stilbenes and Glucose-Intolerance

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).. 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.. At baseline, body mass index was 29 ± 5 kg/m(2), 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 improved (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 improved 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.. 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.

Topics: Aged; Antioxidants; Blood Glucose; Endothelium, Vascular; Female; Glucose Intolerance; Homeostasis; Humans; Male; Pilot Projects; Resveratrol; Stilbenes

Topics: Acetyl-CoA Carboxylase; Animals; Benzoxazoles; Body Weight; Diabetes Mellitus; Enzyme Activators; Fatty Acid Synthases; Fatty Liver; Gene Expression Regulation; Glucose Intolerance; Heterocyclic Compounds, 4 or More Rings; Hypoglycemic Agents; Male; Metabolic Syndrome; Mice, Inbred C57BL; Molecular Docking Simulation; Resveratrol; Sirtuin 1; Sterol Regulatory Element Binding Proteins; Stilbenes

Aging leads to a high prevalence of glucose intolerance and cardiovascular diseases, with oxidative stress playing a potential role. Resveratrol has shown promising effects on glucose tolerance and tends to improve endothelial function in elderly patients. Thioredoxin-interacting protein (TXNIP) was recently proposed as a potential link connecting glucose metabolism to oxidative stress. Here, we investigated the resveratrol-induced improvement of arterial aging phenotype in old mice and the expression of aortic TXNIP. Using an in vivo model of old mice with or without 3-month resveratrol treatment, we investigated the effects of resveratrol on age-related impairments from a cardiovascular Doppler analysis, to a molecular level, by studying inflammation and oxidative stress factors. We found a dual effect of resveratrol, with a decrease of age-related glucose intolerance and oxidative stress imbalance leading to reduced matrix remodeling that forestalls arterial aging phenotype in terms of intima-media thickness and arterial distensibility. These results provide the first evidence that aortic TXNIP mRNA and protein nuclear expressions are increased in the arterial aging and decreased by resveratrol treatment. In conclusion, we demonstrated that resveratrol helped to restore several aging impaired processes in old mice, with a decrease of aortic TXNIP mRNA and protein nuclear expressions.

Topics: Animals; Aorta; Calcium; Carrier Proteins; Echocardiography, Doppler; Glucose Intolerance; Glucose Tolerance Test; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nuclear Proteins; Oxidative Stress; Phenotype; Random Allocation; Real-Time Polymerase Chain Reaction; Resveratrol; RNA, Messenger; Stilbenes; Thioredoxins

Alterations in the gut microbiota play a crucial role in host physiology and metabolism; however, the molecular pathways underlying these changes in diet-induced obesity are unclear. Mechanistic target of rapamycin (mTOR) signaling pathway is associated with metabolic disorders such as obesity and type 2 diabetes (T2D). Therefore, we examined whether changes in the regulation of mTOR signaling induced by diet (a high-fat diet [HFD] or normal-chow diet) and/or therapeutics (resveratrol [a specific inhibitor of mTOR complex 1] or rapamycin [an inhibitor of both mTOR complex 1 and 2]) altered the composition of the gut microbiota in mice. Oral administration of resveratrol prevented glucose intolerance and fat accumulation in HFD-fed mice, whereas rapamycin significantly impaired glucose tolerance and exacerbated intestinal inflammation. The abundance of Lactococcus, Clostridium XI, Oscillibacter, and Hydrogenoanaerobacterium increased under the HFD condition; however, the abundance of these species declined after resveratrol treatment. Conversely, the abundance of unclassified Marinilabiliaceae and Turicibacter decreased in response to a HFD or rapamycin. Taken together, these results demonstrated that changes in the composition of intestinal microbiota induced by changes in mTOR activity correlate with obese and diabetic phenotypes.

