stilbenes and Insulin-Resistance

Diabetes mellitus is a significant health problem that is caused by chronic hyperglycaemia as a result of inadequate insulin production or ineffective insulin action in the body. In recent years, many new pharmacological and non-pharmacological therapies have been developed for improving pancreatic insulin secretion and insulin resistance. Resveratrol is a natural and biologically active stilbenoid polyphenol present in various plant species and has the potential to benefit diabetes. The anti-diabetic actions of resveratrol have also been extensively studied in diabetic human and animal models. Moreover, resveratrol might affect insulin sensitivity by regulating visceral fat derivated adipokine levels. The use of resveratrol in combination with anti-diabetic therapies or alone may have significant potential for the management of diabetes mellitus. This review provides an overview of the anti-diabetic action of resveratrol as well as the possible mechanisms that have an effect on insulin secretion and insulin resistance in diabetics.

Topics: Animals; Diabetes Mellitus; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Obesity; Resveratrol; Stilbenes

Pterostilbene, a phenolic compound derived from resveratrol, possesses greater bioavailability than its parent compound due to the presence of two methoxyl groups. In this review, the beneficial effects of pterostilbene on diabetes, liver steatosis and dyslipidemia are summarized. Pterostilbene is a useful bioactive compound in preventing type 1 diabetes, insulin resistance and type 2 diabetes in animal models. Concerning type 1 diabetes, the main mechanisms described to justify the positive effects of this phenolic compound are increased liver glycogen content and hepatic glucokinase and phosphofructokinase activities, the recovery of pancreatic islet architecture, cytoprotection and a decrease in serum and pancreatic pro-inflammatory cytokines. As for type 2 diabetes, increased liver glucokinase and glucose-6-phosphatase and decreased fructose-1,6-biphosphatase activities are reported. When insulin resistance is induced by diets, a greater activation of insulin signaling cascade has been reported, increased cardiotrophin-1 levels and liver glucokinase and glucose- 6-phosphatase activities, and a decreased fructose-1,6-biphosphatase activity. Data concerning pterostilbene and liver steatosis are scarce so far, but the reduction in oxidative stress induced by pterostilbene may be involved since oxidative stress is related to the progression of steatosis to steatohepatitis. Finally, pterostilbene effectively reduces total cholesterol, LDL-cholesterol and serum triglyceride levels, while increases HDL-cholesterol in animal models of dyslipidemia.

Topics: Animals; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Insulin Resistance; Lipids; Liver; Stilbenes

Numerous natural products available over the counter are commonly consumed by healthy, sub-healthy or ill people for the treatment and prevention of various chronic diseases. Among them, a few dietary polyphenols, including the curry compound curcumin, have been attracting the most attention from biomedical researchers and drug developers. Unlike many so-called "good drug candidates", curcumin and several other dietary polyphenols do not have a single known therapeutic target or defined receptor. In addition, the bioavailability of these polyphenols is usually very low due to their poor absorption in the gut. These recently debated features have created enormous difficulties for drug developers. In this review, I do not discuss how to develop curcumin, other dietary polyphenols or their derivatives into pharmaceutical agents. Instead, I comment on how curcumin and dietary polyphenol research has enriched our knowledge of insulin signaling, including the presentation of my perspectives on how these studies will add to our understanding of the famous hepatic insulin function paradox.

Topics: Animals; Anthocyanins; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line; Curcumin; Drug Discovery; Fibroblast Growth Factors; Humans; Insulin; Insulin Resistance; Nuclear Proteins; Polyphenols; Resveratrol; Signal Transduction; Stilbenes; Transcription Factors

Polycystic ovary syndrome (PCOS) is a complex heterogeneous disorder characterized by androgen excess and ovulatory dysfunction; it is now known to be closely linked to metabolic syndrome. Recent research suggests that insulin resistance plays an important role in the pathogenesis of PCOS which may lead to the excessive production of androgens by ovarian theca cells. Currently there is no single drug that can treat both the reproductive and metabolic complications of the disorder. Existing pharmaceutical agents such as hormonal therapies have been associated with side effects and are not appropriate for PCOS women with infertility. Additionally, insulin sensitizing agents useful for treating the metabolic abnormalities in PCOS have limited efficacy for treating reproductive aspects of the disorder. Chinese herbal medicines have a long history of treating gynaecological problems and infertility and therefore may be a novel approach to the treatment of PCOS. Current research demonstrates that the compounds isolated from herbs have shown beneficial effects for PCOS and when combined in an herbal formula can target both reproductive and metabolic defects simultaneously. Therefore, further investigation into Chinese herbal medicine in the treatment of PCOS is warranted.

Topics: Androgens; Berberine; Drugs, Chinese Herbal; Female; Ginsenosides; Glucosides; Humans; Insulin Resistance; Monoterpenes; Phenanthrenes; Phytotherapy; Polycystic Ovary Syndrome; Resveratrol; Stilbenes; Theca Cells

Resveratrol (RES), a well-known antioxidant, is present in numerous plant species and, as a result, is easily obtained through dietary intake of plant-based foods and beverages. Several studies suggest that RES has anti-carcinogenic, anti-microbial, and anti-viral effects. It may also have beneficial metabolic properties that result in mitigation of insulin resistance (IR) and related metabolic abnormalities, including dyslipidemia, hyperglycemia, and hyperinsulinemia through regulation of gene expression or the activity of rate-limiting enzymes. A large body of evidence supports the beneficial effects of RES in the management and treatment of IR, type 2 diabetes, and related complications through a multitude of mechanisms. This review article focuses on the mechanisms of action of RES, the mechanisms leading to improved insulin sensitivity, and its clinical role in the management and treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Mice; Resveratrol; Signal Transduction; Stilbenes

Nonalcoholic fatty liver disease (NAFLD) is considered to be one of the most common liver pathologies that occur widely among societies with a predominance of the Western dietary pattern. NAFLD may progress from hepatic steatosis to nonalcoholic steatohepatitis (NASH), subsequently leading to cirrhosis and becoming a major cause of hepatocellular carcinoma. Thus its prevention and therapy play an important role in hepatology. To our knowledge, there is no effective treatment for patients with NAFLD. The aim of this review was to summarize the results of recent alternative treatment studies conducted both on cell cultures and in vivo that concern molecular effects of resveratrol (3,5,4'-trihydroxystilbene) in the treatment of NAFLD. The precise metabolism, pharmacology, and clinical trials with different concentrations of resveratrol were described. The review also presents a brief summary of other alternative treatment methods of NAFLD and their mechanisms compared with current clinical understanding.

Topics: Complementary Therapies; Hepatocytes; Humans; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXR)α, sterol regulatory element binding protein (SREBP)-1/1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor α (PPARα), leptin nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), c-Jun amino terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Until now, a series of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the natural products (e.g., curcumin, resveratrol, and (-)-epicatechin) and their mechanisms of ameliorating fructose-induced NAFLD over the past years. Although, as lead compounds, natural products usually have fewer activities compared with synthesized compounds, it will shed light on studies aiming to discover new drugs for NAFLD.

Topics: Animals; Biological Products; Catechin; Curcumin; Fructose; Humans; Inflammation; Insulin Resistance; Lipogenesis; Mitochondria; Non-alcoholic Fatty Liver Disease; Resveratrol; Stilbenes

Potential effects of resveratrol consumption on cardiovascular disease risk factors and body weight in overweight/obese adults have not been fully elucidated. Our present analysis was to evaluate the effects of resveratrol consumption on risk markers related to cardiovascular health in overweight/obese Individuals.. Multiple literature databases were systematically searched, and 21 studies were included. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI), and heterogeneity was assessed with the I2 test. Publication bias and subgroup analyses were also performed.. There were variations in reporting quality of included studies. Resveratrol intervention significantly lowered total cholesterol (WMD, -0.19 mmol/L; 95% CI, -0.32 to -0.06; P = 0.004), systolic blood pressure (WMD, -2.26 mmHg; 95% CI, -4.82 to -0.49; P = 0.02), and fasting glucose (WMD, -0.22 mmol/L; 95% CI, -0.42 to -0.03; P = 0.03). Heterogeneity was noted for these outcomes (35.6%, 38.7% and 71.4%, respectively). Our subgroup analysis showed significant reductions in total cholesterol, systolic blood pressure, diastolic blood pressure, glucose, and insulin in subjects ingesting higher dose of resveratrol (≥300 mg/day).. Our finding provides evidence that daily resveratrol consumption might be a candidate as an adjunct to pharmacological management to better prevent and control cardiovascular disease in overweight/obese individuals.

Topics: Biomarkers; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Cholesterol; Humans; Insulin Resistance; Meta-Analysis as Topic; Obesity; Overweight; Randomized Controlled Trials as Topic; Reproducibility of Results; Resveratrol; Risk Factors; Stilbenes

During the last years, the list of resveratrol effects has grown in parallel with the number of other members of the polyphenol family described to modulate glucose or lipid handling. In the same time, more than ten human studies on the influence of resveratrol supplementation on two related metabolic diseases, obesity and diabetes, have indicated that impressive beneficial effects co-exist with lack of demonstration of clinical relevance, irrespective of the daily dose ingested (0.075 to 1.5 g per capita) or the number of studied patients. Such contrasting observations have been proposed to depend on the degree of insulin resistance of the patients incorporated in the study. To date, no definitive conclusion can be drawn on the antidiabetic or antiobesity benefits of resveratrol. On the opposite, studies on animal models of diabesity consistently indicated that resveratrol impairs diverse insulin actions in adipocytes, blunting glucose transport, lipogenesis and adipogenesis. Since resveratrol also favours lipolysis and limits the production of proinflammatory adipokines, its administration in rodents results in limitation of fat deposition, activation of hexose uptake into muscle, improvement of insulin sensitivity, and facilitation of glucose disposal. Facing to a somewhat disappointing extrapolation to man of these promising antidiabetic and antiobesity properties, attention must be paid to re-examine resveratrol targets, especially those attainable after polyphenol ingestion and to re-define the responses to low doses. In this context, human adipocytes are proposed as a convenient model for the screening of "novel" polyphenols that can reproduce, out class, or reinforce resveratrol metabolic actions, Moreover, the use of combination of polyphenols is proposed to treat diabesity complications in view of recently reported synergisms. Lastly, multidisciplinar approaches are recommended for future investigations, considering the wide range of polyphenol actions that induce body fat reduction, liver disease mitigation, muscle function improvement, cardiovascular and renal protection.

Topics: Adipocytes; Animals; Diabetes Mellitus; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Polyphenols; Resveratrol; Stilbenes

Aging individuals and diabetic patients often exhibit concomitant reductions of skeletal muscle mass/strength and insulin sensitivity, suggesting an intimate link between muscle aging and insulin resistance. Foxo1, a member of the FOXO transcription factor family, is an important player in insulin signaling due to its inhibitory role in glucose uptake and utilization in skeletal muscle. Phosphorylation of Foxo1 is thought to mitigate the transactivation of pyruvate dehydrogenase lipoamide kinase 4 (PDK4), which is a negative regulator of the glycolytic enzyme pyruvate dehydrogenase (PDH). In contrast, how aging would regulate acetylation/deacetylation machineries and glucose utilization in skeletal muscle through the Foxo1/PDH axis remains largely undetermined. Accumulating body of evidence have shown that resveratrol, a natural polyphenol in grapes and red wine, activates the longevity-related protein sirtuin 1 (SIRT1) and augments insulin sensitivity in addition to its well-documented effects on mitochondrial energetics. The present review summarizes the role of Foxo1/SIRT1 in insulin signaling in skeletal muscle and proposes the insight that activation of SIRT1 deacetylase activity to deacetylate and suppress the Foxo1-induced transactivation of PDK4 may represent an anti-hyperglycemic mechanism of resveratrol in aging skeletal muscle.

Topics: Animals; Cellular Senescence; Forkhead Transcription Factors; Humans; Insulin Resistance; Muscle, Skeletal; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

The increasing prevalence, involvement of several signaling pathways, variable pathogenesis, progressive natural history and complications of type 2 diabetes emphasize an urgent need for a molecule with multiple actions. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic antioxidant present in red wine gaining a worldwide interest because of its multi-target effect against diabetes and other life-threatening diseases. Improving insulin sensitivity, enhancing GLUT4 translocation, reducing oxidative stress, regulating carbohydrate metabolizing enzymes, activating SIRT1 and AMPK, and decreasing adipogenic genes are some promising mechanisms established until now for resveratrol. Apart from these, resveratrol attenuates the end organ damage and reduced diabetic complications. Resveratrol exerts its beneficial antidiabetic action as evidenced from the in vitro, preclinical and clinical studies. Considering all the benefits of resveratrol in diabetes, resveratrol based different nutraceutical products have been developed commercially to use in humans. However, this compound is still under investigation because of some limitations. Resveratrol can be taken in to account in the treatment of diabetes after overcoming all hurdles and difficulties. This article examines the basic scientific evidences, animal experiments, and human/clinical data supporting the antidiabetic action of resveratrol and describes the strategies and challenges to recommend resveratrol from preclinical to clinical use.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; Carbohydrate Metabolism; Cardiotonic Agents; Diabetes Mellitus; Enzyme Activation; Glucose Transporter Type 4; Humans; Hypoglycemic Agents; Insulin Resistance; Mice; Oxidative Stress; Rats; Resveratrol; Sirtuin 1; Stilbenes

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis.

Topics: Adipokines; Animals; Carotenoids; Curcumin; Fatty Acids, Omega-3; Fatty Liver; Flavonols; Humans; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Polyphenols; Resveratrol; Stilbenes

Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Atherosclerosis; Bile Acids and Salts; Cholesterol; Chylomicrons; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Dyslipidemias; Exenatide; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Resistance; Intestine, Small; Lipoproteins; Microbiota; Peptides; Receptors, Glucagon; Resveratrol; Secretory Rate; Stilbenes; Triglycerides; Venoms

Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.

Topics: Adiponectin; Antihypertensive Agents; Atherosclerosis; Bariatric Surgery; Cardiovascular Diseases; Clinical Trials as Topic; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metabolic Syndrome; Metabolism, Inborn Errors; Obesity; Peroxisome Proliferator-Activated Receptors; Receptors, Adiponectin; Resveratrol; Stilbenes

The results of human clinical trials investigating the effects of resveratrol on glucose control and insulin sensitivity are inconsistent.. We aimed to quantitatively evaluate the effects of resveratrol on glucose control and insulin sensitivity.. 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.. 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.. 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.

Topics: Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

Adipose tissue has an important endocrine function in the regulation of whole-body metabolism. Obesity leads to a chronic low-grade inflammation of the adipose tissue, which disrupts this endocrine function and results in metabolic derangements, such as type-2 diabetes. Dietary bioactive compounds, such as polyphenols and certain fatty acids, are known to suppress both systemic and adipose tissue inflammation and have the potential to improve these obesity-associated metabolic disorders. Mechanistically, polyphenolic compounds including non-flavonoids, such as curcumin and resveratrol, and flavonoids, such as catechins (tea-polyphenols), quercetin and isoflavones, suppress nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases (MAPK) pathways while activating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway in adipose tissue. Dietary polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (CLA) and monounsaturated fatty acids (MUFA), such as oleic acid, also impart anti-inflammatory effects through several mechanisms. These include activation of AMPK and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as suppression of toll-like receptors (TLRs) and NF-κB pathway. This review discusses the major molecular mechanisms of dietary polyphenols and fatty acids, alone or in combination, which are responsible for adipose tissue-associated anti-inflammatory effects.

Topics: Adipose Tissue; Curcumin; Endocrine Glands; Fatty Acids; Food; Humans; Inflammation; Insulin Resistance; Polyphenols; Quercetin; Resveratrol; Stilbenes

Calorie restriction extends lifespan and confers metabolic benefits similar to the effect of lifestyle interventions. Poor compliance to long-term dietary restriction, however, hinders the success of this approach. Evidence is now persuasive for a role of resveratrol supplementation (a polyphenol in red grapes) as potential alternative to calorie restriction. This review summarizes the latest literature on the effects and the molecular mechanisms by which calorie restriction and resveratrol confer health benefits. Resveratrol activates SIRT1 and the associated improvement in energy utilization and insulin sensitivity closely resembles the benefits of calorie restriction. Current data largely support resveratrol as a potential calorie restriction mimetic to improve metabolic and probably functional health. Future studies which characterize the bioavailability and efficacy of resveratrol supplementation are critical to provide evidence for its long-term health benefits.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Caloric Restriction; Dietary Supplements; Energy Metabolism; Humans; Insulin Resistance; Longevity; Oxidative Stress; Resveratrol; Risk Reduction Behavior; Rodentia; Sirtuin 1; Stilbenes

Topics: Animals; Diabetes Mellitus, Experimental; Insulin Resistance; Resveratrol; Stilbenes

Diabetes mellitus is a complex metabolic disease affecting about 5% of people all over the world. Data from the literature indicate that resveratrol is a compound exerting numerous beneficial effects in organisms. Rodent studies, for example, have demonstrated that resveratrol decreases blood glucose in animals with hyperglycemia. This effect seems to predominantly result from increased intracellular transport of glucose. Resveratrol was also demonstrated to induce effects that may contribute to the protection of β cells in diabetes. In experiments on pancreatic islets, the ability of resveratrol to reduce insulin secretion was demonstrated; this effect was confirmed in animals with hyperinsulinemia, in which resveratrol decreased blood insulin levels. Moreover, inhibition of cytokine action and attenuation of the oxidative damage of the pancreatic tissue by resveratrol were recently shown. Studies of animals with insulin resistance indicate that resveratrol may also improve insulin action. The mechanism through which resveratrol improves insulin action is complex and involves reduced adiposity, changes in gene expression, and changes in the activities of some enzymes. These data indicate that resveratrol may be useful in preventing and treating diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Resveratrol; Stilbenes

SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase activity. Recent experiments using small molecule activators and genetically engineered mice have provided new insight into the role of this enzyme in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1alpha and NFkappaB, however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD(+) metabolism, are emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 activators are entering clinical trials in humans, and "nutraceutical" formulations containing resveratrol are already widely available.

Topics: Animals; Cardiotonic Agents; Energy Metabolism; Enzyme Activation; Heterocyclic Compounds, 4 or More Rings; Humans; Insulin Resistance; Learning; Longevity; Memory; Mice; Models, Biological; NAD; Neoplasms; Niacinamide; O-Acetyl-ADP-Ribose; Resveratrol; Silent Information Regulator Proteins, Saccharomyces cerevisiae; Sirtuin 1; Stilbenes

The metabolic syndrome (MetS) encompasses a constellation of cardio-metabolic abnormalities associated with a high risk of developing type 2 diabetes and cardiovascular disease (CVD), the top killer in the ageing population. Recent studies have demonstrated multiple beneficial effects of moderate wine consumption in the protection against development of the MetS and its related medical complications. The association of moderate wine consumption with lower incidence of the MetS and atherosclerotic heart disease has been repeatedly documented in numerous epidemiological studies on diverse ethnic groups. In addition to the favorable effects of moderate ethanol intake on lipid profiles, polyphenols enriched in red wine possess multiple benefits on the MetS beyond alcohol through their anti-oxidant, anti-inflammatory, vascular-protective and insulin-sensitizing properties. Notable among these red wine polypheolic compounds is resveratrol, a phytoalexin that has recently attracted great attention due to its role in mimicking calorie restriction. This compound can act as a potent activator of the NAD(+)-dependent deacetylases sirtuins to expand the life span and to prevent the deleterious effects of excess intake on insulin resistance and metabolic derangement. In addition, resveratrol exerts its multiple protective effects against the MetS through stimulating AMP-activated protein kinase and promoting mitochondria biogenesis. In this review, we highlight the recent epidemiological and experimental evidences supporting the protective effects of moderate wine intake against the MetS and its associated cardio-metabolic complications, and discuss the molecular mechanisms underlying the multiple beneficial actions of red wine polyphenols with the focus on resveratrol.

Topics: Alcohol Drinking; Animals; Antioxidants; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Metabolic Syndrome; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Wine

Calyx Therapeutics is developing the insulin sensitizer, CLX-0901, as an antidiabetic agent. CLX-0901 is the synthetic analog of CLX-0900 which was originally isolated from a plant source. Phase I and toxicological studies indicate that the compound is safe and well tolerated [363764]. As of March 2001, phase II studies had commenced [402737]. Other antidiabetics being investigated by Calyx include CLX-0301, CLX-0921, CLX-0940, CLX-0100 and CLX-0101 [376032].

Topics: Animals; Clinical Trials as Topic; Contraindications; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Stilbenes; Structure-Activity Relationship

Sirt1 and 5' adenosine monophosphate-activated protein kinase (AMPK) are energy-sensing systems that work cooperatively and regulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan. We have shown that leucine activates Sirt1 and enables synergy with sirtuin co-activators. Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective clinical translation of promising animal data. However, we found that combining low resveratrol doses with leucine increased skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation; these effects result in increased lifespan and marked reductions in insulin resistance, inflammatory markers, body weight, and visceral adiposity in preclinical models. To translate these data to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g) on glucose dynamics in a 4-week placebo-controlled trial of 36 prediabetic subjects. Leucine-resveratrol reduced insulin resistance (homeostatic model assessment for insulin resistance) 33% with corresponding reductions in glucose and insulin area under the curve in oral glucose tolerance tests. We extended these concepts in preclinical studies using both direct Sirt1 activators and Sirt1 pathway activators. Low-dose (10 nM) NAD

Topics: AMP-Activated Protein Kinases; Animals; Humans; Insulin Resistance; Leucine; Longevity; Mice, Obese; Prediabetic State; Resveratrol; Sirtuin 1; Stilbenes

Animal studies have shown the beneficial effects of piceatannol on metabolic health; however, there is a lack of human studies designed to examine these effects. The objective of this study was to investigate the effects of piceatannol on metabolic health in humans. This randomized, placebo-controlled study was conducted on 39 subjects, including 10 overweight men and 9 overweight women (BMI ≥ 25), as well as 10 non-overweight men and 10 non-overweight women (BMI < 25). Subjects received piceatannol (20 mg/day) or placebo capsules for eight weeks in a random order. The primary outcome was the effect of piceatannol on glucose-metabolism, including insulin sensitivity. The secondary outcomes were the effects on other parameters, including blood pressure (BP), heart rate (HR), endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1 and phospho-AMP-activated kinase (p-AMPK) expression in isolated peripheral blood mononuclear cells (PBMNCs). Supplementation with piceatannol in overweight men reduced serum insulin levels, HOMA-IR, BP and HR. Other groups, including non-overweight men, as well as overweight and non-overweight women, showed no beneficial effects on insulin sensitivity, BP and HR. Furthermore, piceatannol is not associated with other data, including body weight (BW), body composition, endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1/p-AMPK expression in PBMNCs. In conclusion, supplementation with piceatannol can improve metabolic health, including insulin sensitivity, BP and HR, in overweight men.

