stilbenes and Diabetes-Mellitus

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

Metabolic diseases (MDs), a series of chronic disorders, severely decreases the quality of life for patients but also cause a heavy economic burden. Emerging evidence suggests that Polydatin (PD), an important glucoside of resveratrol, is widely distributed in many plants and has shown good therapeutic potential in metabolic diseases.. To review the PD discovered before 2021 and their potential to treat metabolic diseases. The activities against diabetes, Obesity, atherosclerosis, NAFLD, NASH, hyperlipidemia, and gout with special emphasis on pharmacology, pharmacokinetics, mechanisms of action, possible roles in current medicine, and future perspectives are discussed.. A comprehensive search of published literature was conducted to locate original publications pertaining to polydatin and MDs through the end of 2021 using MEDLINE, Elsevier, Springer, PubMed, Scholar, and CNKI databases. The main inquiry used was for the presence of the following keywords in various combinations in the abstracts: 'Polydatin', 'Metabolic diseases', 'Pharmacology', 'Toxicology', 'Pharmacokinetics', 'Diabetes', 'Obesity', 'Atherosclerosis', 'Non-alcoholic fatty liver disease', 'Non-alcoholic steatohepatitis', 'Hyperlipidemia', and 'Gout'.. The search yielded 987 articles, of which 33 articles were included in this review. Studies have revealed that PD can promote insulin secretion, alleviate insulin resistance, regulate glucose and lipid metabolism, reduce liver lipid deposition, inhibit inflammation, oxidative stress, and decrease uric acid deposition in preclinical experiments. The underlying mechanisms of PD in treatment MDs may be attributed to the regulation of multiple signaling pathways, including. NF-κB, AGEs/RAGE, MAPK/ERK, AMPK/LDLR, IRS1/PI3K/AKT, LKB1/AMPK, PPARβ-NO, SIRT1-PGC-1α-SOD2, PKC, etc., The pharmacokinetic profiles of PD provide valuable information on therapeutic efficacy in treating metabolic diseases.. This review summarizes the available reports and evidence which support the use of PD as a potential candidate in the treatment of MDs and provides an overview of the modulatory effects of PD in metabolic diseases and cell signaling pathways, which may have important implications in its future clinical use.

Topics: AMP-Activated Protein Kinases; Atherosclerosis; Diabetes Mellitus; Glucosides; Gout; Humans; Non-alcoholic Fatty Liver Disease; Obesity; Phosphatidylinositol 3-Kinases; Quality of Life; Stilbenes

Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors which belong to the ligand-activated nuclear receptor superfamily. They are ubiquitously expressed throughout the body. So far, three major subtypes have been identified, PPARα, PPARβ/δ and PPARγ. They are crucial for lipid and glucose metabolism and are also involved in the regulation of several types of tumors, inflammation, cardiovascular diseases and infertility. The importance of these transcription factors in physiology and pathophysiology has been largely investigated. Synthetic PPAR ligands are widely used in the treatment of dyslipidemia (e.g. fibrates - PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones - PPARγ agonists) while a new generation of dual agonists reveals hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action. Many natural ligands, including polyphenolic compounds, influence the expression of these receptors. They have several health-promoting properties, including antioxidant, anti-inflammatory, and antineoplastic activities. Resveratrol, a stilbene polyphenol, is a biological active modulator of several signaling proteins, including PPARs. Given the enormous pharmacological potential of resveratrol, stilbene-based medicinal chemistry had a rapid increase covering various areas of research. The present review discusses ligands of PPARs that contain stilbene scaffold and summarises the different types of compounds on the basis of chemical structure.

Topics: Diabetes Mellitus; Dyslipidemias; Humans; Ligands; PPAR alpha; PPAR gamma; Stilbenes; Thiazolidinediones

Resveratrol could be beneficial to health and provides protection against a wide array of pathologies and age-associated problems, as evident from preclinical studies. However, a comparison of animal and human studies reveals that this dietary polyphenol cannot protect against metabolic diseases and their associated complications. The clinical outcomes are affected by many factors such as sample size. This article not only presents a comprehensive review of the current advances concerning the dose, the extent of absorption, interaction and toxicity of resveratrol in human studies, but also describes its therapeutic effects against several chronic diseases such as diabetes mellitus, obesity, cardiovascular diseases, cancer and aging and the related diseases.