Topics: Animals; Bacteria; Blood Glucose; Clostridium; Diet, High-Fat; Gastrointestinal Microbiome; Glucose Intolerance; Glucose Tolerance Test; Insulin; Intestines; Lactococcus; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Signal Transduction; Sirolimus; Stilbenes

Nicotinamide (NAM), or vitamin B3, is an essential coenzyme for ATP synthesis and an inhibitor of sirtuin 1. Recently, conflicting results were reported regarding the treatment of NAM in type 2 diabetes and obesity. The aim of this study was to determine whether and how long-term treatment with NAM at lower dose would affect insulin sensitivity in mice fed chow diet. We treated mice with NAM (100 mg/kg/day) and normal chow for 8 weeks. Strikingly, NAM induced glucose intolerance and skeletal muscle lipid accumulation in nonobese mice. NAM impaired mitochondrial respiration capacity and energy production in skeletal muscle, in combination with increased expression of the mediators for mitophagy (p62, PINK1, PARK2 and NIX) and autophagy (FOXO3, Bnip3, CTSL, Beclin1 and LC-3b). Next, we treated mice with high-fat diet (HFD) and resveratrol (RSV; 100 mg/kg/day) for 8 weeks. RSV protected against HFD-induced insulin resistance and obesity. HFD increased skeletal muscle lipid content as well as NAM, but this increase was attenuated by RSV. In contrast to NAM, HFD enhanced fatty acid oxidative capacity. Muscle transcript levels of genes for mitophagy and autophagy were largely suppressed by HFD, whereas RSV did not rescue these effects. These differences suggest that skeletal muscle autophagy may represent adaptive response to NAM-induced lipotoxicity, whereas reduced autophagy in skeletal muscle may promote HFD-induced lipotoxicity. Our results demonstrate that chronic NAM supplementation in healthy individuals, although at lower dose than previously reported, is still detrimental to glucose homeostasis and skeletal muscle lipid metabolism.

Topics: Animals; Antioxidants; Autophagy; Diet, High-Fat; Dietary Supplements; Gene Expression Regulation; Glucose Intolerance; Histone Deacetylase Inhibitors; Insulin Resistance; Lipid Metabolism; Male; Mice, Inbred C57BL; Mitophagy; Muscle Proteins; Muscle, Skeletal; Niacinamide; Obesity; Resveratrol; Sirtuin 1; Stilbenes; Time Factors

Ethanol extracts (Et) from the stem (S) and leaf (L) of Vitis thunbergii var. taiwaniana (VTT) were used to investigate yeast α-glucosidase and porcine kidney dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. Both VTT-Et showed complete α-glucosidase inhibition at 0.1 mg/mL; VTT-S-Et and VTT-L-Et showed 26 and 11% DPP-IV inhibition, respectively, at 0.5 mg/mL. The VTT-Et interventions (20 and 50 mg/kg) resulted in improvements in impaired glucose tolerance of diet-induced obese rats. (+)-Hopeaphenol, (+)-vitisin A, and (-)-vitisin B were isolated from the ethyl acetate fractions of S-Et and showed yeast α-glucosidase inhibition (IC50 = 18.30, 1.22, and 1.02 μM) and porcine kidney DPP-IV inhibition (IC50 = 401, 90.75, and 15.3 μM) compared to acarbose (6.39 mM) and sitagliptin (47.35 nM), respectively. Both (+)-vitisin A and (-)-vitisin B showed mixed noncompetitive inhibition against yeast α-glucosidase and porcine kidney DPP-IV, respectively. These results proposed that VTT extracts might through inhibitions against α-glucosidase and DPP-IV improve the impaired glucose tolerance in diet-induced obese rats.

Topics: alpha-Glucosidases; Animals; Benzofurans; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Intolerance; Glycoside Hydrolase Inhibitors; Kinetics; Male; Obesity; Phenols; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Saccharomyces cerevisiae; Stilbenes; Swine; Vitis

Angiotensin-(1-7) and resveratrol have been described as new potential therapeutic tools on treating and preventing metabolic disorders. In the present study we aimed to evaluate the effect of an oral formulation of angiotensin-(1-7) [Ang-(1-7)] included in HPB-cyclodextrin and resveratrol (RSV), in modulation of sirtuin and renin-angiotensin system (RAS) in adipose tissue of mice treated with a high-fat diet (HFD). We observed that HFD+Ang-(1-7) and HFD+RSV groups presented marked decrease in the adipose tissue mass. Furthermore, these animals showed improved insulin-sensitivity and glucose tolerance as well as lower plasma levels of fasting glucose and lipids. The RT-PCR analysis revealed decreased expression of ACE and an increase of ACE2 [Ang-(1-7) marker] in group treated with resveratrol and also an increased expression of SIRT1 in groups that received Ang-(1-7). We showed for the first time that improved metabolic profile is associated with increased expression of GLUT4 and high expression of AMPK/FOXO1/PPAR-γ pathway in adipose-tissue. Finally, adipocyte primary cell-culture incubated with and without sirtuin and Ang-(1-7)/Mas antagonists pointed out for a cross-talking between RAS and sirtuins. We conclude that oral administration of Ang-(1-7) and RSV improved metabolic profile through a cross-modulation between RAS and Sirtuins.