Topics: Administration, Oral; Adult; Aged; Biomarkers; Blood Pressure; Capsules; Double-Blind Method; Energy Metabolism; Female; Health Status; Heart Rate; Humans; Insulin Resistance; Japan; Male; Middle Aged; Overweight; Passiflora; Phytotherapy; Plants, Medicinal; Seeds; Stilbenes; Time Factors; Treatment Outcome; Young Adult

The aim of this study was to investigate the impact of resveratrol supplementation along with non-surgical periodontal treatment on blood glucose, insulin, insulin resistance, triglyceride (TG), and periodontal markers in patients with type 2 diabetes with periodontal disease. In this double-blind clinical trial study, 43 patients with diabetes with chronic periodontitis were participated. Subjects were randomly allocated to intervention and control groups. The intervention and control groups received either 480 mg/day of resveratrol or placebo capsules (two pills) for 4 weeks. Fasting blood glucose, insulin, insulin resistance (homeostasis model assessment of insulin resistance), TGs, and pocket depth were measured in all subjects' pre-intervention and post-intervention. The mean serum levels of fasting insulin and insulin resistance (homeostasis model assessment of insulin resistance) were significantly lower in the intervention group compared with control group (10.42 ± 0.28 and 10.92 ± 0.9; 3.66 ± 0.97 and 4.49 ± 1.56, respectively). There was a significant difference in the mean pocket depth between intervention and control groups (2.35 ± 0.6 and 3.38 ± 0.5, respectively) following intervention. No significant differences were observed in the mean levels of fasting blood glucose and TGs between two groups' post-intervention. It is recommended that resveratrol supplementation may be beneficial as adjuvant therapy along with non-surgical periodontal treatment in insulin resistance and improving periodontal status among patients with diabetes with periodontal disease. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Blood Glucose; Chronic Periodontitis; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Resveratrol; Stilbenes; Triglycerides

Low-grade inflammation is associated with obesity and the metabolic syndrome (MetS). Preclinical evidence suggests that resveratrol (RSV) has beneficial metabolic and anti-inflammatory effects that could have therapeutic implications.. To investigate effects of long-term RSV treatment on inflammation and MetS.. A randomized, placebo-controlled, double-blind, parallel group clinical trial conducted at Aarhus University Hospital.. Middle-aged community-dwelling men (N = 74) with MetS, 66 of whom completed all visits (mean ± standard error of the mean): age, 49.5 ± 0.796 years; body mass index, 33.8 ± 0.44 kg/m2; waist circumference, 115 ± 1.14 cm.. Daily oral supplementation with 1000 mg RSV (RSVhigh), 150 mg RSV, or placebo for 16 weeks.. Plasma levels of high-sensitivity C-reactive protein (hs-CRP), circulating lipids, and inflammatory markers in circulation and adipose/muscle tissue biopsy specimens; glucose metabolism; and body composition including visceral fat and ectopic fat deposition.. RSV treatment did not lower circulating levels of hs-CRP, interleukin 6, or soluble urokinase plasminogen activator receptor in plasma, and inflammatory gene expression in adipose and muscle tissues also remained unchanged. RSV treatment had no effect on blood pressure, body composition, and lipid deposition in the liver or striated muscle. RSV treatment had no beneficial effect on glucose or lipid metabolism. RSVhigh treatment significantly increased total cholesterol (P < 0.002), low-density lipoprotein (LDL) cholesterol (P < 0.006), and fructosamine (P < 0.013) levels compared with placebo.. RSV treatment did not improve inflammatory status, glucose homeostasis, blood pressure, or hepatic lipid content in middle-aged men with MetS. On the contrary, RSVhigh significantly increased total cholesterol, LDL cholesterol, and fructosamine levels compared with placebo.

Topics: Absorptiometry, Photon; Adipose Tissue; Antioxidants; Blood Glucose; Blood Pressure; Blotting, Western; Body Composition; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fructosamine; Humans; Insulin; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Metabolic Syndrome; Middle Aged; Muscle, Skeletal; Quadriceps Muscle; Real-Time Polymerase Chain Reaction; Receptors, Urokinase Plasminogen Activator; Resveratrol; Stilbenes; Triglycerides

The obese insulin-resistant state is characterized by impairments in lipid metabolism. We previously showed that 3-d supplementation of combined epigallocatechin-3-gallate and resveratrol (EGCG+RES) increased energy expenditure and improved the capacity to switch from fat toward carbohydrate oxidation with a high-fat mixed meal (HFMM) test in men.. The present study aimed to investigate the longer-term effect of EGCG+RES supplementation on metabolic profile, mitochondrial capacity, fat oxidation, lipolysis, and tissue-specific insulin sensitivity.. In this randomized double-blind study, 38 overweight and obese subjects [18 men; aged 38 ± 2 y; body mass index (kg/m(2)): 29.7 ± 0.5] received either EGCG+RES (282 and 80 mg/d, respectively) or placebo for 12 wk. Before and after the intervention, oxidative capacity and gene expression were assessed in skeletal muscle. Fasting and postprandial (HFMM) lipid metabolism was assessed by using indirect calorimetry, blood sampling, and microdialysis. Tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with [6,6-(2)H2]-glucose infusion.. EGCG+RES supplementation did not affect the fasting plasma metabolic profile. Although whole-body fat mass was not affected, visceral adipose tissue mass tended to decrease after the intervention compared with placebo (P-time × treatment = 0.09). EGCG+RES supplementation significantly increased oxidative capacity in permeabilized muscle fibers (P-time × treatment < 0.05, P-EGCG+RES < 0.05). Moreover, EGCG+RES reduced fasting (P-time × treatment = 0.03) and postprandial respiratory quotient (P-time × treatment = 0.01) compared with placebo. Fasting and postprandial fat oxidation was not significantly affected by EGCG+RES (P-EGCG+RES = 0.46 and 0.38, respectively) but declined after placebo (P-placebo = 0.05 and 0.03, respectively). Energy expenditure was not altered (P-time × treatment = 0.96). Furthermore, EGCG+RES supplementation attenuated the increase in plasma triacylglycerol concentrations during the HFMM test that was observed after placebo (P-time × treatment = 0.04, P-placebo = 0.01). Finally, EGCG+RES had no effect on insulin-stimulated glucose disposal, suppression of endogenous glucose production, or lipolysis.. Twelve weeks of EGCG+RES supplementation increased mitochondrial capacity and stimulated fat oxidation compared with placebo, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. This trial was registered at clinicaltrials.gov as NCT02381145.

Topics: Adult; Blood Glucose; Catechin; Dietary Supplements; Double-Blind Method; Energy Metabolism; Fasting; Female; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Male; Mitochondria; Muscles; Obesity; Plant Extracts; Postprandial Period; Resveratrol; Stilbenes

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Hyperandrogenism is the central feature of PCOS. Studies on isolated ovarian theca-interstitial cells suggest that resveratrol, a natural polyphenol, reduces androgen production.. This study was designed to evaluate endocrine and metabolic effects of resveratrol on PCOS.. This was a randomized (1:1) double-blind, placebo-controlled trial that evaluated the effects of resveratrol over a period of 3 months in an academic hospital.. Subjects with PCOS were identified according to the Rotterdam criteria. Thirty-four subjects were enrolled and 30 subjects completed the trial. Evaluations were performed at baseline and repeated after 3 months of treatment.. Resveratrol (1,500 mg p.o.) or placebo were administered daily.. Primary outcome was the change in the serum total T.. Resveratrol treatment led to a significant decrease of total T by 23.1% (P = .01). In parallel, resveratrol induced a 22.2% decrease of dehydroepiandrosterone sulfate (P = .01), a decrease of fasting insulin level by 31.8% (P = .007) and an increase of the Insulin Sensitivity Index (Matsuda and DeFronzo) by 66.3% (P = .04). Levels of gonadotropins, the lipid profile as well as markers of inflammation and endothelial function were not significantly altered.. Resveratrol significantly reduced ovarian and adrenal androgens. This effect may be, at least in part, related to an improvement of insulin sensitivity and a decline of insulin level.

Topics: Adult; Antioxidants; Dehydroepiandrosterone Sulfate; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Outcome Assessment, Health Care; Polycystic Ovary Syndrome; Resveratrol; Stilbenes; Testosterone

To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care.. Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique.. Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction.. Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes.

Topics: Adult; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metformin; Middle Aged; Resveratrol; Stilbenes

Non-alcoholic fatty liver disease is a major health problem worldwide. Resveratrol is a natural polyphenol found in edible plants that has a variety of biochemical and physiological effects.. To evaluate the effect of resveratrol on insulin resistance, glucose and lipid metabolism in non-alcoholic fatty liver disease.. Double-blind, randomized, placebo-controlled trial: 60 subjects with non-alcoholic fatty liver disease were given 2 placebo capsules (placebo group) or 2 150mg resveratrol capsules (resveratrol group) twice daily for three months. Liver ultrasound imaging, anthropometric profile, serum liver enzymes, insulin, glucose, C-peptide, lipid profile, and inflammation-related cytokines were compared pre and post-treatment.. Compared with the placebo group, resveratrol significantly decreased aspartate aminotransferase, glucose and low-density lipoprotein cholesterol [-6.00 (-9.00, -3.00) IU/L, -0.64±0.31mmol/L, and -0.41±0.35mmol/L, respectively, P≤0.001] alanine aminotransferase, total cholesterol [-7.00 (-11.0, -2.50) IU/L and -0.67±0.50mmol/L, respectively, P=0.002], and homeostasis model assessment insulin resistance index (-0.60±1.15, P=0.016). In the resveratrol group significant reductions of the levels of tumour necrosis factor-alpha, cytokeratin 18 fragment, and fibroblast growth factor 21 [-0.53±1.30pg/mL, -26.9 (-70.3, 5.12) IU/L and -23.3 (-43.0, 0.31) pg/mL, respectively, P<0.05] and elevation of adiponectin level [1.22 (-0.37, 1.60) ng/mL, P=0.025] were observed.. Resveratrol supplementation may benefit patients with non-alcoholic fatty liver disease.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Cholesterol; Cytokines; Double-Blind Method; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Resveratrol; Stilbenes; Ultrasonography; Young Adult

Non-alcoholic fatty liver disease (NAFLD) is usually associated with insulin resistance, central obesity, reduced glucose tolerance, type 2 diabetes mellitus and hypertriacylglycerolaemia. The beneficial effects of resveratrol on metabolic disorders have been shown previously. The aim of this study was to evaluate the effects of resveratrol supplementation on cardiovascular risk factors in patients with NAFLD. In this randomised double-blinded placebo-controlled clinical trial, fifty NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and physical activity recommendations. resveratrol supplementation reduced alanine aminotransferase (ALT) and hepatic steatosis significantly more than placebo (P0·05). There were no significant changes in blood pressure, insulin resistance markers and TAG in either group (P>0·05). Our data have shown that 12-week supplementation of 500 mg resveratrol does not have any beneficial effect on anthropometric measurements, insulin resistance markers, lipid profile and blood pressure; however, it reduced ALT and hepatic steatosis in patients with NAFLD.

Topics: Adult; Alanine Transaminase; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Blood Pressure; Cardiovascular Diseases; Dietary Supplements; Double-Blind Method; Fatty Liver; Female; Humans; Insulin Resistance; Lipid Metabolism; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phytotherapy; Plant Extracts; Resveratrol; Risk Factors; Stilbenes; Triglycerides

Non-alcoholic fatty liver (NAFL) disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes mellitus (T2D). Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults. The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth. This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D. This randomized double-blind controlled trial is designed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects (13 to <18 years of age) with NAFL. Secondary objectives are to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity. Adolescents in the intervention arm (n = 10) will receive oral supplementation of resveratrol 75 mg twice daily (with breakfast and dinner) for a total daily dose of 150 mg for the duration of 30 days. The comparison group (n = 10) will receive a placebo twice daily for 30 days. Both cases and controls will receive a standardized lifestyle intervention program. Subjects in both groups will be followed for an additional 30 days post intervention for total study duration of approximately 60 days. Primary outcome measures include a primary side effect profile determined by participant interview, a side effect profile determined by serum biochemistry and vital signs. Secondary outcome measures include an oral glucose tolerance test, liver and cardiac fat content measured by magnetic resonance spectroscopy, anthropometric measures of overweight/obesity, inflammatory markers, and cardiac function and morphology measured with ultrasonography. Additional outcome measures include serum concentrations of resveratrol, compliance to protocol, physical activity, and nutritional assessment. This study will determine the safety and tolerability of resveratrol in an overweight adolescent population and inform the design of a larger randomized controlled trial.

Topics: Administration, Oral; Adolescent; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin Resistance; Male; Non-alcoholic Fatty Liver Disease; Overweight; Pediatric Obesity; Resveratrol; Stilbenes

The primary aims of the study were to examine the effect of resveratrol on skeletal muscle SIRT1 expression and energy expenditure in subjects with Type 2 diabetes mellitus (T2DM).. Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1α activity. Subsequent upregulation of AMPK and GLUT4 expression are associated with improved insulin sensitivity in peripheral tissues.. Ten subjects with T2DM were randomized in a double-blind fashion to receive 3g resveratrol or placebo daily for 12 weeks. Secondary outcomes include measures of AMPK, p-AMPK and GLUT4 expression levels, energy expenditure, physical activity levels, distribution of abdominal adipose tissue and skeletal muscle fiber type composition, body weight, HbA1c, plasma lipid subfraction, adiponectin levels, and insulin sensitivity.. There was a significant increase in both SIRT1 expression (2.01 vs. 0.86 arbitrary units [AU], p = .016) and p-AMPK to AMPK expression ratio (2.04 vs. 0.79 AU, p = .032) in the resveratrol group compared with the placebo group. Although the percentage of absolute change (8.6 vs. -13.9%, p = .033) and percentage of predicted resting metabolic rate (RMR; 7.8 vs. -13.9%, p = .013) were increased following resveratrol, there was a significant reduction in average daily activity (-38 vs. 43.2%, p = .028) and step counts (-39.5 vs. 11.8%, p = .047) when compared with placebo.. In patients with T2DM, treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression. These findings indicate that resveratrol may have beneficial exercise-mimetic effects in patients with T2DM.

Topics: AMP-Activated Protein Kinases; Basal Metabolism; Diabetes Mellitus, Type 2; Double-Blind Method; Energy Metabolism; Exercise; Glucose Transporter Type 4; Humans; Insulin Resistance; Male; Middle Aged; Muscle, Skeletal; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Exertion; Plant Extracts; Rest; Resveratrol; Sirtuin 1; Stilbenes; Transcription Factors; Vitis

Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD.. Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed.. Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated.. Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

Topics: Abdominal Fat; Adult; Aged; Australia; Gastrointestinal Agents; Humans; Insulin Resistance; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Placebos; Resveratrol; Stilbenes; Treatment Outcome

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

Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo.. Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04).. These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48.. www.clinicaltrials.gov. Unique identifier: NCT01451918.

Topics: Adult; Analysis of Variance; Apolipoprotein B-100; Apolipoprotein B-48; Biomarkers; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins; Liver; Male; Middle Aged; Obesity; Ontario; Overweight; Resveratrol; Stilbenes; Time Factors; Treatment Outcome; Triglycerides

Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

Topics: Adolescent; Adult; Aged; Antioxidants; Body Composition; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Energy Metabolism; Gene Expression Regulation; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Pilot Projects; Resveratrol; Stilbenes; Young Adult

Although resveratrol has widely been studied for its potential health benefits, little is known about its metabolic effects in humans. Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action. After an initial general examination (including blood chemistry), nineteen patients enrolled in the 4-week-long double-blind study were randomly assigned into two groups: a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo. Before and after the second and fourth weeks of the trial, insulin resistance/sensitivity, creatinine-normalised ortho-tyrosine level in urine samples (as a measure of oxidative stress), incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio in platelets were assessed and statistically analysed. After the fourth week, resveratrol significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance) and urinary ortho-tyrosine excretion, while it increased the pAkt:Akt ratio in platelets. On the other hand, it had no effect on parameters that relate to β-cell function (i.e. homeostasis model of assessment of β-cell function). The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway.

Topics: Adult; Blood Platelets; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Insulin Resistance; Male; Middle Aged; Oxidative Stress; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Tyrosine

Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group A patients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease.

Topics: Aged; Diabetes Mellitus; Drug Compounding; Endothelium, Vascular; Female; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Life Style; Male; Metabolic Syndrome; Middle Aged; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents

Chronically elevated free fatty acid levels can adversely affect pancreatic β-cells, leading to insulin resistance and eventually type 2 diabetes mellitus (T2DM). Polydatin (PD) from Polygonum cuspidatum has been shown to regulate blood lipid content and lower cholesterol levels. However, there have been no reports on the potential therapeutic effects and actions of PD on lipotoxicity in β-cells.. This study aimed to investigate the protective effects of PD on palmitate (PA)-treated INS-1 insulinoma cells and diabetic mice.. Cells were incubated with PA and varying concentrations of PD for 24 h. Viability assays, morphological observations, flow cytometric analysis, western blotting, and reverse transcription-quantitative polymerase chain reaction were used to assess the effects of PD on PA-induced lipotoxicity. Western blotting was used to measure the endoplasmic reticulum stress (ERS) and the levels of autophagy-related factors after incubation with inducers and inhibitors of ERS and autophagy. Diabetic mice were treated with intragastric PD for 6 weeks followed by the measurement of their physiological and blood lipid indices and assessment of the results of histological and immunofluorescence analyses.. Treatment with PD after PA exposure enhanced insulin secretion and the expression of diabetes-associated genes. PD promoted β-cell function by reducing the levels of proteins associated with ERS and autophagy while also attenuating ERS triggered by tunicamycin. PD also reduced tunicamycin-induced autophagy, indicating that it regulated ERS-mediated autophagy and reduced PA-induced cellular dysfunction. In addition, treatment of db/db mice with PD substantially reduced body weight gain, alleviated dyslipidemia, improved β-cell function, and reduced insulin resistance.. These results suggest that PD protects β-cells from lipotoxicity-induced dysfunction and apoptosis by inhibiting ERS and preventing excessive autophagy. Our study provides a new basis for exploring the potential of PD against β-cell lipotoxicity and T2DM.

Topics: Animals; Apoptosis; Autophagy; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Fatty Acids, Nonesterified; Glucosides; Insulin Resistance; Insulin-Secreting Cells; Mice; Palmitates; Stilbenes; Tunicamycin

Senna siamea has been used as an antidiabetic drug since antiquity. With regard to traditional Thai medicine, the use of S. siamea was described for diabetes therapy. To understand the molecular mechanism regarding insulin resistance. Pure compounds were isolated from wood extract. We studied their biological activities on insulin-resistance using an in vivo zebrafish model. We also performed an in silico study; molecular docking, and in vitro study by taking advantage of the enzyme inhibitory activities of α-glucosidase, PTP1B, and DPP-IV. Based on the preliminary investigation that ethyl acetate and ethanol extracts have potent effects against insulin resistance on zebrafish larvae, five compounds were isolated from two fractions following: resveratrol, piceatannol, dihydropiceatannol, chrysophanol, and emodin. All of the isolated compounds had anti-insulin resistance effects on zebrafish larvae. Resveratrol, piceatannol, and dihydropiceatannol also demonstrated inhibitory effects against α-glucosidase. Chrysophanol and emodin inhibited PTP1B activity, while resveratrol showed a DPP-IV inhibition effect via the molecular docking. The results of enzyme assay were similar. In conclusions, S. siamea components demonstrated effects against insulin resistance. The chemical structure displayed identical biological activity to that of the compounds. Therefore, S. siamea wood extract and their components are potential therapeutic options in the treatment of diabetes.

Topics: alpha-Glucosidases; Animals; Anthraquinones; Diabetes Mellitus; Dipeptidyl Peptidase 4; Emodin; Hypoglycemic Agents; Insulin Resistance; Molecular Docking Simulation; Molecular Structure; Plant Extracts; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Resveratrol; Senna Plant; Stilbenes; Structure-Activity Relationship; Thailand; Wood; Zebrafish

Increased consumption of modern processed foods rich in AGEs is drawing worldwide concerns because they are related with rising diabetes prevalence. This study aimed to investigate if pterostilbene (PTE) regulates glucose metabolism and insulin signaling, as well as its potential mechanism in the context of AGEs exposure.. In vitro, Lo2 and HepG2 cells are treated with vehicle, AGEs with or without PTE. AGEs exposure directly impair insulin action as evidenced by assays of insulin-stimulated glucose uptake, consumption, and output. However, PTE efficiently rescue the AGE-induced phenotypes in both cell lines, and enhance IRS-1/PI3K/AKT insulin signaling in a dose-dependent manner. In vivo, C57BL6 mice are fed with regular, high AGEs diet and high AGEs plus PTE. PTE administration effectively improves hyperglycemia, glucose tolerance, and impaired hepatic insulin signaling induced by AGEs, consistent with the in vitro experiments. Moreover, PTE reduce AGEs accumulation in liver and serum. RNA-seq data indicate that PTE counteracts several AGEs-induced dysfunctions including diabetes related process, glucose metabolic process, immune response, and so on.. PTE treatment prominently reduced AGEs accumulation and alleviated AGEs-associated diabetes symptoms. PTE could be used as a promising glucose-sensitizing agent for nutritional intervention.