Topics: Aging; Cardiovascular Diseases; Chronic Disease; Diabetes Mellitus; Dose-Response Relationship, Drug; Humans; Neoplasms; Obesity; Polyphenols; Resveratrol; Stilbenes

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. The disease results from the defects of insulin secretion and/or action. Resveratrol is a non-flavonoid polyphenol that naturally occurs as phytoalexin. The shell and stem of Vitis vinifera L. (Vitaceae) are the richest source of this compound. In addition to various in vitro and in vivo studies revealing the effectiveness of resveratrol in DM, there are many clinical trials indicating that resveratrol has the potential to benefit in DM patients. The therapeutic action of this compound in relation to diabetes is complex and involves in several beneficial roles. In view of this, clinical studies are necessary to elucidate these roles. In the near future, the use of resveratrol, alone or in combination with current anti-diabetic therapies, might be a conventional approach to effectively manage DM or its complications. This mini-review provides a critical overview of currently available clinical studies examining the effects of resveratrol in DM last decade.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus; Humans; Hypoglycemic Agents; Resveratrol; Stilbenes

Resveratrol, a polyphenol found in grapes, peanuts, and red wine, plays different roles in diseases such as cancer and diabetes. Existing information indicates that resveratrol provides cardioprotection, as evidenced by superior postischemic ventricular recovery, reduced myocardial infarct size, and decreased number of apoptotic cardiomyocytes associated with resveratrol treatment in animal models. Cardiovascular benefits are experienced in humans with routine but not acute consumption of red wine. In this concise review, the paradoxical pro- and antiangiogenic effects of resveratrol are described, and different roles for resveratrol in the formation of new blood vessels are explained through different mechanisms. It is hypothesized that the effects of resveratrol on different cell types are not only dependent on its concentration but also on the physical and chemical conditions surrounding cells. The findings discussed herein shed light on potential therapeutic proapoptotic and antiangiogenic applications of low-dose resveratrol treatment in the prevention and treatment of different diseases.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Diabetes Mellitus; Dose-Response Relationship, Drug; Humans; Neoplasms; Resveratrol; Stilbenes

Despite recent advances in the understanding and management of

Topics: Animals; Diabetes Mellitus; Humans; Hypoglycemic Agents; Resveratrol; 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

Diabetes mellitus is a serious disease affecting about 5% of people worldwide. Diabetes is characterized by hyperglycemia and impairment in insulin secretion and/or action. Moreover, diabetes is associated with metabolic abnormalities and serious complications. Resveratrol is a natural, biologically active polyphenol present in different plant species and known to have numerous health-promoting effects in both animals and humans. Anti-diabetic action of resveratrol has been extensively studied in animal models and in diabetic humans. In animals with experimental diabetes, resveratrol has been demonstrated to induce beneficial effects that ameliorate diabetes. Resveratrol, among others, improves glucose homeostasis, decreases insulin resistance, protects pancreatic β-cells, improves insulin secretion and ameliorates metabolic disorders. Effects induced by resveratrol are strongly related to the capability of this compound to increase expression/activity of AMPK and SIRT1 in various tissues of diabetic subjects. Moreover, anti-oxidant and anti-inflammatory effects of resveratrol were shown to be also involved in its action in diabetic animals. Preliminary clinical trials show that resveratrol is also effective in type 2 diabetic patients. Resveratrol may, among others, improve glycemic control and decrease insulin resistance. These results show that resveratrol holds great potential to treat diabetes and would be useful to support conventional therapy. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clincial findigns to improved patient outcomes.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Liver; Muscle, Skeletal; Resveratrol; Stilbenes; Translational Research, Biomedical