Topics: Administration, Oral; Angiotensin I; Animals; Antimetabolites; Cells, Cultured; Diet, High-Fat; Drug Evaluation, Preclinical; Gene Expression; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Intra-Abdominal Fat; Lipolysis; Male; Mice; Obesity; Peptide Fragments; Primary Cell Culture; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Resistin; Resveratrol; Sirtuins; Stilbenes

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adipose Tissue, White; Aging; AMP-Activated Protein Kinase Kinases; Animals; Caloric Restriction; Cyclic Nucleotide Phosphodiesterases, Type 4; Diet; Glucose Intolerance; Guanine Nucleotide Exchange Factors; Mice; Models, Molecular; Muscle, Skeletal; NAD; Obesity; Protein Kinases; Resveratrol; Rolipram; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Sirtuin 1; Stilbenes

Insulin resistance is recognized as a common metabolic factor which predicts the future development of both type 2 diabetes and atherosclerotic disease. Resveratrol (RSV), an agonist of estrogen receptor (ER), is known to affect insulin sensitivity, but the mechanism is unclear. Evidence suggests that caveolin-3 (CAV-3), a member of the caveolin family, is involved in insulin-stimulated glucose uptake. Our recent work indicated that estrogen via ER improves glucose uptake by up-regulation of CAV-3 expression. Here, we investigated the role of CAV-3 in the effect of RSV on insulin resistance in skeletal muscle both in vivo and in vitro. The results demonstrated that RSV ameliorated high-fat-diet (HFD)-induced glucose intolerance and insulin resistance in ovariectomized rats. RSV elevated insulin-stimulated glucose uptake in isolated soleus muscle in vivo and in C2C12 myotubes in vitro by enhancing GLUT4 translocation to the plasma membrane rather than increasing GLUT4 protein expression. Through ERα-mediated transcription, RSV increased CAV-3 protein expression, which contributed to GLUT4 translocation. Moreover, after knockdown of CAV-3 gene, the effects of RSV on glucose uptake and the translocation of GLUT4 to the plasma membrane, as well as the association of CAV-3 and GLUT4 in the membrane, were significantly attenuated. Our findings demonstrated that RSV via ERα elevated CAV-3 expression and then enhanced GLUT4 translocation to the plasma membrane to promote glucose uptake in skeletal muscle, exerting its protective effects against HFD-induced insulin resistance. It suggests that this pathway could represent an effective therapeutic target to fight against insulin resistance syndrome induced by HFD.

Topics: Animals; Caveolin 3; Cell Membrane; Diet, High-Fat; Estrogen Receptor alpha; Female; Glucose; Glucose Intolerance; Glucose Transporter Type 4; Insulin; Insulin Resistance; Muscle Fibers, Skeletal; Muscle, Skeletal; Ovariectomy; Protective Agents; Protein Transport; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.

Topics: Animals; Blood Glucose; Dietary Fats; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Inflammation; Intestines; Male; Metagenome; Mice; Mice, Inbred C57BL; Receptors, Glucagon; Resveratrol; Stilbenes; Time Factors

Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5' AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKalpha1 or -alpha2 to determine whether the metabolic effects of resveratrol are mediated by AMPK.. Mice deficient in the catalytic subunit of AMPK (alpha1 or alpha2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro.. Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKalpha1(-/-) mice. In the absence of either AMPKalpha1 or -alpha2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly.. We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.

Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; Drug Resistance; Enzyme Inhibitors; Fibroblasts; Glucose Intolerance; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondria; Muscle, Skeletal; NAD; Resveratrol; Sirtuin 1; Stilbenes; Weight Loss