Topics: Acetates; Animals; Benzopyrans; Cell Survival; Gene Expression Regulation; Glucose; Glycation End Products, Advanced; Hep G2 Cells; Hepatocytes; Humans; Hyperglycemia; Insulin; Insulin Resistance; Male; Mice, Inbred C57BL; Proto-Oncogene Proteins c-akt; Stilbenes

Data on resveratrol-(trans-3,5,4'-trihydroxystilbene)-induced caloric-restriction-(CR)-mimicking effects in mice receiving a high-fat diet (HFD) are contradictory. It is hypothesized that this can possibly stem from different bioactivities of resveratrol (RSV) microbial metabolites.. C57BL/6Rj mice are fed an ad-libitum HFD supplemented with RSV or its metabolites, dihydroresveratrol (DHR) and lunularin (LUN) (≈28 mg (dihydro)stilbene kg. Decelerated carbohydrate breakdown by RSV may have contributed to the moderate impact of dietary RSV on mouse insulin sensitivity (lowered fasting and post-glucose-bolus insulin levels).

Topics: Animals; Bibenzyls; Body Composition; Caloric Restriction; Dietary Supplements; Gene Expression Regulation; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Insulin; Insulin Resistance; Leptin; Liver; Male; Metabolome; Mice, Inbred C57BL; Phenols; Resveratrol; Stilbenes

Isorhapontigenin is a natural bioactive stilbene isolated from various plants and fruits. It has been reported to exhibit several physiological activities including anticancer and anti-inflammation activity in vitro and in experimental animal models. This study aimed to investigate whether isorhapontigenin exerts antidiabetic effects in vivo. To this end, diabetic

Topics: 3T3-L1 Cells; Adipocytes; Animals; Blood Glucose; Cell Differentiation; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Mice; PPAR gamma; Stilbenes

Total polysaccharide from Polygonum multiflorum (PS) and 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) could relieve high-fat and high-sugar diet (HF-HSD) induced rats' insulin resistance (IR) by gut microbiota and host regulation. We found that PS and TSG significantly reversed the increase of fasting blood glucose and the decrease of glucose tolerance in HF-HSD induced IR rats. PS and TSG effectively reversed the imbalance of Firmicutes/Bacteroides caused by an HF-HSD, and significantly reduced the relative abundance of Proteobacteria. It also affected the functional genes of gut microbiota and regulated short-chain fatty acids (SCFAs) and its downstream signal protein molecules. Together, these results indicated that PS and TSG alleviated HF-HSD induced IR by promoting gut microbiota and host function. Thus, PS and TSG may be promising lead substances for developing IR inhibitors that could regulate gut microbiota and its molecular messenger SCFAs to remedy IR.

Topics: AMP-Activated Protein Kinases; Animals; Fallopia multiflora; Fatty Acids, Volatile; Feces; Gastrointestinal Microbiome; Glucosides; Insulin; Insulin Resistance; Liver; Male; Metagenomics; Polysaccharides; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; RNA, Ribosomal, 16S; Signal Transduction; Stilbenes

Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we evaluated ability of pterostilbene (PTS), a methoxylated analogue of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated IR in HepG2 cells. PTS prevented reactive oxygen species (ROS) formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 (NOX3) in PA treated HepG2 cells. Hepatic glucose production was used as a measure of IR and PTS reversed PA-mediated increase in hepatic glucose production by reducing expression of genes coding for gluconeogenic enzymes namely glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC); and their transcription factors cAMP response element binding protein (CREB) and fork head class Box O (FOXO1) along with its coactivator peroxisome proliferator-activated receptor gamma co-activator-1 α (PGC1α). PTS reversed PA-mediated activation of c-Jun N-terminal kinase (JNK), which in turn altered insulin signalling pathway by phosphorylating IRS-1 at Ser 307, leading to inhibition of phosphorylation of Akt and GSK-3β. PTS also reduced PA-mediated lipid accumulation by reducing expression of transcription factors SREBP1c and PPARα. SREBP1c activates genes involved in fatty acid and triglyceride synthesis while PPARα activates CPT1, a rate limiting enzyme for controlling entry and oxidation of fatty acids into mitochondria. PTS, however, did not influence PA uptake confirmed by using BODIPY-labelled fluorescent C16 fatty acid analogue. Thus, our data provides a possible mechanistic explanation for reversal of PA-mediated IR in HepG2 cells.

Topics: Hep G2 Cells; Humans; Insulin Resistance; Oxidative Stress; Palmitic Acid; Stilbenes; Triglycerides

Resveratrol (RES) has the ability to ameliorate nonalcoholic fatty liver disease (NAFLD) and the mechanism remains unclear. Hence, using high-fat diet (HFD) obese rat model, we investigated the effect of a low dose of RES (20 mg/kg) on the hepatic sterol regulatory element-binding protein (SREBPs) - lipogenesis pathway, enzymes involved in β-oxidation and activity of pancreatic lipase. Four groups of rats (n = 8) of control (12% of calories as fat) and HFD (40% of calories as fat) were administered orally with either normal saline as a vehicle or RES as a concomitant treatment for 8 weeks on a daily basis. Then, various biochemical, histological, and molecular experiments were carried out. RES prevented the development and progression of NAFLD and significantly improved insulin sensitivity through (1) inhibiting the proteolytic cleavage of SREBPs-1 and SREBPs-2 without affecting their precursor mRNA or protein levels, (2) inhibiting free fatty acid β-oxidation and generation of reactive oxygen species through significant inhibition of CPT-1 and UCP-2, and (3) decreasing activity of pancreatic lipase in vivo and in vitro. In conclusion, our findings are the first in the literature to show new mechanisms of the hepatoprotective effect of RES against HFD induced NAFLD in rats.

Topics: Animals; Antioxidants; Area Under Curve; Diet, High-Fat; Fatty Acids, Nonesterified; Fatty Liver; Feces; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Insulin Resistance; Intestinal Absorption; Lipase; Liver; Male; Organ Size; Oxidation-Reduction; Oxidative Stress; Proteolysis; Rats, Wistar; Resveratrol; RNA, Messenger; Sterol Regulatory Element Binding Proteins; Stilbenes; Triglycerides

The purpose of this study was to evaluate probable protective effects of resveratrol treatment on hepatic oxidative events in a rat model of metabolic syndrome (MetS).. Thirty-two male adult rats were randomly divided into 4 groups: control, fructose, resveratrol, and fructose plus resveratrol. To induce MetS, fructose solution (20 % in drinking water) was used. Resveratrol (10 mg/kg/day) was given by oral gavage. All treatments were given for 8 weeks. Serum lipid profile, glucose and insulin levels, liver total oxidant status (TOS) levels and paraoxonase (PON), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were analyzed.. Fructose-fed rats displayed statistically significant increases in TOS levels, and decreases in PON activity compared to the control group. Resveratrol treatment moderately prevented the decrease in liver PON activity caused by fructose. On the other hand, resveratrol, alone or in combination with fructose, did not change the TOS levels when compared to the fructose group. The SOD and CAT activities in all groups did not change.. In this experimental design, high-fructose consumption led to elevated TOS levels and low PON activities. The resveratrol therapy shown beneficial effects on PON activity. However, it was found to behave like a prooxidant when administered together with fructose and alone in some parameters. Our results can inspire the development of new clinical therapy in patients with MetS (Tab. 2, Ref. 34).

Topics: Animals; Antioxidants; Fructose; Glutathione Peroxidase; Insulin Resistance; Liver; Male; Metabolic Syndrome; Oxidants; Oxidative Stress; Rats; Resveratrol; Stilbenes; Superoxide Dismutase

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is associated with variable degrees of glucose intolerance, impaired insulin secretion, insulin resistance and increased hepatic glucose production. The aim of present study was to investigate the therapeutic potentials of resveratrol (RSV) alone and/or in combination with vitamin-E (Vit-E) against hyperglycemia-induced modulations using experimentally alloxan-induced diabetic animal model. Alloxan was used to induce diabetes mellitus in white albino rats and metformin (MF) was used as standard anti-diabetic drug to compare the therapeutic potentials of RSV (alone and/or with Vit-E) by estimating the effect of treatment on glycemia, insulin resistance, liver and kidney function biomarkers, anti-oxidant status, and serum levels of calcium and magnesium. The results of present study indicate the RSV (P < 0.001) alone and/or in combination with Vit-E (P < 0.001) exhibited a highly significant therapeutic potentials by ameliorating the glycemia-induced modulations. Moreover, we also found that RSV in combination with Vit-E also exhibited a better therapeutic effects when compared with that of MF (P < 0.001) and Vit-E (P < 0.05), respectively. Hence, we conclude that RSV alone and/or in combination with Vit-E exhibit its significant therapeutic potentials against hyperglycemia-induced modulations in experimental diabetic animal model and may be one of the most exciting prospect for future treatment of T2DM.

Topics: Animals; Antioxidants; Blood Glucose; Calcium; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Hyperglycemia; Insulin; Insulin Resistance; Magnesium; Male; Metformin; Rats; Resveratrol; Stilbenes; Vitamin E

Previous investigations on diabetic rats and palmitic corrosive instigated insulin-resistant HepG2 cells have shown that polydatin exhibits hypoglycemic and hypolipidemic impacts. The AMP-activated protein kinase (AMPK) pathway assumes a crucial part in glucose and lipid digestion. We aimed to investigate the regulatory system of polydatin on the glucose and lipid metabolism through the AMPK pathway. Glucose take-up, utilization levels, and oil red O recoloring were distinguished to confirm their impact on improving insulin resistance. A Western blot examination was utilized to investigate the phosphorylation levels of protein kinase B (Akt), glycogen synthase kinase (GSK)-3β, AMPK, acetyl-CoA carboxylase (ACC), and in addition the protein levels of the low-density lipoprotein receptor (LDLR) and sterol regulatory element-binding protein (SREBP)-1c. SREBP-1c nuclear translocation levels were recognized by a laser checking confocal magnifying instrument. One hundred nanomolar insulin treated for 24 h significantly declined the phosphorylation of Akt and AMPK, and increased the nucleoproteins of SREBP-1c compared with HepG2 cells without insulin. The insulin-resistant HepG2 cells prompted by insulin mediated the impact of polydatin on glucose and lipid digestion. Polydatin decreased glucose and lipid digestion of insulin-resistant HepG2 cells. Moreover, polydatin markedly raised phosphorylated Akt, GSK-3β, AMPK, ACC, diminished nuclear protein levels of SREBP-1c, and upgraded the protein levels of LDLR. Regulation of the AMPK pathway and changes in LDLR protein expression are potential focuses of polydatin in the treatment of insulin protection in insulin-resistant HepG2 cells.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Glucose; Glucosides; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; Insulin Resistance; Lipid Metabolism; Proto-Oncogene Proteins c-akt; Receptors, LDL; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Stilbenes

Fenugreek (

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Hypoglycemic Agents; Insulin Resistance; Mice; Mitochondria; Plant Extracts; Polyphenols; Stilbenes; Trigonella

The present study investigated the effects of cajanonic acid A (CAA), extracted from the leaves of Cajanus cajan (L.) Millsp with a purity of 98.22%, on the regulatory mechanisms of glucose and lipid metabolism. HepG2 cells transfected with a protein‑tyrosine phosphatase 1B (PTP1B) overexpression plasmid were established. The cells, induced with insulin resistance by dexamethasone (Dex) treatment, together with type 2 diabetes mellitus (T2DM) model rats and ob/ob mice, were used in the present study. The effects of CAA treatment on the differentiation of 3T3‑L1 adipocytes were determined using Oil Red O. The expression levels of insulin signaling factors were detected via reverse transcription‑quantitative polymerase chain reaction and western blot analyses. The results revealed that the overexpression of PTP1B contributed to insulin resistance, which was reversed by CAA treatment via inhibiting the activity of PTP1B and by regulating the expression of associated insulin signaling factors. The treatment of cell lines with Dex led to increased expression of PTP1B but decreased glucose consumption, and decreased tyrosine phosphorylation of insulin receptor, insulin receptor substrate 1, and phosphoinositide 3‑kinase. Treatment with CAA not only reduced the fasting blood glucose levels and protected organs from damage, but also reduced the serum fasting levels of total cholesterol, triglycerides and low‑density lipoprotein cholesterol in the T2DM rats. CAA treatment also inhibited adipocyte differentiation and decreased the mRNA levels of various adipogenic genes. Furthermore, CAA treatment restored the transduction of insulin signaling by regulating the expression of PTP1B and associated insulin signaling factors. Treatment with CAA also reduced the problems associated with hyperglycemia and hyperlipidemia. In conclusion, CAA may be used to cure T2DM via restoring insulin resistance and preventing obesity.

Topics: 3T3-L1 Cells; Animals; Cajanus; Diabetes Mellitus, Type 2; Glucose; Hep G2 Cells; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Male; Mice; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats, Sprague-Dawley; Stilbenes

SAMP8 mice exhibit multiple metabolic characteristics associated with age, and it is a suitable candidate for researching aging associated metabolic dysfunction.. We aimed to 1) explore how key metabolic markers will be altered in both liver and adipose tissue with aging in SAMP8 mice; and 2) how the combination of vitamin D (VD) with resveratrol (RSV) will affect aging associated metabolic impairment in liver and adipose tissue from SAMP8 mice.. SAMP8 mice and their control SAMR1 mice were divided into 5 groups, i.e. SAMR1, SAMP8, SAMP8 mice supplemented with VD, RSV and VD combined with RSV group, respectively. At the end of the intervention, glucose and insulin tolerance, p-AMP-activated protein kinase (AMPK) and amyloid precursor protein (APP), and endoplasmic reticulum (ER) stress markers in liver and adipose tissue, adiponectin secretion, p-NF-κBp65 and TNF-α protein expression in adipose tissue were determined.. Compared to SAMR1 control, SAMP8 mice demonstrate impaired glucose tolerance and reduction in circulating adiponectin level; in the liver, SAMP8 mice have reduction in p-Aktser473, elevation in PTP1B and APP, p-eIF2α, GRP78 and p-JNK protein expression. In epididymal (EPI) fat, SAMP8 mice also have elevated p-Aktser473 and PTP1B compared to SAMR1 mice. In both epididymal (EPI) and subcutaneous (SC) fat, there were elevated ER stress markers, reduced p-AMPK and elevated APP, as well as elevated p-NF-κBp65 and TNF-α protein expression from SAMP8 compared to SAMR1 mice. In liver, the combined intervention significantly restored p-Aktser473, p-eIF2α and p-JNK protein expression. In both EPI and SC fat, the combined intervention is effective for reducing p-NF-κB p65 and TNF-α in both fat depot, while only partially reduced ER stress markers in SC fat. As for adiponectin, their combination is unable to reverse reduction in adiponectin level. Adiponectin secretion in SC fat from VD, RSV and VDRSV group were also significantly reduced compared to SAMR1.. The combined intervention might exert greater beneficial effects for reversing aging associated metabolic dysfunction in liver and adipose tissue from SAMP8 mice.

Topics: Adipose Tissue; Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Blood Glucose; Body Weight; Drug Combinations; Drug Evaluation, Preclinical; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glucose Tolerance Test; Insulin Resistance; Liver; Male; Mice, Mutant Strains; Organ Size; Oxidative Stress; Resveratrol; Stilbenes; Vitamin D

Piceatannol, a bioactive component in grape and blueberry, was examined for its potential in decreasing the inflammatory activities in adipocytes using a cocultured adipocyte and macrophage system, and suppressing tumor necrosis factor-α (TNF-α)-mediated inflammation and the related insulin resistance using a 3T3-L1 adipocyte model. Piceatannol at 10 μM significantly reduced the release of inflammatory cytokines of TNF-α and monocyte chemoattractant protein-1 (MCP-1) by 19 and 31% in the cocultured system, respectively. Pretreatment with piceatannol also inhibited TNF-α-induced expression of interleukin-6 (IL-6) and MCP-1 at both mRNA and protein levels in the 3T3-L1 adipocytes. Piceatannol also partially improved the malfunction of insulin-stimulated glucose uptake, which was reduced by TNF-α in 3T3-L1 adipocytes. Furthermore, the inhibitions were mediated by significant blocking of IκBα phosphorylation and nuclear factor-κB (NF-κB) activation through suppressing nuclear translocation of NF-κB p65 along with c-Jun N-terminal kinase (JNK)-mitogen activated protein kinase (MAPK) activation. In addition, the Akt-dependent forkhead box O1 (FoxO1) signaling pathway was involved in the restoration of insulin-stimulated glucose uptake through suppressing the down-regulation of phosphorylation of Akt and FoxO1 expressions. These results suggested the potential of piceatannol in improving chronic inflammatory condition and insulin sensitivity in obese adipose tissues.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Chemokine CCL2; Forkhead Box Protein O1; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Mice; Phosphorylation; Plant Extracts; Stilbenes; Tumor Necrosis Factor-alpha

The present investigation was designed to explore the effectiveness of pterostilbene (PT) on insulin resistance, metabolic syndrome and oxidative stress in fructose-fed insulin resistant rats.. Age-matched, male Sprague-Dawley rats (330±30g body weight) were allocated into five groups (n=10). Control (C) group received 65% cornstarch, and the diabetic (D) group received 65% fructose for eight weeks. The third group (D+PT20) received 65% fructose and PT 20mg/kg/day for eight weeks. The fourth group (D+PT40) received 65% fructose and PT 40mg/kg/day for eight weeks. The fifth group (D+M) received 65% fructose and metformin (M) 100mg/kg/day for eight weeks. PT was dissolved in 10% β-cyclodextrin and given orally to rats. Several biochemical parameters were determined to assess the PT efficacy against insulin resistance, metabolic complications, and hepatic oxidative stress.. Significantly high HOMA-IR (p<0.001) values in D group compared to C group indicate the presence of insulin resistance. Significantly high levels of TBARS (p<0.001) and decreased levels of SOD (p<0.001) and GSH (p<0.001) in hepatic tissues of D group indicate oxidative stress associated with insulin resistance. Pterostilbene treatment to fructose-fed diabetic rats significantly decreased HOMA-IR (p<0.001) values. Furthermore, PT treatment significantly decreased hepatic TBARS (p<0.001) and increased SOD (p<0.001) and GSH (p<0.001) levels in fructose-fed diabetic rats.. Current study reveals that PT is successful in ameliorating glycemic control, insulin sensitivity while diminishing metabolic disturbances and hepatic oxidative stress in a fructose-induced T2DM rat model.

Topics: Animals; beta-Cyclodextrins; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructose; Insulin Resistance; Male; Metabolic Syndrome; Metformin; Oxidative Stress; Rats; Rats, Sprague-Dawley; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Lipogenesis is a process that involves the fatty acids synthesis. Resveratrol and enalapril have been studied for their beneficial physiological properties on the glucose and lipid metabolism.. The aim of the present study was to evaluate the oral administration of resveratrol and enalapril effects on glucose and lipid metabolism, evaluating the white pad lipogenesis genes expression in mice.. Swiss male mice were divided into four groups and treated for eight weeks as follows: Standard diet ad libitum (G1); Standard diet + Resveratrol (G2); Standard diet + Enalapril (G3); Standard diet + Resveratrol + Enalapril (G4), where resveratrol was administered with the food and enalapril with the water. Body weight, lipid profile, adiposity, glycemic parameters and epididymal adipocytes area were assessed. The expression levels of FAS, ACC, PPARγ and SREBP-1c were assessed by RT-PCR.. The main findings showed an improvement in the insulin sensitivity and glucose tolerance in the group G2 as compared to G1. Similar results were found for the fasting glucose levels. Decreased triglycerides were observed in the animals treated with resveratrol and enalapril, along with decreased weight of the epididymal adipose tissue in the animals of the G2 group. A mild reduction in the group G4 as compared to the group G1 was observed. Decreased mRNA expression of FAS, ACC and PPARγ in the G4 group when compared to the G1 group were observed.. In conclusion the resveratrol and enalapril association improved the glucose and lipid profiles by modulating the expression of some lipogenesis genes, which are critical regulators of metabolic homeostasis.

Topics: Adipocytes; Adipogenesis; Adipose Tissue, White; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Enalapril; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; Male; Mice; Resveratrol; Stilbenes

Insulin resistance is a characteristic finding in hyperglycaemia and type 2 diabetes. SIRT1 is a NAD

Topics: AMP-Activated Protein Kinases; Animals; Biological Transport; Carbohydrate Metabolism; Cell Culture Techniques; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Glucose; Glucose Transporter Type 4; Heterocyclic Compounds, 3-Ring; Insulin; Insulin Resistance; Lactones; Muscle, Skeletal; Myoblasts; Organelle Biogenesis; Phytochemicals; Rats; Signal Transduction; Sirtuin 1; Stilbenes

To investigate the effects of different intensity exercise combined with resveratrol on retinol binding protein 4(RBP4) mRNA and protein expression in visceral adipose tissue and plasma RBP4 concentration of aged obese rats.. Compared with normal (C) group, the expressions of RBP4 mRNA and protein and plasma concentration and plasma glucose of the model (CO) group were increased obviously (. Different intensities exercise combined with resveratrol could reduce the RBP4 mRNA and protein expression in visceral adipose tissue and plasma RBP4 concentrations of aged obese rats, but less affected by exercise intensity.