Cardiovascular complications in diabetes are particularly serious and represent the primary cause of morbidity and mortality in diabetic patients. Despite early observations of cardiac dysfunction in diabetic humans, cardiomyopathy unique to diabetes has only recently been recognized.. Research has focused on understanding the pathogenic mechanisms underlying the initiation and development of diabetic cardiomyopathy. Emerging data highlight the importance of altered mitochondrial function as a major contributor to cardiac dysfunction in diabetes. Mitochondrial dysfunction occurs by several mechanisms involving altered cardiac substrate metabolism, lipotoxicity, impaired cardiac insulin and glucose homeostasis, impaired cellular and mitochondrial calcium handling, oxidative stress, and mitochondrial uncoupling.. Currently, treatment is not specifically tailored for diabetic patients with cardiac dysfunction. Given the multifactorial development and progression of diabetic cardiomyopathy, traditional treatments such as anti-diabetic agents, as well as cellular and mitochondrial fatty acid uptake inhibitors aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose may not adequately target all aspects of this condition. Thus, an alternative treatment such as resveratrol, which targets multiple facets of diabetes, may represent a safe and promising supplement to currently recommended clinical therapy and lifestyle changes.. Elucidation of the mechanisms underlying the initiation and progression of diabetic cardiomyopathy is essential for development of effective and targeted treatment strategies. Of particular interest is the investigation of alternative therapies such as resveratrol, which can function as both preventative and mitigating agents in the management of diabetic cardiomyopathy.

Topics: Animals; Antioxidants; Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Mitochondria; Myocardium; Resveratrol; 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

Intake of dietary phytochemicals has frequently been associated with health benefits. Noninfectious diseases including cardiovascular disease (CVD), cancer and diabetes are major causes of death, whereas dementia cases are also increasing to 'epidemic' proportion. This review will focus on recent progress on mechanisms underlying the potential role of dietary phytochemicals in CVD, diabetes, cancer and dementia, with consideration of the latest clinical data.. The association of tea (Camellia sinensis), particularly catechins, with reported mechanistic effects for CVD, diabetes, cancer and cognition contributes to our understanding of the suggested benefits of tea consumption on health from limited and inconclusive clinical trial and epidemiological data. Resveratrol, which occurs in grapes (Vitis vinifera) and wine, and curcumin, a component of turmeric (Curcuma longa), are also emerging as potentially relevant to health, particularly for CVD and dementia, with some promising data also concluded for curcumin in cancer. Other phytochemicals mechanistically relevant for health include anthocyanins, isoflavones and glucosinolates, which are also discussed.. Evidence for the role of phytochemicals in health and disease is growing, but associations between phytochemicals and disease need to be more firmly understood and established from more robust clinical data using preparations that have been phytochemically characterized.

Topics: Cardiovascular Diseases; Catechin; Clinical Trials as Topic; Curcuma; Curcumin; Dementia; Diabetes Mellitus; Humans; Micronutrients; Neoplasms; Phytochemicals; Plant Extracts; Resveratrol; Stilbenes; Tea; Vitis; Wine

Resveratrol-a natural polyphenolic compound-was first discovered in the 1940s. Although initially used for cancer therapy, it has shown beneficial effects against most cardiovascular and cerebrovascular diseases. A large part of these effects are related to its antioxidant properties. Here we review: (a) the sources, the metabolism, and the bioavailability of resveratrol; (b) the ability of resveratrol to modulate redox signalling and to interact with multiple molecular targets of diverse intracellular pathways; (c) its protective effects against oxidative damage in cardio-cerebro-vascular districts and metabolic disorders such as diabetes; and (d) the evidence for its efficacy and toxicity in humans. The overall aim of this review is to discuss the frontiers in the field of resveratrol's mechanisms, bioactivity, biology, and health-related use.

