stilbenes and Hyperinsulinism

This study evaluated the effect of resveratrol administration on metabolic syndrome, insulin sensitivity, and insulin secretion.. A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with diagnosis of metabolic syndrome in accordance with the International Diabetes Federation criteria. Glucose and insulin levels were measured after a 75-gram dextrose load. Triglycerides and high-density lipoprotein cholesterol concentrations at baseline were also evaluated. Twelve patients received trans-resveratrol (500 mg) three times per day before meals for 90 days. The remaining 12 patients received placebo at the same dose. The area under the curve (AUC) values of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were calculated.. After resveratrol administration, there were significant differences in total weight (94.4±13.2 vs. 90.5±12.3 kg, P=0.007), body mass index (BMI) (35.6±3.2 vs. 34.3±3.0 kg/m(2), P=0.006), fat mass (41.2±7.9 vs. 38.8±6.0 kg, P=0.001), and waist circumference (WC) (109±9 vs. 105±10 cm, P=0.004). There were also significant differences in AUC of insulin (48,418±22,707 vs. 26,473±8,273 pmol/L, P=0.003) and insulinogenic index (0.48±0.22 vs. 0.28±0.08, P=0.004).. Administration of resveratrol significantly decreases weight, BMI, fat mass, WC, AUC of insulin, and total insulin secretion.

Topics: Adiposity; Adult; Area Under Curve; Biomarkers; Blood Glucose; Body Mass Index; Cholesterol, HDL; Double-Blind Method; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Mexico; Middle Aged; Predictive Value of Tests; Resveratrol; Stilbenes; Time Factors; Treatment Outcome; Triglycerides; Weight Loss

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

Effective and safe pharmacological interventions for hyperlipidemia remains badly needed. By incorporating the key pharmacophore of fibrates into the natural scaffold of resveratrol, a novel structural compound ZBH was constructed. In present study, we found ZBH reserved approximately one third of the sirtuin 1 (SIRT1) activation produced by resveratrol at in-vitro enzyme activity assay, directly bound to and activated all three peroxisome proliferator-activated receptor (PPAR) subtypes respectively in PPAR binding and transactivation assays. Moreover, ZBH (EC₅₀, 1.75 µM) activate PPARα 21 fold more efficiently than the well-known PPAR pan agonist bezafibrate (EC₅₀ 37.37 µM) in the cellular transactivation assays. In the high fat diet induced hyperlipidemic hamsters, 5-week treatment with ZBH significantly lowered serum triglyceride, total cholesterol, LDL-C, FFA, hyperinsulinemia, and improved insulin sensitivity more potently than bezafibrate. Meanwhile, serum transaminases, creatine phosphokinase and CREA levels were found not altered by ZBH intervention. Mechanism study indicated ZBH promoted the expression of PPARα target genes and SIRT1 mRNA. Hepatic lipogenesis was markedly decreased via down-regulation of lipogenic genes, and fatty acid uptake and oxidation was simultaneously increased in the liver and skeletal muscle via up-regulation of lipolysis genes. Glucose uptake and utilization was also significantly promoted in skeletal muscle. These results suggested that ZBH significantly lowered hyperlipidemia and ameliorated insulin resistance more efficiently than bezafibrate in the hyperlipidemic hamsters primarily by activating of PPARα, and SIRT1 promotion and activation. ZBH thus presents a potential new agent to combat hyperlipidemia.

Topics: Animals; Bezafibrate; Cricetinae; Diet, High-Fat; Drug Design; Gene Expression Regulation; Hyperinsulinism; Hyperlipidemias; Hypolipidemic Agents; Liver; Male; Muscle, Skeletal; Pentanoic Acids; PPAR alpha; Resveratrol; Sirtuin 1; Stilbenes; Triglycerides

Topics: Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Stilbenes

Topics: Animals; Diet, High-Fat; Humans; Hyperinsulinism; Male; Obesity; Sirolimus; Stilbenes

High doses of rapamycin, an antiaging agent, can prevent obesity in mice on high fat diet (HFD). Obesity is usually associated with hyperinsulinemia. Here, we showed that rapamycin given orally, at doses that did not affect weight gain in male mice on HFD, tended to decrease fasting insulin levels. Addition of resveratrol, which alone did not affect insulin levels, potentiated the effect of rapamycin, so that the combination decreased obesity and prevented hyperinsulinemia. Neither rapamycin nor resveratrol, and their combination affected fasting levels of glucose (despite lowering insulin levels), implying that the combination might prevent insulin resistance. We and others previously reported that resveratrol at high doses inhibited the mTOR (Target of Rapamycin) pathway in cell culture. Yet, as we confirmed here, this effect was observed only at super-pharmacological concentrations. At pharmacological concentrations, resveratrol did not exert 'rapamycin-like effects' on cellular senescence and did not inhibit the mTOR pathway in vitro, indicating nonoverlapping therapeutic mechanisms of actions of rapamycin and resveratrol in vivo. Although, like rapamycin, resveratrol decreased insulin-induced HIF-1-dependent transcription in cell culture, resveratrol did not inhibit mTOR at the same concentrations. Given distinct mechanisms of action of rapamycin and resveratrol at clinically relevant doses, their combination warrants further investigation as a potential antiaging, antiobesity and antidiabetic modality.

Topics: Animals; Cell Line, Tumor; Cellular Senescence; Diet, High-Fat; Humans; Hyperinsulinism; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Male; Mice; Obesity; Resveratrol; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Transcription, Genetic; Weight Gain

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Blood Glucose; Diet, High-Fat; Disease Resistance; Disease Susceptibility; Echocardiography; Heart; Heart Diseases; Hyperglycemia; Hyperinsulinism; Male; Obesity; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

To investigate whether resveratrol (RSV) can improve non-alcoholic fatty liver disease (NAFLD) and to find the possible mechanism.. Rats fed a high-fat diet were treated with RSV. The liver histology was observed. Hyperinsulinemic euglycemic clamp was performed to assess insulin sensitivity. Fat accumulation was induced in HepG2 cells, and the cells were treated with RSV. AMP-activated protein kinase (AMPK) phosphorylation levels were determined both in the animal study and cell study.. Rats fed a high-fat diet developed abdominal obesity, NAFLD, and insulin resistance (IR), which were markedly improved by 10 weeks of RSV administration. RSV treatment prevented triacylglycerol (TG) accumulation in HepG2 cells that were incubated with high concentration of glucose and insulin. Both in vivo and in vitro studies showed that RSV treatment could promote the phosphorylation of AMPK, which in this study, suppressed 2 lipogenesis gene expressions, contributing to the improvement of NAFLD and IR.. The results indicated that by reducing TG accumulation and improving IR, RSV could protect the liver from NAFLD. The activation of AMPK was involved in the mechanism. RSV has the therapeutic potential for preventing or treating NAFLD and IR-related metabolic disorders.

Topics: Animals; Antioxidants; Cyclic AMP-Dependent Protein Kinases; Diet; Enzyme Activation; Fatty Liver; Glucose Clamp Technique; Humans; Hyperinsulinism; Liver; Male; Rats; Resveratrol; Stilbenes; Triglycerides