Topics: Aging; Animals; Insulin Resistance; Male; Obesity; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Retinol-Binding Proteins, Plasma; Stilbenes

Functional foods can be used alone or in combination with existing therapies in preventing and treating type 2 diabetes (T2D). Trans-2,3,5,4'-tetrahydroxystilbene 2-O-β-glucopyranoside (trans-THSG), a dominant bioactive compound from Polygonum multiflorum (PM)-a popular medicinal food in Asia, has attracted increasing research interests due to its strong antioxidant activity. The content of naturally occurring cis-THSG (cis-2,3,5,4'-tetrahydroxystilbene 2-O-β-glucopyranoside) was very low in PM root, but was prepared in this study by mimicking the traditional process of PM. The anti-diabetic effects of trans- and cis-THSG were evaluated in T2D to search for more efficacious food ingredient(s).. Trans-THSG was chromatographically purified from PM roots and cis-THSG was prepared with our innovative process via exposure of trans-THSG to UV-light. The anti-diabetic effects of both THSGs were tested with HFD-induced male CF-1 diabetic mice. Cis-THSG was found more effective than trans-THSG in hypoglycemic effect and in ameliorating glucose intolerance and insulin resistance. In HepG2 cells, cis-THSG also demonstrated more potent activity than trans-THSG in suppressing transcription of phosphoenopyruvate carboxykinase (PEPCK).. Cis-THSG can be an enriched bioactive ingredient in PM roots from post-processing and is significantly more effective against hyperglycemia than trans-THSG. One of the effective pathways was through inhibition of PEPCK.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Enzyme Inhibitors; Fallopia multiflora; Glucosides; Hep G2 Cells; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Phosphoenolpyruvate Carboxykinase (ATP); Stilbenes

This study aimed to determine whether resveratrol treatment alleviates endoplasmic reticulum stress and changes the expression of adipokines in adipose tissues and cells.. 8-week-old male C57BL/6 mice were fed a high-calorie diet (HCD group) or high-calorie diet supplemented with resveratrol (high-calorie diet  + resveratrol group) for 3 months. Insulin resistance, serum lipids and proinflammatory indices, the size and inflammatory cell infiltration in subcutaneous and visceral adipose tissues were analyzed. The gene expressions of endoplasmic reticulum stress, adipokines, and inflammatory cytokines were determined. The induced mature 3T3-L1 cells were pretreated with resveratrol and then palmitic acid, and the gene expressions of endoplasmic reticulum stress, adipokines, and inflammatory cytokines were determined.. Subcutaneous and visceral adipose tissues in the high-calorie diet-fed mice exhibited adipocyte hypertrophy, inflammatory activation, and endoplasmic reticulum stress. Resveratrol alleviated high-calorie diet-induced insulin resistance and endoplasmic reticulum stress, increased expression of SIRT1, and reversed expression of adipokines in varying degrees in both subcutaneous and visceral adipose tissues. The effects of resveratrol on palmitic acid-treated adipocytes were similar to those shown in the tissues.. Resveratrol treatment obviously reversed adipocyte hypertrophy and insulin resistance by attenuating endoplasmic reticulum stress and inflammation, thus increasing the expression of SIRT1 and inverting the expression of adipokines in vivo and in vitro.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Adipose Tissue; Animals; Cell Differentiation; Endoplasmic Reticulum Stress; Insulin Resistance; Lipids; Male; Mice; Palmitic Acid; Resveratrol; Stilbenes

We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg

Topics: Animals; Antioxidants; Energy Metabolism; Exercise Tolerance; Fatigue; Glucose; Heart Failure; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Microbiota; Muscle, Skeletal; Oxidation-Reduction; Oxygen Consumption; Physical Conditioning, Animal; Physical Exertion; Resveratrol; Stilbenes; Stroke Volume

Oxyresveratrol has been proven effective in inhibiting adipogenesis in a 3T3-L1 cell model. We investigated the preventive effect of oxyresveratrol supplementation on obesity development in high-fat diet-fed mice. Male C57bl/6 mice were randomly subjected to control (5% fat by weight, LF), high-fat (30% fat by weight, HF), and high-fat supplemented with 0.25% and 0.5% oxyresveratrol (OXY1 and OXY2, respectively) diet groups for eight weeks. Oxyresveratrol supplementation effectively alleviated obesity-associated symptoms such as insulin resistance, hyperglycemia, and hepatic steatosis in high-fat diet-fed mice. Compared to the high-fat diet group, oxyresveratrol supplementation suppressed expression of glucose-6-phosphatase, sterol regulatory element-binding proteins 1, fatty acid synthase and CCAAT/Enhancer-binding proteins α, and elevated AMP-activated protein kinase (α2-catalytic subunit) level in liver, upregulated insulin-dependent glucose transporter type 4 level in adipose tissue, and increased expression of insulin receptor substrate 1, insulin-dependent glucose transporter type 4, AMP-activated protein kinase α, peroxisome proliferator-activated receptor γ coactivator-1α, and sirtuin 1 in muscle to regulate lipid and glucose homeostasis in these tissues. This study demonstrated that oxyresveratrol supplementation effectively ameliorated obesity-associated symptoms in high-fat diet-fed mice, presumably attributed to mediating critical regulators involved in lipid and glucose homeostasis in liver, visceral fat, and muscle.

Topics: Adipogenesis; Animals; Diet, High-Fat; Dietary Supplements; Fatty Liver; Glucose; Homeostasis; Hyperglycemia; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Muscles; Obesity; Plant Extracts; Stilbenes

Resveratrol (RSV) has been proposed as an energy restriction mimetic. This study aimed to compare the effects of RSV and energy restriction on insulin resistance induced by an obesogenic diet. Any additive effect of both treatments was also analyzed. Rats were fed a high-fat high-sucrose diet for 6 weeks. They were then distributed in four experimental groups which were either fed a standard control diet (C), or treated with RSV (30 mg/kg/d), or submitted to energy restriction (R, 15%), or treated with RSV and submitted to energy restriction (RR). A glucose tolerance test was performed, and serum glucose, insulin, fructosamine, adiponectin, and leptin concentrations determined. Muscle triacylglycerol content and protein expression of insulin receptor (IRβ), protein kinase B (Akt), Akt substrate of 160 kDa (AS160) and glucose transporter 4 (GLUT-4) were measured. In RSV rats, fructosamine concentrations were reduced, HOMA-IR remained unchanged, but glucose tolerance was improved, without changes in phosphorylation of IRβ, Akt, and AS160 or in GLUT-4 protein expression. Rats under energy restriction showed an improvement in all the markers related to glycemic control, as well as increased phosphorylation of AS160 and protein expression of GLUT-4. In rats from RR group the results were similar to R group, with the exception of IRβ and Akt phosphorylation, which were increased. In conclusion, mild energy restriction is more efficient than intake of RSV within a standard balanced diet, and acts by means of a different mechanism from that of RSV. No additive effects between RSV and energy restriction were observed. © 2017 BioFactors, 43(3):371-378, 2017.

Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Caloric Restriction; Diet, High-Fat; Fructosamine; Gene Expression; Glucose Tolerance Test; Glucose Transporter Type 4; Insulin; Insulin Resistance; Leptin; Male; Muscle, Skeletal; Obesity; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor, Insulin; Resveratrol; Stilbenes; Sucrose; Triglycerides

Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either resveratrol or placebo treatment for four months. Changes in steroid hormones across all four matrices were the most pronounced changes observed. Resveratrol treatment reduced sulfated androgen precursors in blood, adipose tissue, and muscle tissue, and increased these metabolites in urine. Furthermore, markers of muscle turnover were increased and lipid metabolism was affected, with increased intracellular glycerol and accumulation of long-chain saturated, monounsaturated, and polyunsaturated (n3 and n6) free fatty acids in resveratrol-treated men. Finally, urinary derivatives of aromatic amino acids, which mainly reflect the composition of the gut microbiota, were altered upon resveratrol treatment. In conclusion, the non-targeted metabolomics approach applied to four different matrices provided evidence of subtle but robust effects on several metabolic pathways following resveratrol treatment for four months in men with metabolic syndrome-effects that, for the most part, would not have been detected by routine analyses. The affected pathways should be the focus of future clinical trials on resveratrol's effects, and perhaps particularly the areas of steroid metabolism and the gut microbiome.

Topics: Adipose Tissue; Biomarkers; Blood Pressure; Gastrointestinal Microbiome; Humans; Insulin Resistance; Male; Metabolic Syndrome; Metabolomics; Middle Aged; Muscles; Obesity; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

Gestational diabetes mellitus (GDM), which complicates up to 20% of all pregnancies, is associated with low-grade maternal inflammation and peripheral insulin resistance. Sterile inflammation and infection are key mediators of this inflammation and peripheral insulin resistance. Resveratrol, a stilbene-type phytophenol, has been implicated to exert beneficial properties including potent anti-inflammatory and antidiabetic effects in non-pregnant humans and experimental animal models of GDM. However, studies showing the effects of resveratrol on inflammation and insulin resistance associated with GDM in human tissues have been limited. In this study, human placenta, adipose (omental and subcutaneous) tissue and skeletal muscle were stimulated with pro-inflammatory cytokines TNF-α and IL-1β, the bacterial product lipopolysaccharide (LPS) and the synthetic viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) to induce a GDM-like model. Treatment with resveratrol significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, IL-1α, IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in human placenta and omental and subcutaneous adipose tissue. Resveratrol also significantly restored the defects in the insulin signalling pathway and glucose uptake induced by TNF-α, LPS and poly(I:C). Collectively, these findings suggest that resveratrol reduces inflammation and insulin resistance induced by chemical and microbial products. Resveratrol may be a useful preventative therapeutic for pregnancies complicated by inflammation and insulin resistance, like GDM.

Topics: Adipose Tissue; Diabetes, Gestational; Female; Humans; Infant; Inflammation; Insulin; Insulin Resistance; Muscle, Skeletal; Placenta; Pregnancy; Resveratrol; Signal Transduction; Stilbenes

Resveratrol is a phytoalexin with beneficial effects on human health. The aim of the present study was to investigate the effects of resveratrol on endothelial dysfunction involved in insulin signaling and inflammation.. Endothelial cells were stimulated with palmitate (PA) to induce insulin resistance characterized by a loss of insulin-mediated nitric oxide (NO) production. Diabetes was induced in rats by fructose feeding. The effects of resveratrol and the mechanisms involved were investigated using an aortic relaxation assay and Western blot analysis.. In endothelial cells, 0.1-10 μmol/L resveratrol suppressed IκB kinase β (IKKβ)/nuclear factor-κB phosphorylation, as well as tumor necrosis factor-α and interleukin-6 production, and restored the insulin receptor substrate-1 (Irs-1)/Akt/endothelial NO synthase signaling pathway. Furthermore, resveratrol effectively inhibited the mitogenic actions of insulin by decreasing the secretion of endothelin-1 and plasminogen activator inhibitor-1. It also positively regulated AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) activation, which contributed to the inhibition of inflammation implicated in endothelial insulin resistance. Stimulation with PA and long term-fructose feeding impaired insulin-mediated vessel dilation in rat aorta, whereas pretreatment of aortic rings with resveratrol (0.1-10 μmol/L) or treatment of rats with 5 or 20 mg/kg resveratrol counteracted these changes.. The results indicate that resveratrol inhibits inflammation and facilitates insulin phosphatidylinositol 3-kinase signaling by beneficial modulation of IRS-1 function partly via regulation of AMPK and SIRT1 activity in the endothelium.

Topics: AMP-Activated Protein Kinases; Animals; Blotting, Western; Cytokines; Diabetes Mellitus, Experimental; Endothelium, Vascular; Fructose; Gene Expression Regulation; Inflammation; Insulin Resistance; Male; Microscopy, Fluorescence; Nitric Oxide; Phosphorylation; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Vasodilation

Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol.. Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

Topics: Adipose Tissue; Animals; Antioxidants; Blood Glucose; Body Weight; Epididymis; Gene Expression Profiling; Glucose; Glucose Tolerance Test; Homeostasis; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Leukocytes; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Osmosis; Resveratrol; Stilbenes

Piceatannol is a phytochemical in the seeds of passion fruit that has a hypoglycemic effect when orally administered. To elucidate the contribution of intact and metabolites of piceatannol after gastro-intestinal absorption to hypoglycemic effect, we examined the influence of piceatannol and isorhapontigenin on blood glucose concentrations during fasting and glucose tolerance tests by administering them intravascularly to freely moving healthy rats. We found that intravascularly administered piceatannol reduced the blood glucose concentrations during both fasting and glucose tolerance tests, but isorhapontigenin did not during either of them. Furthermore, we found that piceatannol increased the insulinogenic index during glucose tolerance tests and that piceatannol had no influence on insulin sensitivity by performing hyperinsulinemic euglycemic clamping tests. These results suggest that piceatannol orally intaken may enhance glucose tolerance by the effect of intact piceatannol through enhanced early-phase secretion of insulin. Therefore, oral intake of piceatannol might contribute to proper control of postprandial glycemic excursions in healthy subjects.

Topics: Administration, Oral; Animals; Blood Glucose; Dose-Response Relationship, Drug; Fasting; Glucose Tolerance Test; Hypoglycemic Agents; Injections, Intra-Arterial; Injections, Intravenous; Insulin Resistance; Male; Rats; Rats, Sprague-Dawley; Stilbenes; Treatment Outcome

Abnormalities in lipid and glucose metabolism are constantly observed in type 2 diabetes. However, these abnormalities can be ameliorated by polydatin. Considering the important role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in metabolic diseases, we explore the possible mechanism of polydatin on lipid and glucose metabolism through its effects on PCSK9.. An insulin-resistant HepG2 cell model induced by palmitic acid (PA) and a db/db mice model were used to clarify the role of polydatin on lipid and glucose metabolism.. In insulin-resistant HepG2 cells, polydatin upregulated the protein levels of LDLR and GCK but repressed PCSK9 protein expression, besides, polydatin also inhibited the combination between PCSK9 and LDLR. Knockdown and overexpression experiments indicated that polydatin regulated LDLR and GCK expressions through PCSK9. In the db/db mice model, we found that polydatin markedly enhanced GCK and LDLR protein levels, and inhibited PCSK9 expression in the liver. Molecular docking assay was further performed to analyze the possible binding mode between polydatin and the PCSK9 crystal structure (PDB code: 2p4e), which indicated that steady hydrogen bonds formed between polydatin and PCSK9.. Our study indicates that polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating PCSK9.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Female; Germinal Center Kinases; Glucosides; Hep G2 Cells; Hepatocytes; Humans; Hydrogen Bonding; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Palmitic Acid; Proprotein Convertase 9; Proprotein Convertases; Protein Binding; Protein Conformation; Protein Serine-Threonine Kinases; Receptors, LDL; RNA Interference; Serine Endopeptidases; Stilbenes; Time Factors; Transfection

This study aims to investigate the effects of metformin and resveratrol on muscle insulin resistance with emphasis on the regulation of lipolysis in hypoxic adipose tissue. ICR mice were fed with high fat diet (HFD) for 10days with administration of metformin, resveratrol, or intraperitoneal injection of digoxin. Adipose hypoxia, inflammation and cAMP/PKA-dependent lipolysis were investigated. Moreover, lipid deposition and insulin resistance were examined in the muscle. Metformin and resveratrol attenuated adipose hypoxia, inhibited HIF-1α expression and inflammation in the adipose tissue of HFD-fed mice. Metformin and resveratrol inhibited lipolysis through prevention of PKA/HSL activation by decreasing the accumulation of cAMP via preserving PDE3B. Metformin and resveratrol reduced FFAs influx and DAG accumulation, and thus improved insulin signaling in the muscle by inhibiting PKCθ translocation. This study presents a new view of regulating lipid metabolism to ameliorate insulin resistance and provides the clinical guiding significance for obesity and type 2 diabetes with metformin and resveratrol treatment.

Topics: 3T3-L1 Cells; Adipose Tissue; Administration, Oral; Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diet, High-Fat; Diglycerides; Fatty Acids; Feeding Behavior; Glucose; Hypoxia; Inflammation; Insulin; Insulin Resistance; Lipolysis; Male; Metformin; Mice; Mice, Inbred ICR; Models, Biological; Muscles; Resveratrol; Signal Transduction; Stilbenes

Titanium dioxide nanoparticle (TiO2 NP) is an authorized food additive. Previous studies determined oral administration of TiO2 NPs increases plasma glucose in mice via inducing insulin resistance. An increase in reactive oxygen species (ROS) has been considered the possible mechanism of increasing plasma glucose. However, persistently high plasma glucose is also a mechanism of increasing ROS. This study aims to explore whether TiO2 NPs increase plasma glucose via ROS. We found after oral administration of TiO2 NPs, an increase in ROS preceded an increase in plasma glucose. Subsequently, mice were treated with two antioxidants (resveratrol and vitamin E) at the same time as oral administration of TiO2 NPs. Results showed resveratrol and vitamin E reduced TiO2 NPs-increased ROS. An increase in plasma glucose was also inhibited. Further research showed resveratrol and vitamin E inhibited the secretion of TNF-α and IL-6, and the phosphorylation of JNK and p38 MAPK, resulting in improved insulin resistance. These results suggest TiO2 NPs increased ROS levels, and then ROS activated inflammatory cytokines and phosphokinases, and thus induced insulin resistance, resulting in an increase in plasma glucose. Resveratrol and vitamin E can reduce TiO2 NPs-increased ROS and thereby inhibit an increase in plasma glucose in mice.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blood Glucose; Insulin Resistance; Male; Metal Nanoparticles; Mice; Reactive Oxygen Species; Resveratrol; Stilbenes; Titanium; Vitamin E

Adipose tissue inflammation is believed to play a pivotal role in the development obesity-related morbidities such as insulin resistance. However, it is not known how this (low-grade) inflammatory state develops. It has been proposed that the leakage of lipopolysaccharides (LPS), originating from the gut microbiota, through the gut epithelium could drive initiation of inflammation. To get a better understanding of which proteins and intracellular pathways are affected by LPS in adipocytes, we performed SILAC proteomic analysis and identified proteins that were altered in expression. Furthermore, we tested the anti-inflammatory compound resveratrol. A total of 927 proteins were quantified by the SILAC method and of these 57- and 64 were significantly up- and downregulated by LPS, respectively. Bioinformatic analysis (GO analysis) revealed that the upregulated proteins were especially involved in the pathways of respiratory electron transport chain and inflammation. The downregulated proteins were especially involved in protein glycosylation. One of the latter proteins, GALNT2, has previously been described to regulate the expression of liver lipases such as ANGPTL3 and apoC-III affecting lipid metabolism. Furthermore, LPS treatment reduced the protein levels of the insulin sensitizing adipokine, adiponectin, and proteins participating in the final steps of triglyceride- and cholesterol synthesis. Generally, resveratrol opposed the effect induced by LPS and, as such, functioning as an ameliorating factor in disease state. Using an unbiased proteomic approach, we present novel insight of how the proteome is altered in adipocytes in response to LPS as seen in obesity. We suggest that LPS partly exerts its detrimental effects by altering glycosylation processes of the cell, which is starting to emerge as important posttranscriptional regulators of protein expression. Furthermore, resveratrol could be a prime candidate in ameliorating dysfunctioning adipose tissue induced by inflammatory stimulation.

Topics: Adipocytes; Adipose Tissue; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Gastrointestinal Microbiome; Gene Expression Regulation; Glycosylation; Humans; Inflammation; Insulin; Insulin Resistance; Lipid Metabolism; Lipogenesis; Lipopolysaccharides; N-Acetylgalactosaminyltransferases; Obesity; Polypeptide N-acetylgalactosaminyltransferase; Proteome; Proteomics; Resveratrol; Stilbenes

The polyphenol compound resveratrol (RSV) has attracted attention due to its reputed beneficial effects on insulin sensitivity. Our lab has previously identified protective effects of RSV against the development of type 2 diabetes in rats. These effects occurred in a manner similar to thiazolidinedione's (TZDs), a class of insulin sensitizing drugs. TZDs are commonly prescribed in combination with metformin (MET) and thus we sought to examine the combined effects of RSV and MET in treating insulin resistance. Male C57BL6 mice were fed a low- (LFD; 10% Kcal from fat) or high-fat diet (HFD; 60% Kcal from fat) for 9 weeks to induce glucose and insulin intolerance. HFD mice were then assigned to control (HFD), MET (231.28 ± 12.24 mg/kg/day), RSV (93.68 ± 3.51 mg/kg/day), or combined (COM; MET 232.01 ± 17.12 mg/kg/day and RSV 92.77 ± 6.92 mg/kg/day) treatment groups. Changes in glucose and insulin tolerance and tissue-specific insulin signaling were measured 4 weeks post-treatment. RSV or MET alone did not have beneficial effects on glucose tolerance, although MET significantly improved insulin tolerance compared to HFD Glucose and insulin tolerance were significantly improved in COM compared to HFD and this was mirrored by enhanced insulin-stimulated AKT phosphorylation in triceps muscle and inguinal subcutaneous adipose tissue in COM compared to HFD mice. Improvements with COM treatment were not explained by differences in body weight, adiposity, or markers of adipose tissue inflammation. In summary, this study provides evidence of beneficial effects of combined RSV and MET therapy in treating impairments in glucose homeostasis.