Topics: Antioxidants; Biological Availability; Cardiovascular Diseases; Cerebrovascular Disorders; Clinical Trials as Topic; Diabetes Mellitus; Humans; Metabolic Diseases; Oxidation-Reduction; Oxidative Stress; Resveratrol; Stilbenes

Although reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxyl radical are generated as the natural byproduct of normal oxygen metabolism, they can create oxidative damage via interaction with bio-molecules. The role of oxidative stress as a remarkable upstream part is frequently reported in the signaling cascade of inflammation as well as chemo attractant production. Even though hydrogen peroxide can control cell signaling and stimulate cell proliferation at low levels, in higher concentrations it can initiate apoptosis and in very high levels may create necrosis. So far, the role of ROS in cellular damage and death is well documented with implicating in a broad range of degenerative alterations e.g. carcinogenesis, aging and other oxidative stress related diseases (OSRDs). Reversely, it is cleared that antioxidants are potentially able to suppress (at least in part) the immune system and to enhance the normal cellular protective responses to tissue damage. In this review, we aimed to provide insights on diverse OSRDs, which are correlated with the concept of oxidative stress as well as its cellular effects that can be inhibited by antioxidants. Resveratrol, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins, nebivolol and carvedilol, pentaerythritol tetranitrate, mitochondria-targeted antioxidants, and plant-derived drugs (alone or combined) are the potential medicines that can be used to control OSRD.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Benzopyrans; Carbazoles; Carvedilol; Diabetes Mellitus; Disease Models, Animal; Ethanolamines; Humans; Hydrogen Peroxide; Inflammatory Bowel Diseases; Nebivolol; Neoplasms; Neurodegenerative Diseases; Osteoporosis; Oxidative Stress; Propanolamines; Reactive Oxygen Species; Resveratrol; Stilbenes; Vascular Diseases

Resveratrol is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs.

Topics: Animals; Diabetes Mellitus; Humans; Hypoglycemic Agents; Plant Extracts; Resveratrol; Stilbenes

A reduction in calorie intake [caloric restriction (CR)] appears to consistently decrease the biological rate of aging in a variety of organisms as well as protect against age-associated diseases including chronic inflammatory disorders such as cardiovascular disease and diabetes. Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by CR has generated interest in finding molecular targets that could be modulated by CR mimetics. This review describes the general concepts of CR and CR mimetics as well as discusses evidence related to their effects on inflammation and chronic inflammatory disorders. Additionally, emerging evidence related to the effects of CR on periodontal disease in non-human primates is presented. While the implementation of this type of dietary intervention appears to be challenging in our modern society where obesity is a major public health problem, CR mimetics could offer a promising alternative to control and perhaps prevent several chronic inflammatory disorders including periodontal disease.

Topics: Adaptive Immunity; Animals; Biomimetics; Caloric Restriction; Cardiovascular Diseases; Chronic Disease; Diabetes Mellitus; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Insulin-Like Growth Factor I; Metformin; Periodontitis; Resveratrol; Signal Transduction; Sirolimus; Sirtuins; Stilbenes; TOR Serine-Threonine Kinases

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

In the past decade, the small polyphenol resveratrol has received widespread attention as either a potential therapy or as a preventive agent for numerous diseases. Studies using purified enzymes, cultured cells, and laboratory animals have suggested that resveratrol has anti-aging, anti-carcinogenic, anti-inflammatory, and anti-oxidant properties that might be relevant to chronic diseases and/or longevity in humans. Although the supporting research in laboratory models is quite substantial, only recently data has emerged to describe the effects of resveratrol supplementation on physiological responses in humans. The limited number of human clinical trials that are available has largely described various aspects of resveratrol's safety and bioavailability, reaching a consensus that it is generally well-tolerated, but have poor bioavailability. Very few published human studies have explored the ability of resveratrol to achieve the physiological benefits that have been observed in laboratory models, although many clinical trials have recently been initiated. This review aims to examine the current state of knowledge on the effects of resveratrol on humans and to utilize this information to develop further guidelines for the implementation of human clinical trials.

Topics: Animals; Biological Availability; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Dietary Supplements; Humans; Liver; Obesity; Oxidative Stress; Resveratrol; Stilbenes; Wine

To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin.. A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well.. Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials.. Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies.. While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Diabetes Mellitus; Ghrelin; Humans; Hypoglycemic Agents; Inflammation; Leptin; Obesity; Resveratrol; Stilbenes

