the results after the test. Thank you Gavin for these products, I am so grateful that I’ve found Glucose Blocker and Vital Force Combo, I believe they will be life changing for me!
Rated 5 out of 5

Shakun Kumar (verified owner) – May 24, 2022

My mother had a glucose of 200 mg in morning, with 1/8 spoon of glucose blocker it came down to 160 and after a couple of doses it’s normal now.

Also, I tried Glucose Blocker for a couple of days 1/8 spoon before sleeping while increasing my carbs intake. And I have lost 2 kgs in 2 days…it’s amazing how glucose blocker helps with insulin sensitivity and weight-loss.

It’s an amazing product
Rated 5 out of 5

Annie – May 30, 2022

This blend really does work! My blood sugar reading was always all over the place no matter how clean I ate.

I started taking the blend twice a day and have actually noticed weight loss since taking this and I’m not so hungry for carbs anymore. This is seriously life changing and I feel better than ever. I even have more energy throughout the day and will need to order some more soon to restock.
Rated 5 out of 5

Vlado – June 11, 2022

Even I’am taking the blend just one time a day it still keep my blood sugar about 90. I am loosing weight and best benefit – I sleep very well. It is amazing how it works.
Rated 5 out of 5

Marie (verified owner) – August 17, 2022

I’ve been using the blends for a while now . I’ve tried most of them over that time .
Initially to help me lose some weight and just to see the overall effect of them.
I’m 56 and have had no flare ups with the arthritis in my joints . I fractured my L1 and L3 in my back and wrist and had healed within a couple of weeks . The doctors were surprised by how quickly. Now the blends don’t stop you doing stupid shit, but they are awesome at helping your body heal and repair in record time .
I even have my 2 bulldogs on a little peel and spice and they haven’t had any inflammation issues since .
My ultimate favourites are purge , glucose blocker they are my daily go to along with spice , peel.
I use plush and pine pollen and have noticed a difference in my skin texture. Luteolin really helps balance my mood and help me focus . It’s actually hard to pick a fav because they are all so effective . Try them and see what works best for you . I haven’t tried Rewire yet but it’s next on the list !
Oh and the weight I lost has pretty much stayed off unless I’ve really kicked the arse out of it … remember the above stupid statement 😉 but then I get back on it the right way and it comes back off . Gavin is super helpful and knows his stuff.
Rated 5 out of 5

Nichole Fausey (verified owner) – August 18, 2022

Review of Interstellar Blends

I wanted to wait a few months before writing a review of Interstellar Blends products but I did feel the effects within fifteen minutes of my first time using them. Of course, I thought I was experiencing a placebo effect. I felt intense, wonderful, joyful aliveness, similar to how I felt after 4 years of veganism and taking my first bite of brisket. I am writing this on August 18th, and I’ve been taking Interstellar Blends since March. My first time purchase was the March Special. I followed “the Life-changing 22/2 Intermittent Fasting Protocol” using all the blends listed, except a few that weren’t part of the March Special.

I had wanted to jump in with both feel and lose the excess weight I had, but the Special was recommended to me because I had already had some experience with dry-fasting. I noticed my weight dropping about ½ to ¾ of a pound pretty consistently daily, without doing anything else, but taking the blends at the recommended intervals with coffee or grapefruit juice and doing my usual treadmill walk.

After a day or two, I noticed a real sense of “get-it-done” that I hadn’t had for quite a long time. I am not just a gardener; I am the owner of a Permaculture business in north Texas—my property is largely a food forest. Ninety-eight percent of what grows here is edible, medicinal, or native to the area. I understand the value of food as medicine and I further understand how challenging it is to get precisely what’s needed for healing. Interstellar Blends are largely made in the ratio of 200:1. That ratio would be nearly impossible to take in inside a 24-hour period, let alone be absorbed and utilized in the body. It would also be completely impossible to grow and process on a mid-sized suburban property. I could go on to say that would double in difficultly for a couple, and triple for a family of three, which I have. Yes, we all take the blends. Back to the “get it done” feeling, I noticed that I would just get things done in the garden instead of putting them off. This was a great point of pride in accomplishment for me, and of course the garden benefitted and I became a better role model for my 14 year old daughter.

Yes, my daughter also takes the blends–Trinity, Autonomous, Glucose Blocker, Super Hair and Plush. She has keratosis pilaris and it has noticeably reduced. She’s very happy with the skin on her arms and face. In addition to this, her hair has transformed from thin and limp–a point of daily disappointment for her–to thick and shiny and an aspect she now truly loves about herself. She is growing it out and it looks beautiful. What teenager wouldn’t want these results? I’m also enjoying the improvement in my hair with the blends. It’s definitely thicker. I think Super Hair has made the growth better and the falling out less. I’m 54 years old and have had hair issues since my second pregnancy 15 years ago. With Super Hair and Plush, I honestly think I am youthening. I’ve also had issues with extra skin from years of being overweight. Plush seems to be reducing that. I’ve had family tell me I’m looking very healthy and vibrant. My mother even told me I look so little (thin) and pinched my waist. That never happened in my whole life—again, I’m 54!

I want to talk about a few products in this general review of Interstellar Blends, though I could (and probably will) write reviews for all of them. Glucose Blocker is some incredible product. I had been traveling since July 21st. I ran out of Glucose Blocker on August 14th. I had been eating fairly well during my travels, mostly keto, but there has been a real difference without the Glucose Blocker. I went to bed after a day of too many carbs, plus chocolate. It was the first time since starting out on the road that I had nighttime cramps. I don’t know if Glucose Blocker affects magnesium balance, but I’m thinking it might. Occasionally during the traveling and visiting family I, of course, indulged more in things I wouldn’t have at home, and with Glucose Blocker, I never had issues. It’s like a defender for balanced physiology. I’m really happy to know how well the Glucose Blocker really works. When I first started the 22/2, I wondered if I’d ever really understand the effect of the individual products, but over time I have noticed how each product affects me. I’m grateful to have that affirming knowledge.

I’ll just mention Victorious before I close this overall review. My daughter came home from orchestra camp and had laryngitis (I thought), but I also became ill from being around her and we both started taking Victorious. We were better in a few days. We did not test for the “current thing,” but may have had it. Victorious was a wonderful helper, as were the rest of the blends. If either of us sneezed more than once during our travels and different hotels almost every night for three plus weeks, I’d just take a bit of Victorious. Another defender!

Most places we’d been to had lot of people still wearing masks. It’s laughable, but very sad to me at once. We continue to live unafraid and we keep taking our Interstellar Blends. OH! I have to say that my husband is a professional, long haul truck driver and greatly enjoys the blends. He was a health coach for years and has tried dozens of powders from different companies. He is currently a flatbed driver and that’s a very physically demanding job. He is required to strap down and tarp most of the loads, which involves climbing up on top of the flatbed trailer and often up on top of the actual load and back down again a few dozen times per load and then doing it again for the unload. Before he heads out for that activity, he takes Supernova and powers right through it. I was concerned that Supernova might make him aggressive behind the wheel, but I traveled with him for 8 days straight and he showed none of that behavior. It makes him more focused and determined. He loves the product.

So, if you are on the fence about starting Interstellar Blends, I think you should take the opportunity . It’s an investment in yourself, your longevity, and your quality of life. I honestly didn’t think the blends would live up to the reviews, but they certainly do. Give them a good try. I recommend getting the monthly special, but if you just don’t think you can, get Glucose Blocker, Trinity, and Rewire. You’ll thank yourself!