Topics: Adiposity; Animals; Blood Glucose; Diet, High-Fat; Drug Therapy, Combination; Inflammation Mediators; Insulin Resistance; Male; Metformin; Mice; Mice, Inbred C57BL; Oncogene Protein v-akt; Organ Specificity; Resveratrol; 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

Hyperglycaemia in diabetes is either caused by reduced availability of insulin (type 1 diabetes, T1D) or insulin resistance to the cells (type 2 diabetes, T2D). In recent years, the prevalence of T2D has increased to an alarming proportion, encompassing 95 percent of the total diabetic burden, probably due to economy-driven changes in lifestyle. Recent epidemiological studies show comorbid depression, anxiety and related mental illness. To explore the molecular mechanisms underlying this comorbid conditions, we used Sprague-Dawley rats on high-fructose diet for 8 weeks to induce prediabetic condition. Rats with this metabolic syndrome also showed hyper-anxiety when they were subjected to anxiety-related behavioural assays. Rats were administered with resveratrol, an activator of sirtuins, and metformin, a standard antidiabetic drug, simultaneously with fructose. We observed that resveratrol was more effective in protecting from both the metabolic (prediabetic) and affective (anxiety) disorders than metformin. Molecular studies showed that recovery was associated with the upregulation of few nuclear sirtuins that act epigenetically - Sirt 1 and 7, which were significantly attenuated in the striatum of prediabetic rats. In conclusion, our study showed that hyper-anxiety associated with prediabetic condition is ameliorated by resveratrol through modulation of sirtuins, which is more or less similar to metformin.

Topics: Animals; Antioxidants; Anxiety Disorders; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Epigenesis, Genetic; Fructose; Gene Expression Regulation; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Metformin; Prediabetic State; Rats; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

Catch up growth (CUG) motivated by under-nutrition can lead to insulin resistance (IR) and visceral fat over-accumulation. However, the precise mechanisms on IR induced by adipose tissue changes during CUG remain unresolved.. Experimental rats were divided into three groups: normal chow group, catch up growth group and resveratrol administrated group. The whole experiment was carried out in four stages: 4, 6, 8 and 12 weeks. Peroxisome-proliferator activated receptor gamma (PPAR-γ) and fat-specific protein 27 (FSP27) expression level in epididymal adipose tissues (EAT) and subcutaneous adipose tissues (SAT) were detected along with other IR indicators.. Calorie restriction (CR) significantly increased PPAR-γ expression in EAT while decreased FSP27 expression. During re-feeding, both of the expression of PPAR-γ and FSP27 increased, even FSP27 returned to normal level when CUG for 4 weeks. Although PPAR-γ expression declined slightly at 8 weeks, it was still much stronger than normal chow groups. However, no changes were seen in SAT. Relative insufficiency of FSP27 expression in EAT results in a decrease in lipid storage capacity, causing a series of path physiological changes that led to the formation of IR. Resveratrol inhibited the expression of PPAR-γ and promoted FSP27 expression, thus fundamentally improving IR.. The imbalance between adipose synthesis and storage mediated by PPAR-γ / FSP27 in the EAT plays a pivotal role in the formation of IR during CUG. Resveratrol can correct fat formation and storage imbalance status by up-regulating FSP27 and down-regulating PPAR-γ expression level, ameliorating insulin sensitivity.

Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis Regulatory Proteins; Caloric Restriction; Energy Intake; Epididymis; Epididymitis; Gene Expression Regulation; Humans; Insulin Resistance; Intra-Abdominal Fat; Male; Obesity; PPAR gamma; Proteins; Rats; Resveratrol; Stilbenes; Subcutaneous Fat

Stress is associated with many diseases and dysfunctions, such as depression, cardiovascular alterations, immunological function disorder, inflammation, obesity, and insulin resistance. Stress-induced inflammation is associated with the genesis of insulin resistance. Stress activates hypothalamic pituitary adrenal axis, Renin Angiotensin System pathway, and sympatho-adrenal system, all of which are involved in the production of cytokines, causing the negative downregulation of insulin signaling either by phosphorylating serine residues of IRS or by inhibiting the activity of Akt leading to insulin resistance. In this study, male LACA mice (20-30 g) were subjected to 2 h of chronic restraint stress daily for 30 days at variable time. Resveratrol, caffeic acid, glibenclamide, and their combinations were administered 45 min prior to restraint stress daily for 30 days and their anti-inflammatory effect was examined on CRS-induced behavioral, biochemical, and metabolic alterations. Induction of stress in mice was evident by increased corticosterone and decreased bodyweight. Chronic restraint stress for 30 days developed insulin resistance characterized by hyperglycemia, hyperinsulinemia, increased glycosylated haemoglobin (HbA1c), and homeostasis model assessment of insulin resistance index, hyperlipidemia, increased inflammatory cytokines, and TNF-α. Treatment with resveratrol, caffeic acid, and their combinations has attenuated stress-induced insulin resistance by reducing inflammation.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Caffeic Acids; Corticosterone; Cytokines; Drug Therapy, Combination; Glyburide; Hypoglycemic Agents; Insulin Resistance; Male; Mice, Inbred Strains; Restraint, Physical; Resveratrol; Stilbenes; Stress, Psychological

Growing evidence indicates that in diabetes, high glucose concentrations affect podocyte metabolism and function. The crucial pathological feature of type 2 diabetes mellitus and metabolic syndrome is insulin resistance, often developed as a result of dysregulation of nutrient-responsible systems and disturbance of cellular homeostasis under diabetic conditions. Here, we report the involvement of the reciprocal interplay between deacetylase SIRT1 and protein kinase AMPK in podocyte high glucose-induced abolition of insulin-dependent glucose uptake, manifesting insulin resistance. Experiments were performed on primary rat podocytes cultured in standard or high glucose conditions. Immunodetection methods were used to determine SIRT1 protein level and AMPK phosphorylation degree. Insulin-stimulated changes in glucose uptake were used to determine podocyte responsiveness to insulin. SIRT1 activity was modulated by resveratrol, EX-527, or small interfering RNA targeting SIRT1. We have demonstrated that the absence of the stimulating effect of insulin on glucose uptake into primary rat podocytes after long-time exposition to high glucose concentrations, is a result of decreased SIRT1 protein levels and activity, associated with decreased AMPK phosphorylation degree, presumably underlying the induction of insulin resistance. Our findings suggest that the interplay between SIRT1 and AMPK is involved in the regulation of insulin action in podocytes.

Topics: AMP-Activated Protein Kinases; Animals; Glucose; Insulin; Insulin Resistance; Phosphorylation; Podocytes; Rats; Resveratrol; RNA, Small Interfering; Signal Transduction; Sirtuin 1; Stilbenes

Sleep fragmentation (SF) increases food intake and the risk of obesity, and recruits macrophages to visceral white adipose tissue (VWAT) promoting tissue inflammation and insulin resistance. Administration of resveratrol (Resv) has been associated with significant improvements in high-fat diet-induced obesity, inflammation and insulin resistance.. Male mice were subjected to SF or sleep control conditions for 8 weeks, and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin and leptin were obtained and VWAT insulin sensitivity tests were performed (phosphorylated AKT/total AKT), along with flow-cytometric assessments for VWAT macrophages (M1 and M2) and T-cell lymphocytes (CD4+, CD8+ and T regulatory cell (Treg)).. SF-Veh and SF-Resv mice showed increased food consumption and weight gain. However, although SF-Veh mice exhibited increased fasting insulin and leptin levels, and reduced VWAT p-AKT/AKT responses to insulin, such alterations were abrogated in SF-Resv-treated mice. Increases in M1, reduced M2 counts and increased tumor necrosis factor-α release emerged in SF-Veh macrophages compared with all other three groups. Similarly, increased CD8+ and reduced Treg lymphocyte counts were apparent in SF-Veh.. Resveratrol does not reverse the SF-induced increases in food intake and weight gain, but markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy in the context of sleep disorders manifesting metabolic morbidity.

Topics: Animals; Anti-Obesity Agents; Diet, High-Fat; Disease Models, Animal; Eating; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Male; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Sleep Apnea Syndromes; Stilbenes; Tumor Necrosis Factor-alpha; Weight Gain

The pathophysiology of non-alcoholic fatty liver disease remains to be elucidated, and the currently available treatments are not entirely effective. Polydatin, a stilbenoid compound derived from the rhizome of Polygonum cuspidatum, has previously been demonstrated to possess hepatoprotective effects. The present study aimed to determine the effects of polydatin supplementation on hepatic fat accumulation and injury in rats fed a high-fat diet. In addition, the mechanisms underlying the protective effects of polydatin were examined. Male Sprague Dawley rats were randomly divided into four groups and received one of four treatment regimes for 12 weeks: Control diet, control diet supplemented with polydatin, high-fat diet, or high-fat diet supplemented with polydatin. Polydatin was supplemented in the drinking water at a concentration of 0.3% (wt/vol). The results of the present study showed that long-term high-fat feeding resulted in fatty liver in rats, which was manifested by excessive hepatic neutral fat accumulation and elevated plasma alanine aminotransferase and aspartate aminotransferase levels. Polydatin supplementation alleviated the hepatic pathological changes, and attenuated the insulin resistance, as shown by an improved homeostasis model assessment of basal insulin resistance values and a glucose tolerance test. Polydatin supplementation also corrected abnormal leptin and adiponectin levels. Specifically, polydatin supplementation enhanced insulin sensitivity in the liver, as shown by improved insulin receptor substrate 2 expression levels and Akt phosphorylation in the rat liver, following high-fat diet feeding. The results of the present study suggest that polydatin protects rats against high-fat feeding-induced insulin resistance and hepatic steatosis. Polydatin may be an effective hepatoprotective agent and a potential candidate for the prevention of fatty liver disease and insulin resistance.

Topics: Adiponectin; Animals; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Fatty Liver; Gene Expression; Glucose Tolerance Test; Glucosides; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Rats; Stilbenes

Obstructive sleep apnea can induce chronic intermittent hypoxia (CIH) during sleep and is associated with obesity and diabetes. Resveratrol (RSV), a polyphenolic phytoalexin, can regulate glucose metabolism, thereby reducing insulin resistance. The present study aimed to assess whether RSV attenuates CIH-induced insulin resistance in rats and the underlying mechanisms. A total of 40 rats were randomly assigned into five groups: i) Control; ii) subjected to CIH only; iii) subjected to CIH and treated with 3 mg/kg/day of RSV; iv) subjected to CIH and treated with 30 mg/kg/day of RSV; v) subjected to CIH and treated with 60 mg/kg/day of RSV. All animals were sacrificed following 28 days of treatment. Subsequently, the blood and livers were harvested and blood insulin and glucose levels were measured. Levels of sirtuin (Sirt) 1, insulin receptor (InsR) and glucose transporter 2 (Glut2) in the liver were measured. RSV treatment was demonstrated to suppress weight gain and improve hepatic morphology. RSV treatment also significantly reduced the homeostasis model assessment estimate of insulin resistance of the rats exposed to CIH. This effect occurred in a dose-dependent manner. RSV significantly upregulated liver Sirt1 levels and inhibited InsR and Glut2 expression in the liver. Additionally, RSV activated the phosphorylation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and AKT. The present study demonstrates that RSV prevents CIH-induced insulin resistance in rats. Upregulation of Sirt1 and activation of PI3K/AKT signaling may be involved in this process.

Topics: Animals; Blood Glucose; Body Weight; Gene Expression Regulation; Glucose Transporter Type 2; Hypoxia; Insulin; Insulin Resistance; Liver; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Receptor, Insulin; Resveratrol; RNA, Messenger; Signal Transduction; Sirtuin 1; Stilbenes

Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

Topics: Animals; Anti-Obesity Agents; Drug Evaluation, Preclinical; Eating; Hypoxia; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Macrophages; Male; Mice, Inbred C57BL; Random Allocation; Resveratrol; Stilbenes; Weight Gain

Although resveratrol (RES) is thought to be a key regulator of insulin sensitivity in rodents, the exact mechanism underlying this effect remains unclear. Therefore, we sought to investigate how RES affects skeletal muscle oxidative and antioxidant levels of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations in high-fat diet (HFD)-induced insulin resistance (IR) rats. Systemic and skeletal muscle insulin sensitivity together with expressions of several genes related to mitochondrial biogenesis and skeletal muscle SIRT1, SIRT3 protein levels were studied in rats fed a normal diet, a HFD, and a HFD with intervention of RES for 8 weeks. Oxidative stress levels and antioxidant enzyme activities were assessed in SS and IMF mitochondria. HFD fed rats exhibited obvious systemic and skeletal muscle IR as well as decreased SIRT1 and SIRT3 expressions, mitochondrial DNA (mtDNA), and mitochondrial biogenesis (p < 0.05). Both SS and IMF mitochondria demonstrated elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels. In addition, SS mitochondrial antioxidant enzyme activities were significantly lower, while IMF mitochondrial antioxidant enzyme activities were higher (p < 0.05). By contrast, RES treatment protected rats against diet induced IR, increased SIRT1 and SIRT3 expressions, mtDNA, and mitochondrial biogenesis (p < 0.05). Moreover, the activities of SS and IMF mitochondrial antioxidant enzymes were increased, which reverted the increased SS mitochondrial oxidative stress levels (p < 0.05). This study suggests that RES ameliorates insulin sensitivity consistent with improved SIRT3 expressions and rebalance between SS mitochondrial oxidative stress and antioxidant competence in HFD rats.

Topics: Animals; Antioxidants; Diet, High-Fat; DNA, Mitochondrial; Insulin; Insulin Resistance; Male; Mitochondria; Muscle, Skeletal; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Sirtuin 3; Stilbenes

Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability, and when they reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and, in turn, improve gut health. Wistar rats were randomised into four groups fed an HFS diet supplemented or not with trans-resveratrol [15 mg/kg body weight (BW)/day], quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS-diet-induced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin scarcely modified the profile of gut bacteria but acted at the intestinal level, altering the mRNA expression of tight-junction proteins and inflammation-associated genes.

Topics: Animals; Bacillus; Bacteroidetes; Diet, High-Fat; Dietary Supplements; DNA, Bacterial; Fatty Acids, Volatile; Feces; Firmicutes; Gas Chromatography-Mass Spectrometry; Gastrointestinal Microbiome; Gastrointestinal Tract; Insulin Resistance; Obesity; Quercetin; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sucrose; Weight Gain

Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice.. We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2(-/-)) mice and streptozotocin (STZ)-injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice.. Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes.

Topics: Animals; Antioxidants; Crosses, Genetic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Enzyme Inhibitors; Female; Hypoglycemic Agents; Insulin Receptor Substrate Proteins; Insulin Resistance; Islets of Langerhans; Liver; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance--a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Gene Expression Regulation; HEK293 Cells; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Nerve Net; Neurons; Niacinamide; Obesity; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Stilbenes; Streptozocin

Methylglyoxal (MG) has been found to cause inflammation and insulin resistance in vitro and in vivo in recent studies. Resveratrol has been proposed as an effective treatment that helps lower the risk of developing complications of diabetes. To study the significance of glycosylation-related stress on the pathology of diabetes, the effects of resveratrol were examined in a mouse model of diabetes induced by MG. Resveratrol was given via oral gavage in MG-treated mice, and diabetes-related tests and markers were assessed using biochemical and immunohistochemical analyses. Treatment with resveratrol markedly improved blood glucose level from the oral glucose tolerance test and promoted nuclear factor erythroid 2-related factor-2 (Nrf2) phosphorylation (p < 0.05) in the pancreas of MG-treated mice. However, these effects were abolished by retinoic acid, Nrf2 inhibitor, in resveratrol and retinoic acid-treated and MG-induced mice. These findings support that resveratrol may be useful in the treatment of type-2 diabetes by protecting against pancreatic cell dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Disease Models, Animal; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Pancreas; Pancreatic Diseases; Phosphorylation; Pyruvaldehyde; Resveratrol; Stilbenes

This study aims to determine whether pterostilbene improves glycaemic control in rats showing insulin resistance induced by an obesogenic diet. Rats were divided into 3 groups: the control group and two groups treated with either 15 mg kg(-1) d(-1) (PT15) or 30 mg kg(-1) d(-1) of pterostilbene (PT30). HOMA-IR was decreased in both pterostilbene-treated groups, but this reduction was greater in the PT15 group (-45% and -22% respectively vs. the control group). The improvement of glycaemic control was not due to a delipidating effect of pterostilbene on skeletal muscle. In contrast, GLUT4 protein expression was increased (+58% and +52% vs. the control group), suggesting an improved glucose uptake. The phosphorylated-Akt/total Akt ratio was significantly enhanced in the PT30 group (+25%), and therefore a more efficient translocation of GLUT4 is likely. Additionally, in this group the amount of cardiotrophin-1 was significantly increased (+65%). These data suggest that the effect of pterostilbene on Akt is mediated by this cytokine. In the liver, glucokinase activity was significantly increased only in the PT15 group (+34%), and no changes were observed in glucose-6-phosphatase activity. The beneficial effect of pterostilbene on glycaemic control was more evident with the lower dose, probably because in the PT15 group both the muscle and the liver were contributing to this effect, but in the PT30 group only the skeletal muscle was responsible. In conclusion, pterostilbene improves glycaemic control in rats showing insulin resistance induced by an obesogenic diet. An increase in hepatic glucokinase activity, as well as in skeletal muscle glucose uptake, seems to be involved in the anti-diabetic effect of this phenolic compound.

Topics: Animals; Cytokines; Diet, High-Fat; Dietary Sucrose; Dietary Supplements; Glucokinase; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Muscle, Skeletal; Obesity; Organ Specificity; Phosphorylation; Prediabetic State; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Random Allocation; Rats, Wistar; Stilbenes; Up-Regulation

Previous research demonstrated that resveratrol possesses promising properties for preventing obesity. Endoplasmic reticulum (ER) stress was proposed to be involved in the pathophysiology of both obesity and hepatic steatosis. In the current study, we hypothesized that resveratrol could protect against high-fat diet (HFD)-induced hepatic steatosis and ER stress and regulate the expression of genes related to hepatic steatosis. Rats were fed either a control diet or a HFD for 12 weeks. After 4 weeks, HFD-fed rats were treated with either resveratrol or vehicle for 8 weeks. Body weight, serum metabolic parameters, hepatic histopathology, and hepatic ER stress markers were evaluated. Moreover, an RT2 Profiler Fatty Liver PCR Array was performed to investigate the mRNA expressions of 84 genes related to hepatic steatosis. Our work showed that resveratrol prevented dyslipidemia and hepatic steatosis induced by HFD. Resveratrol significantly decreased activating transcription factor 4, C/EBP-homologous protein and immunoglobulin binding protein levels, which were elevated by the HFD. Resveratrol also decreased PKR-like ER kinase phosphorylation, although it was not affected by the HFD. Furthermore, resveratrol increased the expression of peroxisome proliferator-activated receptor δ, while decreasing the expression of ATP citrate lyase, suppressor of cytokine signaling-3, and interleukin-1β. Our data suggest that resveratrol can prevent hepatic ER stress and regulate the expression of peroxisome proliferator-activated receptor δ, ATP citrate lyase, suppressor of cytokine signaling-3, tumor necrosis factor α, and interleukin-1β in diet-induced obese rats, and these effects likely contribute to resveratrol's protective function against excessive accumulation of fat in the liver.

Topics: Animals; Diet, High-Fat; Dyslipidemias; Endoplasmic Reticulum Stress; Gene Expression; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Topics: Blood Glucose; Female; Humans; Insulin Resistance; Lipid Metabolism; Male; Non-alcoholic Fatty Liver Disease; Stilbenes

Topics: Blood Glucose; Female; Humans; Insulin Resistance; Lipid Metabolism; Male; Non-alcoholic Fatty Liver Disease; Stilbenes

Topics: Blood Glucose; Female; Humans; Insulin Resistance; Lipid Metabolism; Male; Non-alcoholic Fatty Liver Disease; Stilbenes

Topics: Blood Glucose; Female; Humans; Insulin Resistance; Lipid Metabolism; Male; Non-alcoholic Fatty Liver Disease; Stilbenes

Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL(-1) heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min(-1)) with or without resveratrol (3 mg·kg(-1)·h(-1)), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.

Topics: Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Dyslipidemias; Emulsions; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; I-kappa B Kinase; I-kappa B Proteins; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Muscle, Skeletal; NF-KappaB Inhibitor alpha; Phospholipids; Phosphorylation; Rats, Wistar; Resveratrol; Serine; Soybean Oil; Stilbenes; Time Factors; Up-Regulation

Gestational diabetes mellitus (GDM) is a disease often manifests in mid to late pregnancy with symptoms including hyperglycemia, insulin resistance and fetal mal-development. The C57BL/KsJ-Lep (db/+) (db/+) mouse is a genetic GDM model that closely mimicked human GDM symptoms. Resveratrol (RV) is a naturally existing compound that has been reported to exhibit beneficial effects in treating type-2 diabetes.. In this study, we investigated the effect of RV on the pregnant db/+ GDM mouse model, and the underlying molecular mechanism.. RV greatly improved glucose metabolism, insulin tolerance and reproductive outcome of the pregnant db/+ females. Moreover, we found that RV relieved GDM symptoms through enhancing AMPK activation, which in turn reduced production and activity of glucose-6-phosphatase in both pregnant db/+ females and their offspring.. Our findings further supported the potential therapeutic effect of RV on not only diabetes, but also alleviating GDM.

Topics: Adenylate Kinase; Animals; Blood Glucose; Diabetes, Gestational; Female; Insulin Resistance; Mice; Pregnancy; Resveratrol; Signal Transduction; Stilbenes; Treatment Outcome

Aging leads to increased insulin resistance and arterial dysfunction, with oxidative stress playing an important role. This study explored the metabolic and arterial effects of a chronic treatment with resveratrol, an antioxidant polyphenol compound that has been shown to restore insulin sensitivity and decrease oxidative stress, in old mice with or without a high-protein diet renutrition care. High-protein diet tended to increase insulin resistance and atheromatous risk. Resveratrol improved insulin sensitivity in old mice fed standard diet by decreasing homeostasis model of assessment-insulin resistance and resistin levels. However, resveratrol did not improve insulin resistance status in old mice receiving the high-protein diet. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and diminishing aortic distensibility. In conclusion, we demonstrate that resveratrol has beneficial or deleterious effects on insulin sensitivity and arterial function, depending on nutritional status in our models.