Resveratrol belongs to the large group of biologically active substances found in plants. This compound is classified as phytoestrogen because of its ability to interact with estrogen receptor. Numerous beneficial effects of resveratrol described in the literature involve cardioprotective, anti-cancer, anti-inflammatory and antioxidant action. Recently, this broad spectrum of effects is enlarged by new data demonstrating a great potency of this compound in relation to obesity and diabetes. It is well established that resveratrol exerts beneficial effects in rodents fed a high-calorie diet. In some studies, resveratrol was reported to reduce body weight and adiposity in obese animals. The action of this compound involves favourable changes in gene expressions and in enzyme activities. The accumulating evidence also indicates the benefits of resveratrol in diabetes and diabetic complications. It is known that resveratrol affects insulin secretion and blood insulin concentration. In animals with hyperinsulinemia, resveratrol was found to reduce blood insulin. Moreover, numerous data indicate that in diabetic rats, resveratrol is able to reduce hyperglycemia. The mechanism of resveratrol's action is complex and is demonstrated to involve both insulin-dependent and insulin-independent effects. These data point to the potential possibility of use of resveratrol in preventing and/or treating both obesity and diabetes.

Topics: Animals; Diabetes Mellitus; Humans; Obesity; Resveratrol; Stilbenes

The inverse association between alcohol intake and coronary heart disease has been consistently reported in cross-culture, case-control, and cohort studies. Over the past couple of decades, however, many studies have explained promising health benefits associated with wine consumption. Some studies suggest that red wine is more cardioprotective than white wine, possibly due to the increased content of flavanoid antioxidants found in red wine. Several experimental studies, including ours, support the evidence that these beneficial effects are due to resveratrol, the polyphenolic compound present in red wine. Many studies have provided evidence that resveratrol possesses antioxidant and antiapoptotic effects apart from activation of longevity proteins (such as SIRT-1). We have recently reported the angiogenic, antihypercholesterolemic, and antidiabetic effects of resveratrol and the mechanisms involved in reduced ventricular remodeling and increased cardiac functions. We have also shown different strategic target molecules involved in resveratrol-mediated cardioprotection. Therefore, this review discusses the potential effect of resveratrol and the mechanisms involved in resveratrol-mediated cardioprotection during myocardial infarction, hypercholesterolemia, and diabetes rendering its beneficial effects during health and disease.

Topics: Animals; Coronary Disease; Diabetes Mellitus; Endothelial Cells; Glucose; Glucose Transporter Type 4; Heart; Humans; Hypercholesterolemia; Myocardial Infarction; Nitric Oxide; Nitric Oxide Synthase Type III; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases such as type 2 diabetes. SIRT1, an NAD(+)-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produces beneficial effects on glucose homeostasis and insulin sensitivity. Activation of SIRT1 leads to enhanced activity of multiple proteins, including peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) and FOXO which helps to mediate some of the in vitro and in vivo effects of sirtuins. Resveratrol, a polyphenolic SIRT1 activator, mimics the effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance. In this review, we summarize recent research advances in unveiling the molecular mechanisms that underpin sirtuin as therapeutic candidates and discuss the possibility of using resveratrol as potential drug for treatment of diabetes.

Topics: Animals; Antioxidants; Caloric Restriction; Diabetes Mellitus; Drug Design; Enzyme Activation; Humans; Insulin; Male; Mice; Rats; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes; Substrate Specificity

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.

Topics: Cardiovascular Diseases; Cell Cycle; Chemoprevention; Chemotherapy, Adjuvant; Diabetes Mellitus; Gene Expression Regulation; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Resveratrol; Signal Transduction; Stilbenes

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

Topics: Animals; Brain-Gut Axis; Cognitive Dysfunction; Diabetes Mellitus; Inflammation; Mice; Neuroinflammatory Diseases; NF-kappa B; Stilbenes; Toll-Like Receptor 4

Peroxisome proliferator-activated receptors are promising therapeutic targets for metabolic diseases, including obesity, diabetes, and dyslipidemia. This study describes the design, synthesis and pharmacological evaluation of stilbene-based compounds as dual PPARα/γ partial agonists with potency in the nanomolar range. In vitro and in vivo assays revealed that the lead compound (E)-4-styrylphenoxy-propanamide (5b) removed

Topics: Adipogenesis; Animals; Cholesterol; Diabetes Mellitus; Diet, High-Fat; Dyslipidemias; Glucose; Lipoproteins, HDL; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR alpha; Stilbenes