Topics: Aging; Animals; Antioxidants; Aorta; Blood Glucose; Chemokine CCL5; Chemokine CXCL1; Dietary Proteins; Disease Models, Animal; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Nutritional Status; Oxidative Stress; Phenols; Resistin; Resveratrol; Ribonucleotide Reductases; Serum Albumin; Stilbenes; Superoxides; Tumor Necrosis Factor-alpha; Vascular Capacitance; Vascular Diseases; Vasodilation

In this study, we aimed to investigate the therapeutic effects and involved mechanisms of resveratrol on an established non-alcoholic fatty liver disease (NAFLD) murine model. Wild-type and autophagic mediator ULK1 heterozygous knockout mice were induced to have NAFLD by high-fat diet for 8weeks. After that, resveratrol treatment was applied with the high-fat diet feeding for another 4weeks. Typical features of NAFLD, including histological changes, fibrosis, insulin resistance, oxidative status, and inflammation were characterized. After-treatment with resveratrol showed ameliorative effects on all measured features of NAFLD, from histology, insulin resistance, glucose tolerance to oxidative stress and inflammation. resveratrol treatment also reduced the activity of nuclear factor-κB (NF-κB) through the restoration of its inhibitor IκBα. Partial inhibition of ULK1 expression impaired the ameliorative effects of resveratrol on hepatic histology, fibrosis, oxidative status, inflammation, and NF-κB activity. In conclusion, resveratrol improved NAFLD-caused hepatic injury partially through regulating autophagic and IκBα-NF-κB pathways.

Topics: Animals; Autophagy; Diet, High-Fat; Disease Models, Animal; DNA Primers; Fatty Liver; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Polymerase Chain Reaction; Resveratrol; Stilbenes

The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol.. These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders.

Topics: Animals; Antioxidants; ARNTL Transcription Factors; Circadian Rhythm; CLOCK Proteins; Darkness; Down-Regulation; Hepatocytes; Insulin Resistance; Liver; Mice; Mice, Knockout; Promoter Regions, Genetic; Resveratrol; Sirtuin 1; Stilbenes

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

Obesity is characterized by dysfunctional white adipose tissue (WAT) that ultimately may lead to metabolic diseases. Calorie restriction (CR) reduces the risk for age and obesity-associated complications. The impact of CR on obesity has been examined with human intervention studies, which showed alterations in circulating adipokines. However, a direct effect of CR on the human adipocyte secretome remains elusive. Therefore, the effect of a 96h low glucose CR on the secretion profile of in vitro cultured mature human SGBS adipocytes was investigated by using proteomics technology. Low-glucose CR decreased the adipocyte triglyceride contents and resulted in an altered secretion profile. Changes in the secretome indicated an improved inflammatory phenotype. In addition, several adipocyte-secreted proteins related to insulin resistance showed a reversed expression after low-glucose CR. Furthermore, 6 novel CR-regulated adipocyte-secreted proteins were identified. Since resveratrol (RSV) mimics CR we compared results from this study with data from our previous RSV study on the SGBS adipocyte secretome. The CR and RSV adipocyte secretomes partly differed from each other, although both treatment strategies lead to secretome changes indicating a less inflammatory phenotype. Furthermore, both treatments induced SIRT1 expression and resulted in a reversed expression of detrimental adipokines associated with metabolic complications.

Topics: Adipocytes; Adipokines; Adipose Tissue, White; Antioxidants; Arrhythmias, Cardiac; Caloric Restriction; Cells, Cultured; Electrophoresis, Gel, Two-Dimensional; Gene Expression Regulation; Genetic Diseases, X-Linked; Gigantism; Glucose; Heart Defects, Congenital; Humans; Insulin Resistance; Intellectual Disability; Molecular Sequence Annotation; Obesity; Proteome; Proteomics; Resveratrol; Sirtuin 1; Stilbenes; Tandem Mass Spectrometry

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

Hemorrhagic shock (HS) may contribute to organ failure, by profoundly altering mitochondrial function. Resveratrol (RSV), a naturally occurring polyphenol, has been shown to promote mitochondrial function and regulate glucose homeostasis in diabetes. We hypothesized that RSV during resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss.. With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before hemorrhage (sham), at severe shock, following resuscitation, and 18 hours after resuscitation. At each time point, the liver and kidney mitochondria were isolated to assess individual respiratory complexes (CI, CII, and CIV) and the production of reactive oxygen species (ROS). Blood samples were assayed for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model Assessment-Insulin Resistance index was used to quantify insulin resistance.. RSV supplementation following HS significantly improved mitochondrial function and decreased mitochondrial ROS production in both liver and kidney. RSV-treated animals had significantly lower blood glucose levels following resuscitation when compared with sham animals (116.0 ± 20.2 mg/dL vs. 227.7 ± 8.3 mg/dL, p < 0.05) or those resuscitated with lactated Ringer's solution (116.0 ± 20.2 mg/dL vs. 359.0 ± 79.5 mg/dL, p < 0.05). RSV supplementation was associated with significantly decreased plasma insulin levels (1.0 ± 0.4 ng/mL vs. 6.5 ± 3.7 ng/mL, p < 0.05), increased total GLP-1 levels (385.8 ± 56.6 ng/mL vs. 187.3 ± 11.1 ng/mL, p < 0.05), and a lower natural Log Homeostatic Model Assessment-Insulin Resistance index (1.30 ± 0.42 vs. 4.18 ± 0.68, p < 0.05) but had minimal effect on plasma corticosterone, glucagon, or cytokine levels.. Resuscitation with RSV restores mitochondrial function and decreases insulin resistance but may be associated with increased hypoglycemia. The observed antiglycemic effects of RSV may be mediated by decreased mitochondrial ROS and increased GLP-1 secretion.

Topics: Animals; Blood Glucose; Corticosterone; Glucagon; Glucagon-Like Peptide 1; Hypoglycemia; Insulin; Insulin Resistance; Kidney; Male; Mitochondria; Mitochondria, Liver; Rats, Long-Evans; Reactive Oxygen Species; Resuscitation; Resveratrol; Shock, Hemorrhagic; Stilbenes

Recently, the effect of polydatin on lipid regulation has gained considerable attention. And previous study has demonstrated that polydatin has hypoglycemic effect on experimental diabetic rats. Repressed Akt pathway contributes to glucose and lipid disorders in diabetes. Thus, whether polydatin regulates glucose and lipid metabolism in experimental diabetic models through the Akt pathway arouses interest. The purpose was to explore the regulatory mechanism of polydain on glucose and lipid through Akt pathway. We used a diabetic rat model induced by high-fat and -sugar diet with low-dose of streptozocin and an insulin resistant HepG2 cell model induced by palmitic acid to clarify the role of polydatin on glucose and lipid metabolism. Here, we found that polydatin significantly attenuated fasting blood–glucose, glycosylated hemoglobin, glycosylated serum protein, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in diabetic rats. Furthermore, polydatin significantly increased glucose uptake and consumption and decreased lipid accumulation in insulin resistant HepG2 cells. Polydatin markedly increased serum insulin levels in diabetic rats, and obviously activated the Akt signaling pathway in diabetic rat livers and insulin resistant HepG2 cells. Polydatin markedly increased phosphorylated GSK-3β, decreased the protein levels of G6Pase and SREBP-1c, and increased protein levels of GCK, LDLR, and phosphorylated IRS in livers and HepG2 cells. Overall, the results indicate that polydatin regulates glucose and lipid metabolism in experimental diabetic models, the underlying mechanism is probably associated with regulating the Akt pathway. The effect of polydatin on increased Akt phosphorylation is independent of prompting insulin secretion, but dependent of increasing IRS phosphorylation.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; Glucokinase; Glucose; Glucose-6-Phosphatase; Glucosides; Hep G2 Cells; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, LDL; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Stilbenes

High Capacity Runner (HCR) rats have been developed by divergent artificial selection for treadmill endurance running capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running and the antioxidant capacity of resveratrol is also demonstrated. In this study we examine whether 12 weeks of treadmill exercise training and/or resveratrol can enhance performance in HCR. Indeed, resveratrol increased aerobic performance and strength of upper limbs of these rats. Moreover, we have found that resveratrol activated the AMP-activated protein kinase, SIRT1, and mitochondrial transcription factor A (p<0.05). The changes in mitochondrial fission/fusion and Lon protease/HSP78 levels suggest that exercise training does not significantly induce damage of proteins. Moreover, neither exercise training nor resveratrol supplementation altered the content of protein carbonyls. Changes in the levels of forkhead transcription factor 1 and SIRT4 could suggest increased fat utilization and improved insulin sensitivity. These data indicate, that resveratrol supplementation enhances aerobic performance due to the activation of the AMPK-SIRT1-PGC-1α pathway.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Biomarkers; DNA-Binding Proteins; Insulin Resistance; Male; Mitochondria; Mitochondrial Proteins; Oxidative Stress; Physical Conditioning, Animal; Protein Carbonylation; Rats; Reactive Oxygen Species; Resveratrol; Running; Sirtuin 1; Stilbenes; Transcription Factors

Topics: Antioxidants; Body Composition; Humans; Insulin Resistance; Male; Obesity; Resveratrol; Stilbenes

Resveratrol (RSV), 3,5,4'-trihydroxy-trans-stilbene, is known to have many beneficial physiological activities. We have synthesized several stilbene analogues and have reported that the hydroxyl group in the 4' position of RSV exhibited strong radical scavenging action. Using stilbene analogs, we investigated the structure of RSV to explain its protective effect against obesity and type 2 diabetes. All six analogs used in this study inhibited the differentiation of 3T3-L1 adipocytes. 3-Hydroxy-trans stilbene (3(OH)ST), and 3,4'-dihydroxy-trans stilbene (3,4'(OH)2ST) increased glucose uptake and induced adenosine monophosphate kinase (AMPK) phosphorylation in C2C12 myotubes independently of insulin. An in vivo study using mice fed high-fat diets indicated that 3(OH)ST was more effective than RSV in improving insulin resistance. In conclusion, RSV and its derivatives, particularly 3(OH)ST, inhibited adipocyte differentiation and enhanced glucose uptake in the myotubes, resulting in a reduction of obesity and an improvement in glucose tolerance in vivo.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Humans; Insulin; Insulin Resistance; Mice; Obesity; Resveratrol; Stilbenes

Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examined. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 weeks) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body weight/day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body weights of rats. Impaired nitric oxide-mediated relaxation to insulin (10⁻⁹ to 3×10⁻⁶ M), and enhanced contraction to endothelin-1 (10⁻¹¹ to 10⁻⁸ M) were associated with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS production. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.

Topics: Animals; Body Weight; Cholesterol, VLDL; Endothelin-1; Fructose; Gene Expression; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Stilbenes; Sweetening Agents; Triglycerides

Eating a "Westernized" diet high in fat and sugar leads to weight gain and numerous health problems, including the development of type 2 diabetes mellitus (T2DM). Rodent studies have shown that resveratrol supplementation reduces blood glucose levels, preserves β-cells in islets of Langerhans, and improves insulin action. Although rodent models are helpful for understanding β-cell biology and certain aspects of T2DM pathology, they fail to reproduce the complexity of the human disease as well as that of nonhuman primates. Rhesus monkeys were fed a standard diet (SD), or a high-fat/high-sugar diet in combination with either placebo (HFS) or resveratrol (HFS+Resv) for 24 months, and pancreata were examined before overt dysglycemia occurred. Increased glucose-stimulated insulin secretion and insulin resistance occurred in both HFS and HFS+Resv diets compared with SD. Although islet size was unaffected, there was a significant decrease in β-cells and an increase in α-cells containing glucagon and glucagon-like peptide 1 with HFS diets. Islets from HFS+Resv monkeys were morphologically similar to SD. HFS diets also resulted in decreased expression of essential β-cell transcription factors forkhead box O1 (FOXO1), NKX6-1, NKX2-2, and PDX1, which did not occur with resveratrol supplementation. Similar changes were observed in human islets where the effects of resveratrol were mediated through Sirtuin 1. These findings have implications for the management of humans with insulin resistance, prediabetes, and diabetes.

Topics: Animals; Blood Glucose; Body Weight; Cell Dedifferentiation; Densitometry; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Fluorescent Antibody Technique; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Tolerance Test; Glycated Hemoglobin; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Macaca mulatta; Nuclear Proteins; Protective Agents; Resveratrol; Sirtuin 1; Stilbenes; Transcription Factors

Mitochondrial dysfunction and reactive oxygen species (ROS) have been implicated in the aetiology of skeletal muscle insulin resistance, although there is considerable controversy regarding these concepts. Mitochondrial function has been traditionally assessed in the presence of saturating ADP, but ATP turnover and the resultant ADP is thought to limit respiration in vivo. Therefore, we investigated the potential link between submaximal ADP-stimulated respiration rates, ROS generation and skeletal muscle insulin sensitivity in a model of type 2 diabetes mellitus, the ZDF rat. Utilizing permeabilized muscle fibres we observed that submaximal ADP-stimulated respiration rates (250-2000 μm ADP) were lower in ZDF rats than in lean controls, which coincided with decreased adenine nucleotide translocase 2 (ANT2) protein content. This decrease in submaximal ADP-stimulated respiration occurred in the absence of a decrease in electron transport chain function. Treating ZDF rats with resveratrol improved skeletal muscle insulin resistance and this was associated with elevated submaximal ADP-stimulated respiration rates as well as an increase in ANT2 protein content. These results coincided with a greater ability of ADP to attenuate mitochondrial ROS emission and an improvement in cellular redox balance. Together, these data suggest that mitochondrial dysfunction is present in skeletal muscle insulin resistance when assessed at submaximal ADP concentrations and that ADP dynamics may influence skeletal muscle insulin sensitivity through alterations in the propensity for mitochondrial ROS emission.

Topics: Adenine Nucleotide Translocator 2; Adenosine Diphosphate; Animals; Cell Respiration; Diabetes Mellitus, Type 2; Glutathione; Glutathione Disulfide; Hydrogen Peroxide; Insulin Resistance; Male; Mitochondria; Muscle, Skeletal; Rats; Rats, Zucker; Resveratrol; Stilbenes

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.

Topics: Animals; Antioxidants; Blood Glucose; Dyslipidemias; Fatty Liver; Female; Glutathione Peroxidase; Hyperphagia; Hypertension; Insulin Resistance; Liver; Obesity; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Weaning

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

Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Blotting, Western; Cells, Cultured; Culture Media, Conditioned; Dietary Fats; Inflammation; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Stilbenes

Topics: Animals; Anti-Inflammatory Agents; Insulin; Insulin Resistance; Male; Resveratrol; Signal Transduction; Stilbenes

Caloric restriction followed by refeeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We investigated the potential of resveratrol (RES) in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. Rats (8 weeks of age) were divided into 3 groups: normal chow, CUG, and CUG with RES intervention. Skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed. Catch-up growth-induced IR resulted in significant reductions in both average glucose infusion rate(60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase activity was lower; and the activity of complexes I to IV in the intermyofibrillar and subsarcolemmal (SS) mitochondria were reduced by 20% to 40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species levels were significantly higher in intermyofibrillar and SS mitochondria, whereas activities of antioxidant enzymes were decreased. Oral administration of RES, however, increased silent information regulator 1 activity and improved mitochondrial number and insulin sensitivity. Resveratrol treatment decreased levels of reactive oxygen species and restored activities of antioxidant enzymes. This study demonstrates that RES protects insulin sensitivity of skeletal muscle by improving activities of mitochondrial complexes and antioxidant defense status in CUG rats. Thus, RES has therapeutic potential for preventing CUG-related metabolic disorders.

Topics: Animals; Antioxidants; Caloric Restriction; Citrate (si)-Synthase; Glucose; Insulin Resistance; Male; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Refeeding Syndrome; Resveratrol; Stilbenes

Resveratrol (Res) has attracted great interest regarding its effects related to metabolic syndrome, especially for lipid metabolic disorder or insulin resistance; however, the underlying mechanisms remain elusive. To explore the effects of Res on insulin sensitivity and the underlying mechanism, insulin-resistant KKA(y) mice were treated with 2 and 4 g/kg diets of Res for 12 weeks. After the treatment, blood glucose, serum insulin, glucose tolerance, and insulin tolerance, as well as other indices such as adiponectin mRNA in epididymal adipose tissues, silent information regulator 1 (Sirt1), AMP-activated protein kinase (AMPK), insulin receptor substrate 1 (IRS1), and phosphorylated protein kinase B (PKB/AKT) proteins in liver and soleus muscles, were investigated. The results indicate that Res intervention reduces blood glucose and serum insulin levels, improves insulin and glucose tolerance, increases serum adiponectin and adiponectin mRNA levels in epididymal adipose tissues, and more importantly, elevates Sirt1, p-AMPK, p-IRS1, and p-AKT levels in liver and soleus muscles. In conclusion, Res could improve insulin sensitivity and ameliorate insulin resistance in KKA(y) mice, which may be associated with the upregulation of Sirt1 protein in liver and soleus muscles and consequent AMPK activation, as well as insulin-signaling related proteins.

Topics: Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Blood Glucose; Disease Models, Animal; Glucose Metabolism Disorders; Glucose Tolerance Test; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Time Factors

Obesity-induced diabetes is associated with chronic inflammation and is considered a risk factor for neurodegeneration. We tested the hypothesis that an AMP-activated protein kinase activator, resveratrol (RES), which is known to exert potent anti-inflammatory effects, would attenuate peripheral and central inflammation and improve memory deficit in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD or an HFD supplemented with RES for 20 weeks. Metabolic parameters in serum were evaluated, and Western blot analysis and immunohistochemistry in peripheral organs and brain were completed. We used the Morris water maze test to study the role of RES on memory function in HFD-treated mice. RES treatment reduced hepatic steatosis, macrophage infiltration, and insulin resistance in HFD-fed mice. In the hippocampus of HFD-fed mice, the protein levels of tumor necrosis factor-α and Iba-1 expression were reduced by RES treatment. Choline acetyltransferase was increased, and the phosphorylation of tau was decreased in the hippocampus of HFD-fed mice upon RES treatment. In particular, we found that RES significantly improved memory deficit in HFD-fed mice. These findings indicate that RES reverses obesity-related peripheral and central inflammation and metabolic derangements and improves memory deficit in HFD-fed diabetic mice.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diet, High-Fat; Fatty Liver; Glucose Tolerance Test; Inflammation; Insulin Resistance; Male; Maze Learning; Memory Disorders; Mice; Obesity; Resveratrol; Stilbenes

Diet-induced obesity is associated with metabolic heart disease characterized by left ventricular hypertrophy and diastolic dysfunction. Polyphenols such as resveratrol and the synthetic flavonoid derivative S17834 exert beneficial systemic and cardiovascular effects in a variety of settings including diabetes mellitus and chronic hemodynamic overload.. We characterized the structural and functional features of a mouse model of diet-induced metabolic syndrome and used the model to test the hypothesis that the polyphenols prevent myocardial hypertrophy and diastolic dysfunction. Male C57BL/6J mice were fed a normal diet or a diet high in fat and sugar (HFHS) with or without concomitant treatment with S17834 or resveratrol for up to 8 months. HFHS diet-fed mice developed progressive left ventricular hypertrophy and diastolic dysfunction with preservation of systolic function in association with myocyte hypertrophy and interstitial fibrosis. In HFHS diet-fed mice, there was increased myocardial oxidative stress with evidence of oxidant-mediated protein modification via tyrosine nitration and 4-OH-2-nonenol adduction. HFHS diet-fed mice also exhibited increases in plasma fasting glucose, insulin, and homeostasis model assessment of insulin resistance indicative of insulin resistance. Treatment with S17834 or resveratrol prevented left ventricular hypertrophy and diastolic dysfunction. For S17834, these beneficial effects were associated with decreases in oxidant-mediated protein modifications and hyperinsulinemia and increased plasma adiponectin.. Resveratrol and S17834 administered concurrently with a HFHS diet prevent the development of left ventricular hypertrophy, interstitial fibrosis, and diastolic dysfunction. Multiple mechanisms may contribute to the beneficial effects of the polyphenols, including a reduction in myocardial oxidative stress and related protein modifications, amelioration of insulin resistance, and increased plasma adiponectin. The polyphenols resveratrol and S17834 may be of value in the prevention of diet-induced metabolic heart disease.

Topics: Adiponectin; Animals; Antihypertensive Agents; Benzopyrans; Diastole; Diet, High-Fat; Dietary Carbohydrates; Hypertrophy, Left Ventricular; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Protein Processing, Post-Translational; Resveratrol; Stilbenes; Ventricular Function, Left

The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR) without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV), a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL) animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus) were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic changes.

Topics: Animal Feed; Animals; Blood Glucose; Caloric Restriction; Diet; Dietary Supplements; Glucose Tolerance Test; Insulin; Insulin Resistance; Lemur; Male; Oxygen Consumption; Resveratrol; Stilbenes; Time Factors

Endoplasmic reticulum (ER) stress has been implicated in the pathology of type 2 diabetes mellitus (T2DM). Although SIRT1 has a therapeutic effect on T2DM, the mechanisms by which SIRT1 ameliorates insulin resistance (IR) remain unclear. In this study, we investigated the impact of SIRT1 on palmitate-induced ER stress in HepG2 cells and its underlying signal pathway. Treatment with resveratrol, a SIRT1 activator significantly inhibited palmitate-induced ER stress, leading to the protection against palmitate-induced ER stress and insulin resistance. Resveratrol and SIRT1 overexpression induced the expression of oxygen-regulated protein (ORP) 150 in HepG2 cells. Forkhead box O1 (FOXO1) was involved in the regulation of ORP150 expression because suppression of FOXO1 inhibited the induction of ORP150 by SIRT1. Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.

Topics: Endoplasmic Reticulum Stress; Forkhead Box Protein O1; Forkhead Transcription Factors; Hep G2 Cells; HSP70 Heat-Shock Proteins; Humans; Insulin Resistance; Palmitates; Proteins; Resveratrol; 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

Metabolic syndrome and oxidative stress are common complications of type 2 diabetes mellitus. The present study was designed to determine whether resveratrol, a widely used nutritional supplement, can improve insulin sensitivity, metabolic complication as well as hepatic oxidative stress in fructose-fed rats. Male Sprague Dawley rats (180-200 g) were divided into four groups with 8 animals each. Fructose-fed insulin resistant group (Dia) animals were fed 65% fructose (Research diet, USA) for a period of 8 weeks, whereas control group (Con) animals were fed 65% cornstarch (Research Diet, USA). Resveratrol, 10 mg/kg/day (Dia+Resv) or metformin 300 mg/kg/day (Dia+Met) were administered orally to the 65% fructose-fed rats for 8 weeks. At the end of the feeding schedule, Dia group had insulin resistance along with increased blood glucose, triglyceride, uric acid and nitric oxide (NO) levels. Significant (p<0.05) increase in hepatic TBARS and conjugated dienes, and significant (p<0.05) decrease in hepatic SOD and vitamin C was observed in Dia group compared to Con group. Administration of metformin or resveratrol significantly (p<0.05) normalized all the altered metabolic parameters. However, a marked insulin sensitizing action was only observed in the Dia+Resv group. Similarly, while metformin administration failed to normalize the increased TBARS levels and decreased SOD activity, resveratrol showed a more promising effect of all oxidative stress parameters measured in the present study. Attenuation of hepatic oxidative stress in fructose-fed rat liver after resveratrol administration was associated with significant (p<0.05) increase in nuclear level of NRF2 compared with other groups. The present study demonstrates that resveratrol is more effective than metformin in improving insulin sensitivity, and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats.

Topics: Animals; Ascorbic Acid; Blood Glucose; Body Weight; Catalase; Eating; Fructose; Glucose Tolerance Test; Glutathione; Insulin; Insulin Resistance; Liver; Male; Metabolic Syndrome; Metformin; NF-E2-Related Factor 2; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Triglycerides; Uric Acid

Reduced mitochondrial capacity in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus (T2DM). However, data obtained from human subjects concerning this putative relation indicate that the mitochondrial defect observed in diabetic muscle might be secondary to the insulin-resistant state instead of being a causal factor. Nonetheless, diminished mitochondrial function, even secondary to insulin resistance, may accelerate lipid deposition in non-adipose tissues and aggravate insulin resistance. Indeed, improving mitochondrial capacity via exercise training and calorie restriction is associated with positive metabolic health effects. Here we review muscle mitochondrial dysfunction in humans and propose that targeting muscle mitochondria to improve muscle oxidative capacity should be considered as a strategy for improving metabolic health.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Mitochondria, Muscle; Resveratrol; Stilbenes

Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import.

Topics: 3T3 Cells; Acetylation; Adipose Tissue, Brown; Adipose Tissue, White; Adult; Amino Acid Sequence; Animals; Cells, Cultured; Energy Metabolism; Female; Humans; Insulin Resistance; Ligands; Lysine; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Obesity; PPAR gamma; Resveratrol; Sequence Alignment; Sirtuin 1; Stilbenes; Thermogenesis; Thiazolidinediones

Recent studies have suggested resveratrol (RSV) as a new natural therapeutic agent to treat type 2 diabetes and lipid-induced insulin resistance. Here, we investigated whether RSV could reverse palmitate-induced insulin resistance in human primary muscle cells.. Myotubes obtained from six healthy men (54 ± 3 years (mean ± SE), BMI 25.0 ± 1.7 kg/m(2), fasting plasma glucose concentration (fP-glucose) 5.47 ± 0.09 mmol/l) were treated for 4 h with 100 μmol/l RSV and/or 0.2 mmol/l palmitate, and stimulated with or without 100 nmol/l insulin. Assays of glucose uptake, glycogen synthesis, palmitate oxidation, intracellular signalling and AMP-activated protein kinase (AMPK) activity were performed.. RSV did not reverse palmitate-induced impairment of glucose metabolism. Surprisingly, RSV decreased glucose uptake and glycogen synthesis in human skeletal muscle cells. Palmitate oxidation and phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase β (ACCβ) were inhibited by RSV, and RSV completely blocked the activity of AMPK isoform complexes α1/β2/γ1 and α2/β2/γ1 in in-vitro kinase activity assays. Endoplasmic reticulum (ER) stress was increased in response to RSV, as indicated by increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) and increased expression of CCAAT/enhancer binding protein homologous protein (CHOP).. Acute exposure to RSV inhibits AMPK activity, fatty-acid oxidation and glucose metabolism in human myotubes.

Topics: AMP-Activated Protein Kinases; Cell Differentiation; Diabetes Mellitus, Type 2; Drug Interactions; Enzyme Inhibitors; Glucose; Glycogen; Humans; Insulin Resistance; Male; Middle Aged; Muscle Fibers, Skeletal; Palmitates; Phosphorylation; Primary Cell Culture; Resveratrol; Signal Transduction; Stilbenes

Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.

Topics: Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Heme Oxygenase-1; Hep G2 Cells; Humans; Hyperglycemia; Insulin Resistance; NF-E2-Related Factor 2; Pyruvaldehyde; Resveratrol; Stilbenes; Up-Regulation

The purpose of this study was to examine the effects of alcohol in the context of metabolic syndrome on insulin signaling pathways in the liver and skeletal muscle.. Twenty-six Yorkshire swine were fed a hypercaloric, high-fat diet for 4 weeks then split into 3 groups: hypercholesterolemic diet alone (HCC, n = 9), hypercholesterolemic diet with vodka (HCVOD, n = 9), and hypercholesterolemic diet with wine (HCW, n = 8) for 7 weeks. Animals underwent intravenous dextrose challenge before euthanasia and tissue collection.. HCC, HCVOD, and HCW groups had similar blood fasting glucose levels, liver function test, and body mass index. Thirty and 60 minutes after dextrose infusion, HCVOD and HCW groups had significantly increased blood glucose levels compared with the HCC group. The HCW group had significantly increased levels of insulin compared with the HCC group. Immunoblotting in skeletal muscle demonstrated that alcohol up-regulates p-IRS1, IRS2, AKT, AMPKα, PPARα, Fox01, and GLUT4. In the liver, HCW had up-regulation of AKT, AMPKα, and GLUT4 compared with HCC. Skeletal muscle immunohistochemistry demonstrated increased sarcolemmal expression of GLUT4 in both alcohol groups compared with HCC.. Moderate alcohol consumption in a swine model of metabolic syndrome worsens glucose metabolism by altering activation of the insulin signaling pathway in the liver and skeletal muscle.

Topics: Alcohol Drinking; Alcoholic Beverages; Animals; Blood Glucose; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Glucose Transporter Type 4; Immunohistochemistry; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Liver Function Tests; Male; Metabolic Syndrome; Muscle, Skeletal; PPAR alpha; Resveratrol; Stilbenes; Swine; Up-Regulation

Resveratrol (RSV) has anti-inflammatory and anti-oxidant actions which may contribute to its cardiovascular protective effects. We examined whether RSV has any beneficial effects on pancreatic islets in db/db mice, an animal model of type 2 diabetes. The db/db and db/dm mice (non-diabetic control) were treated with (db-RSV) or without RSV (db-control) (20 mg/kg daily) for 12 weeks. After performing an intraperitoneal glucose tolerance test and insulin tolerance test, mice were sacrificed, the pancreas was weighed, pancreatic β-cell mass was quantified by point count method, and the amount of islet fibrosis was determined. 8-Hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, was determined in 24 h urine and pancreatic islets. RSV treatment significantly improved glucose tolerance at 2 hrs in db/db mice (P = 0.036), but not in db/dm mice (P = 0.623). This was associated with a significant increase in both pancreas weight (P = 0.011) and β-cell mass (P = 0.016). Islet fibrosis was much less in RSV-treated mice (P = 0.048). RSV treatment also decreased urinary 8-OHdG levels (P = 0.03) and the percentage of islet nuclei that were positive for 8-OHdG immunostaining (P = 0.019). We conclude that RSV treatment improves glucose tolerance, attenuates β-cell loss, and reduces oxidative stress in type 2 diabetes. These findings suggest that RSV may have a therapeutic implication in the prevention and management of diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; Disease Models, Animal; Fibrosis; Glucose Tolerance Test; Immunohistochemistry; Insulin; Insulin Resistance; Islets of Langerhans; Male; Mice; Organ Size; Oxidative Stress; Resveratrol; Stilbenes

Werner syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many features of Werner syndrome, including a pro-oxidant status and a shorter mean life span. Here, we show that resveratrol supplementation improved the hyperglycemia and the insulin resistance phenotype in these Wrn mutant mice. In addition, resveratrol reversed liver steatosis, lipid peroxidaton, and the defenestration phenotypes observed in such mice. Resveratrol, however, did not improve the hypertriglyceridemia, inflammatory stress, nor extend the mean life span of these mutant mice. Microarray and biologic pathway enrichment analyses on liver tissues revealed that resveratrol mainly decreased lipidogenesis and increased genes involved in the insulin signaling pathway and the glutathione metabolism in Wrn mutant mice. Finally, resveratrol-treated mutant mice exhibited an increase in the frequency of lymphoma and of several solid tumors. These results indicate that resveratrol supplementation might exert at least metabolic benefits for Werner syndrome patients.

Topics: Animals; Anticarcinogenic Agents; Disease Models, Animal; Fatty Liver; Hyperglycemia; Hypertriglyceridemia; Inflammation; Insulin Resistance; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Werner Syndrome

The protein deacetylase SIRT1, and its activator resveratrol, exert beneficial effects on glucose metabolism. Different SIRT1 targets have been identified, including PTP1B, AMPK, FOXO, PGC-1α and IRS2. The latter may underscore a tight link between SIRT1 and insulin signaling components. However, whether SIRT1 has a direct effect on insulin resistance and whether resveratrol acts directly or indirectly in this context is still a matter of controversy and this question has not been addressed in muscle cells. Here, we show that SIRT1 protein expression is decreased in muscle biopsies and primary myotubes derived from type 2 diabetic patients, suggesting a contribution of diminished SIRT1 in the determination of muscle insulin resistance. To investigate the functional impact of SIRT1 on the insulin pathway, the activation of insulin downstream effector PKB was evaluated after SIRT1 inactivation by RNAi, SIRT1 overexpression, or resveratrol treatments. In muscle cells and HEK293 cells, downregulation of SIRT1 reduced, while overexpression increased, insulin-induced PKB activatory phosphorylation. Further molecular characterisation revealed that SIRT1 interacts in an insulin-independent manner with the PI3K adapter subunit p85. We then investigated whether resveratrol may improve insulin signaling in muscle cells via SIRT1, or alternative targets. Incubation of muscle cells with resveratrol reverted the insulin-resistant state induced by prolonged TNFα or insulin treatment. Resveratrol-dependent improvement of insulin-resistance occurred through inhibition of serine phosphorylation of IRS1/2, implicating resveratrol as a serine kinase inhibitor. Finally, a functional interaction between PI3K and SIRT1 was demonstrated in C. elegans, where constitutively active PI3K - mimicking increased IIS signaling - lead to shortened lifespan, while removal of sir-2.1 abolished PI3K-induced lifespan shortening. Our data identify SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K, and this mechanism appears to be conserved from C. elegans through humans.

Topics: Adult; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Case-Control Studies; Cell Line; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Longevity; Middle Aged; Muscle Fibers, Skeletal; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Binding; Recombinant Fusion Proteins; Resveratrol; RNA Interference; Signal Transduction; Sirtuin 1; Stilbenes; Tumor Necrosis Factor-alpha

Although resveratrol (RES) is implicated in the regulation of insulin sensitivity in rodents, the exact mechanism underlying this effect remains unclear. Therefore, we sought to investigate how RES affects skeletal muscle lipid transportation and lipid oxidation of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations in high-fat diet (HFD)-induced insulin resistance (IR) rats. Systemic and skeletal muscle insulin sensitivity together with expressions of several genes related to mitochondrial biogenesis and skeletal muscle lipid transportation was studied in rats fed a normal diet, an HFD, and an HFD with intervention of RES for 8 weeks. Citrate synthase (CS), electron transport chain (ETC) activities, and several enzymes for mitochondrial β-oxidation were assessed in SS and IMF mitochondria from tibialis anterior muscle. The HFD-fed rats exhibited obvious systemic and skeletal muscle IR as well as intramuscular lipid accumulation. SIRT1 activity and expression of genes related to mitochondrial biogenesis were greatly declined, whereas the gene for lipid transportation, FAT/CD36, was upregulated (P < .05). Subsarcolemmal but not IMF mitochondria displayed lower CS, ETC, and β-oxidation activities. By contrast, RES treatment protected rats against diet-induced intramuscular lipid accumulation and IR, increased SIRT1 activity and mitochondrial biogenesis, and reverted the decline in SS mitochondrial CS and ETC activities. Importantly, although expression of FAT/CD36 was increased (11%, P < .05), activities of SS mitochondrial β-oxidation enzymes were largely enhanced (41%~67%, P < .05). This study suggests that RES ameliorates insulin sensitivity consistent with an improved balance between skeletal muscle lipid transportation and SS mitochondrial β-oxidation in HFD rats.

Topics: Animals; Biological Transport; Diet, High-Fat; Down-Regulation; Insulin Resistance; Lipid Metabolism; Male; Mitochondria, Muscle; Muscle, Skeletal; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Resveratrol; Sarcolemma; Stilbenes

Diabetic foot syndrome (DFS) is a late-stage complication of type 2 diabetes which originates from interplay among impaired tissue regeneration, vasculopathy, neuropathy and inflammation all on the background of insulin resistance. Despite astonishing mortality rate pharmacological approach in management of diabetic ulceration is almost non-existent. Foot pressure relief, wound debridement and infection control remain widely accepted options in the treatment of DFS. We hypothesize that resveratrol treatment and subsequent activation of SIRT1 pathway might be highly beneficial for patients with DFS. This prediction is based on multiple lines of evidence implicating resveratrol and sirtuins in restoration of insulin sensitivity, microcirculation, tissue regeneration, function of peripheral nerves and production of cytokines. Stabilized "nutraceutical" formulations of resveratrol with high absorption rate are essential to examine its potential medical benefits since dietary polyphenols are known to be rapidly metabolized by gut microflora and oxidized during absorption. Clinical trials with nutraceutical formulations and placebo are required to understand if resveratrol indeed holds the promise for treatment of DFS.

Topics: Diabetic Foot; Dietary Supplements; Humans; Insulin Resistance; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes; Wound Healing

Long-term spaceflight induces hypokinesia and hypodynamia, which, along microgravity per se, result in a number of significant physiological alterations, such as muscle atrophy, force reduction, insulin resistance, substrate use shift from fats to carbohydrates, and bone loss. Each of these adaptations could turn to serious health deterioration during the long-term spaceflight needed for planetary exploration. We hypothesized that resveratrol (RES), a natural polyphenol, could be used as a nutritional countermeasure to prevent muscle metabolic and bone adaptations to 15 d of rat hindlimb unloading. RES treatment maintained a net protein balance, soleus muscle mass, and soleus muscle maximal force contraction. RES also fully maintained soleus mitochondrial capacity to oxidize palmitoyl-carnitine and reversed the decrease of the glutathione vs. glutathione disulfide ratio, a biomarker of oxidative stress. At the molecular level, the protein content of Sirt-1 and COXIV in soleus muscle was also preserved. RES further protected whole-body insulin sensitivity and lipid trafficking and oxidation, and this was likely associated with the maintained expression of FAT/CD36, CPT-1, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in muscle. Finally, chronic RES supplementation maintained the bone mineral density and strength of the femur. For the first time, we report a simple countermeasure that prevents the deleterious adaptations of the major physiological functions affected by mechanical unloading. RES could thus be envisaged as a nutritional countermeasure for spaceflight but remains to be tested in humans.

Topics: Adipose Tissue; Animals; Biological Availability; Biomarkers; Body Temperature Regulation; Bone Density; Enzyme Inhibitors; Glucose Tolerance Test; Hindlimb Suspension; Inflammation; Insulin Resistance; Male; Muscle, Skeletal; Muscular Atrophy; Physical Conditioning, Animal; Rats; Rats, Wistar; Resveratrol; Stilbenes

trans-Resveratrol has been shown to improve insulin sensitivity and to enhance cellular glucose uptake. Evidence from recent studies indicates that these effects depend on SIRT1-pathways.. Since ingestion of resveratrol leads to the presence of resveratrol and resveratrol metabolites in the body, we aimed at investigating (i) whether a daily dose of 300 mg resveratrol/kg body weight in healthy male Wistar rats for a period of 8 wk affects the selected parameters of glucose and lipid metabolism and (ii) whether the resulting plasma concentrations of resveratrol metabolites were effective in modulating SIRT1 expression. The dietary dose was based on the results from preceding toxicity studies. The results from the feeding experiment revealed plasma concentrations of resveratrol and its metabolites below 1 μmol/L and showed that fasting glucose and insulin levels were decreased by 35 and 41%, respectively, in the resveratrol group compared with controls. Insulin sensitivity was enhanced by 70%, whereas liver SIRT1 protein expression was not affected. Treatment of HepG2 cells with 10 μM resveratrol (1.49-fold) or its diglucuronides (1.21-fold) increased SIRT1 expression.. These results suggest that the improved insulin sensitivity after dietary administration of 300 mg resveratrol/kg body weight does not involve increased protein expression of SIRT1.

Topics: Animals; Blood Glucose; Cholesterol; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Liver; Male; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Triglycerides

We hypothesized that supplemental resveratrol would affect glucose metabolism in the skeletal muscle and liver to improve blood glucose control.. Case-control study.. Hospital laboratory.. Yorkshire miniswine.. The swine developed metabolic syndrome by consuming a high-calorie, high–fat/cholesterol diet for 11 weeks. Pigs were fed either a normal diet (control) (n = 7), a hypercholesterolemic diet (HCC) (n = 7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d) (HCRV) (n = 7). Animals underwent dextrose challenge prior to euthanasia and tissue collection.. Measurements of glucose and insulin levels, skeletal muscle and liver protein expression, and liver function test results.. The HCC group had significantly increased blood glucose levels at 30 minutes as compared with the control and HCRV groups. The HCC group demonstrated increased fasting serum insulin levels and levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Oil red O staining demonstrated increased lipid deposition in the livers of the HCC animals. Immunoblotting in the liver showed increased levels of mammalian target of rapamycin, insulin receptor substrate 1, and phosphorylated AKT in the HCRV group. Immunoblotting in skeletal muscle tissue demonstrated increased glucose transporter type 4 (Glut 4), peroxisome proliferating activation receptor coactivator 1α, peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor , and phosphorylated AKT at threonine 308 expression as well as decreased retinol binding protein 4 in the HCRV group. Immunofluorescence staining for Glut 4 in the skeletal muscle demonstrated increased Glut 4 staining in the HCRV group compared with the HCC or control groups.. Supplemental resveratrol positively influences glucose metabolism pathways in the liver and skeletal muscle and leads to improved glucose control in a swine model of metabolic syndrome.

Topics: Animals; Blood Glucose; Case-Control Studies; Dietary Carbohydrates; Energy Intake; Energy Metabolism; Insulin; Insulin Resistance; Liver; Liver Function Tests; Metabolic Syndrome; Microscopy, Fluorescence; Muscle, Skeletal; Phytotherapy; Plant Extracts; Resveratrol; Signal Transduction; Stilbenes; Swine; Swine, Miniature; Treatment Outcome

A prenatal hypoxic insult leading to intrauterine growth restriction (IUGR) increases the susceptibility to develop metabolic syndrome (MetS) later in life. Since resveratrol (Resv), the polyphenol produced by plants, exerts insulin-sensitizing effects, we tested whether Resv could prevent deleterious metabolic effects of being born IUGR.. Pregnant rats were exposed to either a normoxic (control; 21% O(2)) or a hypoxic (IUGR; 11.5% O(2)) environment during the last third of gestation. After weaning, male offspring were randomly assigned to receive either a high-fat (HF; 45% fat) diet or an HF diet with Resv (4 g/kg diet) for 9 weeks when various parameters of the MetS were measured.. Relative to normoxic controls, hypoxia-induced IUGR offspring developed a more severe MetS, including glucose intolerance and insulin resistance, increased intra-abdominal fat deposition and intra-abdominal adipocyte size, and increased plasma triacylglycerol (TG) and free fatty acids, as well as peripheral accumulation of TG, diacylglycerol, and ceramides. In only IUGR offspring, the administration of Resv reduced intra-abdominal fat deposition to levels comparable with controls, improved the plasma lipid profile, and reduced accumulation of TG and ceramides in the tissues. Moreover, Resv ameliorated insulin resistance and glucose intolerance as well as impaired Akt signaling in the liver and skeletal muscle of IUGR offspring and activated AMP-activated protein kinase, which likely contributed to improved metabolic parameters in Resv-treated IUGR rats.. Our results suggest that early, postnatal administration of Resv can improve the metabolic profile of HF-fed offspring born from pregnancies complicated by IUGR.

Topics: Animals; Antioxidants; Body Weight; Calorimetry, Indirect; Dietary Fats; Energy Intake; Female; Fetal Growth Retardation; Hypoxia; Insulin Resistance; Male; Metabolic Syndrome; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Resveratrol; Stilbenes

Sirtuin 1 (SIRT1) and its activator resveratrol are emerging as major regulators of metabolic processes. We investigate the site of resveratrol action on glucose metabolism and the contribution of SIRT1 to these effects. Because the arcuate nucleus in the mediobasal hypothalamus (MBH) plays a pivotal role in integrating peripheral metabolic responses to nutrients and hormones, we examined whether the actions of resveratrol are mediated at the MBH.. Sprague Dawley (SD) male rats received acute central (MBH) or systemic injections of vehicle, resveratrol, or SIRT1 inhibitor during basal pancreatic insulin clamp studies. To delineate the pathway(s) by which MBH resveratrol modulates hepatic glucose production, we silenced hypothalamic SIRT1 expression using a short hairpin RNA (shRNA) inhibited the hypothalamic ATP-sensitive potassium (K(ATP)) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally.. Our studies show that marked improvement in insulin sensitivity can be elicited by acute administration of resveratrol to the MBH or during acute systemic administration. Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production. In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.. Taken together, these studies demonstrate that resveratrol improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of resveratrol action.

Topics: Animals; Enzyme Activators; Enzyme Inhibitors; Gene Silencing; Glucose; Hypoglycemic Agents; Hypothalamus, Middle; Insulin; Insulin Antagonists; Insulin Resistance; KATP Channels; Liver; Male; Organ Specificity; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Small Interfering; Sirtuin 1; Stilbenes

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

Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that regulate metabolism and life span. We used peripheral blood mononuclear cells (PBMCs) to determine ex vivo whether insulin resistance/metabolic syndrome influences SIRTs. We also assessed the potential mechanisms linking metabolic alterations to SIRTs in human monocytes (THP-1) in vitro.. SIRT1-SIRT7 gene and protein expression was determined in PBMCs of 54 subjects (41 with normal glucose tolerance and 13 with metabolic syndrome). Insulin sensitivity was assessed by the minimal model analysis. Subclinical atherosclerosis was assessed by carotid intima-media thickness (IMT). In THP-1 cells exposed to high glucose or fatty acids in vitro, we explored SIRT1 expression, p53 acetylation, Jun NH(2)-terminal kinase (JNK) activation, NAD(+) levels, and nicotinamide phosphoribosyltransferase (NAMPT) expression. The effects of SIRT1 induction by resveratrol and of SIRT1 gene silencing were also assessed.. In vivo, insulin resistance and metabolic syndrome were associated with low PBMC SIRT1 gene and protein expression. SIRT1 gene expression was negatively correlated with carotid IMT. In THP-1 cells, high glucose and palmitate reduced SIRT1 and NAMPT expression and reduced the levels of intracellular NAD(+) through oxidative stress. No effect was observed in cells exposed to linoleate or insulin. High glucose and palmitate increased p53 acetylation and JNK phosphorylation; these effects were abolished in siRNA SIRT1-treated cells. Glucose- and palmitate-mediated effects on NAMPT and SIRT1 were prevented by resveratrol in vitro.. Insulin resistance and subclinical atherosclerosis are associated with SIRT1 downregulation in monocytes. Glucotoxicity and lypotoxicity play a relevant role in quenching SIRT1 expression.

Topics: Angiogenesis Inhibitors; Atherosclerosis; Carotid Arteries; Down-Regulation; Glucose; Glucose Tolerance Test; Humans; Insulin Resistance; Longevity; Metabolic Syndrome; Monocytes; Palmitic Acid; Reference Values; Resveratrol; Sirtuin 1; Stilbenes; Tunica Intima; Tunica Media

Resveratrol is a potent inhibitor of inflammation and has anti-diabetic potentiality, however whether its anti-inflammatory potency contributes to the amelioration of diabetes or insulin resistance remains to be determined. This study aims at evaluating the effects of resveratrol on inflammation-related adipokines expression and insulin sensitivity in adipocytes. We stimulated RAW264.7 cells with LPS and collected the supernatant as a conditioned medium (CM) for the culture of adipocytes. Resveratrol, at concentrations ranging from 0.1 to 10 muM, effectively inhibited lipopolysaccharide (LPS)-induced TNF-alpha and IL-6 production with the downregulation of relative genes expression in macrophages. Exposing differentiated 3T3-L1 cells to RAW264.7 CM resulted in gene over-expressions of TNF-alpha, IL-6 and resistin, however, mRNA expression of adiponectin and PPARgamma were down-regulated. Pretreatment of CM from resveratrol-treated macrophages reduced the elevated levels of TNF-alpha and IL-6, and significantly reversed inflammation-related changes in adipokine gene expression in 3T3-L1 adipocytes. Resveratrol suppressed extracellular receptor-activated kinase (ERK) and transcription factor-kappaB (NF-kappaB) activation by reducing the phosphorylation of ERK1/2 and NF-kappaB p65; moreover, it modulated insulin signaling transduction by modification of Ser/Thr phosphorylation of insulin receptor substrate-1 (IRS-1) and downstream AKT (T308), and thereby improved insulin sensitivity in adiposities. These results demonstrated that resveratrol modulated adipokines expression and improved insulin sensitivity which relative to inhibition of inflammatory-like response in adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Anti-Inflammatory Agents; Culture Media, Conditioned; Gene Expression Regulation; Glucose; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Phosphorylation; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Topics: AMP-Activated Protein Kinases; Animals; Cardiovascular Diseases; Enzyme Inhibitors; Humans; Insulin Resistance; Obesity; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol (Res) has been associated with protective effects against oxidative stress. This study evaluated the effect of Res over lipid peroxidation, antioxidant defense, hepatic sirtuin 1 (SIRT1), which up-regulates antioxidant enzymes, and copper/zinc superoxide dismutase (Cu/Zn SOD) in adult offspring whose mothers were protein restricted during lactation. Lactating Wistar rats were divided into control (C) group, which were fed a normal diet (23% protein), and low-protein and high-carbohydrate (LPHC) group, which were fed a diet containing 8% protein. After weaning (21 days), C and LPHC offspring were fed a normal diet until they were 180 days old. At the 160th day, animals were separated into four groups as follows: control, control+Res, LPHC, and LPHC+Res. Resveratrol was given for 20 days (30  mg/kg per day by gavage). LPHC animals showed a higher total antioxidant capacity (TAC) without change in lipid peroxidation and SIRT1 expression. The treatment with Res increased TAC only in the control group without effect on lipid peroxidation and SIRT1. LPHC animals treated with Res had lower lipid peroxidation and higher protein and mRNA expression of SIRT1 without any further increase in TAC. No significant difference in liver Cu/Zn SOD expression was observed among the groups. In conclusion, maternal protein restriction during lactation programs the offspring for a higher antioxidant capacity, and these animals seem to respond to Res treatment with a lower lipid peroxidation and higher hepatic SIRT1 expression that we did not observe in the Res-treated controls. It is probable that the protective effect can be attributed to Res activating SIRT1, only in the LPHC-programmed group.

Topics: Animals; Animals, Newborn; Antioxidants; Blood Glucose; Diet, Protein-Restricted; Female; Insulin; Insulin Resistance; Lipid Peroxidation; Lipids; Liver; Male; Rats; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes; Superoxide Dismutase

Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes. However, we do not know how quercetin and trans-RSV individually affected these outcomes.. The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-α (TNF-α)-an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.. Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-α. Subsequently, gene and protein markers of inflammation and insulin resistance were measured.. Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-α-induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1. Quercetin attenuated TNF-α-mediated phosphorylation of extracellular signal-related kinase and c-Jun-NH₂ terminal kinase, whereas trans-RSV attenuated only c-Jun-NH₂ terminal kinase phosphorylation. Quercetin and trans-RSV attenuated TNF-α-mediated phosphorylation of c-Jun and degradation of inhibitory κB protein. Quercetin, but not trans-RSV, decreased TNF-α-induced nuclear factor-κB transcriptional activity. Quercetin and trans-RSV attenuated the TNF-α-mediated suppression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ target genes and of PPARγ protein concentrations and transcriptional activity. Quercetin prevented the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1 and protein tyrosine phosphatase-1B gene expression and the suppression of insulin-stimulated glucose uptake, whereas trans-RSV prevented only the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1.. These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-α-mediated inflammation and insulin resistance in primary human adipocytes.

Topics: Adipocytes; Adult; Anti-Inflammatory Agents; Female; Gene Expression; Glucose; Humans; Inflammation; Insulin; Insulin Resistance; Middle Aged; Phosphorylation; Phytotherapy; Plant Extracts; PPAR gamma; Quercetin; Resveratrol; Signal Transduction; Stilbenes; Transcription, Genetic; Tumor Necrosis Factor-alpha; Vitis; Young Adult

To investigate the effects of resveratrol on the secretion of NO induced by insulin in high glucose cultured primary human umbilical vein endothelial cells (HUVEC). HUVEC were treated with 1 μmol/l resveratrol for 24 h before cultured in high glucose medium for 48 h, then all cells were stimulated by 100 nmol/l insulin for 30 min. Method based on nitric acid reductase was used to analyze the NO contents in the supernatant. Cells were collected to analyze the expression of eNOS, endothelin-1, E-selectin, and SIRT1. In order to investigate the dependence of resveratrol on SIRT1, the effects of resveratrol on cells treated by SIRT1 siRNA were also examined. Compared with control cells, high glucose decreased the secretion of NO induced by insulin. Resveratrol treatment increased the expression of SIRT1 and the secretion of NO. After interfering the expression of SIRT1 using SIRT1 siRNA, the effects of resveratrol on the NO secretion induced by insulin was impaired. Resveratrol also counteracted other pro-atherosclerotic effects of high glucose, including the up-regulating roles of high glucose on the expression of endothelin-1 mRNA and E-selectin mRNA, and the down-regulating roles of high glucose on the expression of eNOS mRNA and the basal NO secretion without the stimulating of insulin. Resveratrol can improve the NO stimulating function of insulin in high glucose cultured HUVEC in SIRT1-dependent manner. Thus, our results imply that resveratrol may have the preventive roles of atherosclerosis in diabetic patients.

Topics: Antioxidants; E-Selectin; Endothelial Cells; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Nitric Oxide; Nitric Oxide Synthase Type III; Resveratrol; RNA, Messenger; RNA, Small Interfering; Sirtuin 1; Stilbenes; Umbilical Veins

Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1beta) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A(2), cyclooxygenase-2, and PGF(2alpha). In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor gamma (PPARgamma) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPARgamma activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLA-mediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPARgamma activity.

Topics: Adipocytes; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Fatty Acids; Humans; Inflammation Mediators; Insulin Resistance; Linoleic Acids, Conjugated; Middle Aged; PPAR gamma; Resveratrol; Stilbenes; Transfection; Triglycerides

To study the effect of resveratrol on the nonalcoholic fatty liver (NAFL).. Thirty Wistar rats were allocated into three groups (10 for each): a normal control group (NC, fed with standard chow), a high fat feeding group (HF, fed with a high fat diet) and a resveratrol treated group (RT). The RT rats were fed a high fat diet all the time (as the HF) and received resveratrol administration (100 mg . kg-1. d-1) started on the 6th week of the experiment. The experiment lasted for 16 weeks. Then all the rats were sacrificed and hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity. Liver histology was studied by HE stained microscopic preparations of the livers. Phosphorylation of AMP-activated protein kinase (AMPK) levels were determined by Western blot.. Compared to the NC, visceral fat index and liver mass index was lower and fasting serum insulin (FINS) was higher and glucose infusion rate (GIR) was lower in the HF (t=10.554, P less than 0.01). Severe liver steatosis was observed microscopically in the HF. In addition, phosphorylation of AMPK levels in the HF was 45.8% lower than that of the NC (t=8.384, P less than 0.01). Compared with the HF, the visceral fat index, liver mass index, FINS and GIR were all much lower, and the liver steatosis was milder than those in the RT. Further phosphorylation of AMPK seen was 70.2% higher in RT compared with that in the NC (t=3.816, P less than 0.01).. Resveratrol administration improved high-fat feeding induced insulin resistance and fatty liver by activating AMPK.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver; Insulin Resistance; Male; Phytotherapy; Rats; Rats, Wistar; Resveratrol; Stilbenes

Although few epidemiological studies have demonstrated that C-reactive protein (CRP) is related to insulin resistance, no study to date has examined the molecular mechanism. Here, we show that recombinant CRP attenuates insulin signaling through the regulation of spleen tyrosine kinase (Syk) on small G-protein RhoA, jun N-terminal kinase (JNK) MAPK, insulin receptor substrate-1 (IRS-1), and endothelial nitric oxide synthase in vascular endothelial cells. Recombinant CRP suppressed insulin-induced NO production, inhibited the phosphorylation of Akt and endothelial nitric oxide synthase, and stimulated the phosphorylation of IRS-1 at the Ser307 site in a dose-dependent manner. These events were blocked by treatment with an inhibitor of RhoA-dependent kinase Y27632, or an inhibitor of JNK SP600125, or the transfection of dominant negative RhoA cDNA. Next, anti-CD64 Fcgamma phagocytic receptor I (FcgammaRI), but not anti-CD16 (FcgammaRIIIa) or anti-CD32 (FcgammaRII) antibody, partially blocked the recombinant CRP-induced phosphorylation of JNK and IRS-1 and restored, to a certain extent, the insulin-stimulated phosphorylation of Akt. Furthermore, we identified that recombinant CRP modulates the phosphorylation of Syk tyrosine kinase in endothelial cells. Piceatannol, an inhibitor of Syk tyrosine kinase, or infection of Syk small interference RNA blocked the recombinant CRP-induced RhoA activity and the phosphorylation of JNK and IRS-1. In addition, piceatannol also restrained CRP-induced endothelin-1 production. We conclude that recombinant CRP induces endothelial insulin resistance and dysfunction, and propose a new mechanism by which recombinant CRP induces the phosphorylation of JNK and IRS-1 at the Ser307 site through a Syk tyrosine kinase and RhoA-activation signaling pathway.

Topics: Animals; C-Reactive Protein; Cattle; Cells, Cultured; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Nitric Oxide; Nitric Oxide Synthase Type III; Oncogene Protein v-akt; Phosphoproteins; Phosphorylation; Protein-Tyrosine Kinases; Receptors, IgG; Recombinant Proteins; rhoA GTP-Binding Protein; Signal Transduction; Stilbenes; Syk Kinase

Topics: Acetylation; Animals; Antioxidants; Caloric Restriction; Heat-Shock Proteins; Humans; Insulin Resistance; Longevity; Mice; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protein Processing, Post-Translational; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Trans-Activators; Transcription Factors; Wine

Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes. SIRT1 has been reported to be involved in the processes of glucose metabolism and insulin secretion. However, whether SIRT1 is directly involved in insulin sensitivity is still largely unknown. Here we show that SIRT1 is downregulated in insulin-resistant cells and tissues and that knockdown or inhibition of SIRT1 induces insulin resistance. Furthermore, increased expression of SIRT1 improved insulin sensitivity, especially under insulin-resistant conditions. Similarly, resveratrol, a SIRT1 activator, enhanced insulin sensitivity in vitro in a SIRT1-dependent manner and attenuated high-fat-diet-induced insulin resistance in vivo at a dose of 2.5 mg/kg/day. Further studies demonstrated that the effect of SIRT1 on insulin resistance is mediated by repressing PTP1B transcription at the chromatin level. Taken together, the finding that SIRT1 improves insulin sensitivity has implications toward resolving insulin resistance and type 2 diabetes.

Topics: Animals; Chromatin; Down-Regulation; Gene Expression Regulation; Insulin; Insulin Resistance; Mice; Mice, Knockout; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Resveratrol; RNA, Small Interfering; Sirtuin 1; Sirtuins; Stilbenes

Extracts from Rhei Rhizoma extracts (RR) have been reported to attenuate metabolic disorders such as diabetic nephropathy, hypercholesterolemia and platelet aggregation. With this study we investigated the anti-diabetic action of 70% ethanol RR extract in streptozotocin-induced diabetic mice, and determined the action mechanism of active compounds of RR in vitro. In the diabetic mice, serum glucose levels at fasting and post-prandial states and glucose area under the curve at modified oral glucose tolerance tests were lowered without altering serum insulin levels, indicating that RR contained potential anti-diabetic agents. The fractions fractionated from RR extracts by XAD-4 column revealed that 60%, 80% and 100% methanol fractions enhanced insulin sensitivity and inhibited alpha-glucoamylase activity. The major compounds of these fractions were sennosides, rhein and rhaponticin. Rhaponticin and rhein enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Rhaponticin increased adipocytes with a differentiating effect similar to pioglitazone, but rhein and sennoside B decreased triglyceride accumulation. Sennoside A and B inhibited alpha-glucoamylase activity as much as acarbose. In conclusion, a crude extract of RR improves glucose intolerance by enhancing insulin-stimulated glucose uptake and decreasing carbohydrate digestion via inhibiting alpha-glucoamylase activity. Rhein and rhaponticin are potential candidates for hypoglycemic agents.

Topics: Adipocytes; Animals; Anthraquinones; Blood Pressure; Body Weight; Cell Differentiation; Cell Line; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Ethanol; Fibroblasts; Glucan 1,4-alpha-Glucosidase; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Senna Extract; Sennosides; Solvents; Stilbenes; Triglycerides

Topics: Animals; Caloric Restriction; Energy Intake; Health; Humans; Insulin Resistance; Longevity; Mice; Obesity; Resveratrol; Stilbenes

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

Topics: Acetylation; Adult; Animals; Dietary Fats; Energy Metabolism; Gene Expression Regulation; Humans; Insulin Resistance; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mitochondria, Muscle; Motor Activity; Muscle Fibers, Skeletal; Obesity; Oxidative Phosphorylation; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Single Nucleotide; Resveratrol; Sirtuin 1; Sirtuins; Specific Pathogen-Free Organisms; Stilbenes; Trans-Activators; Transcription Factors

There is intriguing recent evidence that the beta subunit of the signalsome--IKKbeta, a crucial catalyst of NF-kappaB activation--is an obligate mediator of the disruption of insulin signaling induced by excessive exposure of tissues to free fatty acids and by hypertrophy of adipocytes. Thus, agents which safely inhibit or suppress the activation of IKKbeta may have utility for reversing insulin resistance syndrome and aiding control of type 2 diabetes. Two natural agents which can achieve this effect in vitro--and which may have clinical potential in this regard--are the polyphenols resveratrol and silibinin. To date, limited absorbability and/or rapid glucuronidation have prevented these agents from achieving full therapeutic utility, but, by administering these agents in optimally absorbable forms, and co-administering inhibitors of glucuronidation such as probenecid, it may prove feasible to make these agents more clinically viable. Oral silibinin, in the guise of the milk thistle extract silymarin, already has documented clinical utility in a range of hepatic disorders, and recent evidence that dietary silibinin can inhibit the growth of certain cancers in rodents suggests that this agent may indeed have clinical potential as an IKKbeta inhibitor. A report that silymarin has a favorable impact on glycemic and lipidemic control in type 2 diabetics with cirrhosis, may or may not be indicative of IKKbeta inhibition in skeletal muscle and adipocytes. In light of the fact that IKKbeta plays a crucial role, not only in the induction of insulin resistance, but also atherogenesis, a host of inflammatory disorders, and the survival and spread of cancer, the development of pharmaceutical agents that could safely and feasibly achieve a down-regulation of IKKbeta activity would have broad therapeutic and preventive implications.

Topics: Adipocytes; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Flavonoids; Humans; I-kappa B Kinase; Insulin Resistance; Models, Biological; Phenols; Polyphenols; Probenecid; Protein Serine-Threonine Kinases; Resveratrol; Silybin; Silymarin; Stilbenes

There seems to be a link between the cluster of risk factors known as insulin resistance syndrome with endothelial dysfunction. Resveratrol (3,4,5-trihydroxyestilbene) (RV), an antioxidant found in many components of the human diet, has been proposed as an effective agent in the prevention of several pathologic processes. This study examined the effect of chronic administration of RV on endothelial nitric oxide synthase (eNOS) activity in cardiovascular tissues and on plasma lipid peroxidation in fructose-fed rats (FFR), an experimental model of this syndrome.. Male Sprague Dawley rats were separated into four groups: Control, Control + RV, FFR, and FFR + RV (n = 8 in each group). The RV (10 mg/kg/d by gavage) and fructose (10% in drinking water) were administered for 45 days. Metabolic variables and systolic blood pressure (BP) were measured. The eNOS activity was estimated in the mesenteric arterial bed and cardiac tissue homogenates by conversion of (3)H-arginine to (3)H-citrulline. Lipid peroxidation was estimated through the measurement of plasmatic thiobarbituric acid-reactive substances (TBARS).. The RV chronic treatment prevented the increase in systolic BP and cardiac hypertrophy, restored FFR mesenteric and cardiac eNOS activities, and decreased the elevated TBARS levels that characterize FFR, without an effect on other metabolic variables.. In concert with other effects, the increase in eNOS activity may contribute to the protective properties attributed to RV and, thus, to its beneficial effects on the cardiovascular system. These results suggest that an adequate supplementation of RV might help to prevent or delay the occurrence of atherogenic cardiovascular diseases associated to insulin-resistant states.

Topics: Administration, Oral; Animal Feed; Animals; Antioxidants; Arteriosclerosis; Biomarkers; Blood Pressure; Follow-Up Studies; Fructose; Heart Ventricles; Hypertension; Insulin Resistance; Lipid Peroxidation; Male; Mesenteric Arteries; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Resveratrol; Risk Factors; Spectrophotometry; Stilbenes; Sweetening Agents; Thiobarbituric Acid Reactive Substances; Time Factors