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

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

Diabetes mellitus (DM) is a chronic metabolic disease and the subgroup of DM is called type II which is the most common form. The incidence of type II is increasing worldwide and it focuses on several new approaches to efficiently treatment of diabetes. Resveratrol (RSV) is known to be strong antioxidant and has an insulin-like effect in streptozotocin (STZ)-induced diabetic cells. It plays an active role at treatment of diabetes with reducing the oxidative stress, lowering glucose levels and protection of beta cells which are responsible for insulin secretion. In our study, we prepared two different RSV-loaded nanoliposomes (LPs), characterized in vitro and evaluated efficiencies of LPs on diabetes and related oxidative stress. Release and transport studies of RSV through dialyse membrane and pancreatic beta TC (β TC) cells were investigated from its solution and LPs. Stability studies were performed at two different conditions (4 °C and 25 °C ± 60% relative humidity) for 3 months. Particle size (PS), zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE) and type of the formulations were determined. β TC cell line was used in cell culture studies and cell viability was measured with using 3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity test. The antidiabetic effects of RSV LPs were investigated on β TC cell induced with glucose and STZ and we evaluated relationship between glucose and insulin concentration before and after incubation with LPs containing RSV. Antioxidant and preventive effects of RSV-loaded LPs against diabetes-associated oxidative stress were determined with superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme assay. When all results were evaluated together, these new developed liposomal formulations significantly decreased high glucose levels in diabetic cell groups synchronous with increasing insulin levels and they showed prolonged antioxidant activity against oxidative stress for 24 hours compared to RSV solution.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Drug Delivery Systems; Insulin; Liposomes; Nanoparticles; Oxidative Stress; Rats, Wistar; Resveratrol; Stilbenes; Streptozocin

Oxidative stress has a pivotal role in the pathogenesis of diabetes-associated cardiovascular problems, which has remained a primary cause of the increased morbidity and mortality in diabetic patients. It is of paramount importance to prevent the diabetes-associated cardiac complications by reducing oxidative stress with the help of nutritional or pharmacological agents. Pterostilbene (PT), the primary antioxidant in blueberries, has recently gained attention for its promising health benefits in metabolic and cardiac diseases. However, the mechanism whereby PT reduces diabetic cardiac complications is currently unknown.. Sprague-Dawley rats were fed with 65% fructose diet with or without PT (20 mg kg. Fructose-fed rats demonstrated cardiac hypertrophy, hypertension, enhanced myocardial oxidative stress, inflammation and increased NF-κB expression. Administration of PT significantly decreased cardiac hypertrophy, hypertension, oxidative stress, inflammation, NF-κB expression and NLRP3 inflammasome. We demonstrated that PT improved mitochondrial biogenesis as evidenced by increased protein expression of PGC-1α, complex III and complex V in fructose-fed diabetic rats. Further, PT increased protein expressions of AMPK, Nrf2, HO-1 in cardiac tissues, which may account for the prevention of cardiac oxidative stress and inflammation in fructose-fed rats.. Collectively, PT reduced cardiac oxidative stress and inflammation in diabetic rats through stimulation of AMPK/Nrf2/HO-1 signalling.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Diabetes Mellitus; Diabetic Cardiomyopathies; Disease Models, Animal; Fructose; Heme Oxygenase (Decyclizing); Hemodynamics; Inflammasomes; Inflammation; Inflammation Mediators; Male; Mitochondria, Heart; Myocardium; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

Methylglyoxal (MGO) and glyoxal (GO) are attracting considerable attention because of their role in the onset of diabetes symptoms. Therefore, to comprehend the molecular fundamentals of their pathological actions is of the utmost importance. In this study, the molecular interactions between resveratrol (RES) and human serum albumin (HSA) and the ability of the stilbene to counteract the oxidative damage caused by pathological concentrations of MGO and GO to the human plasma protein, was assessed. The oxidation of Cys34 in HSA as well as the formation of specific protein semialdehydes AAS (α-aminoadipic), GGS (γ-glutamic) and the accumulation of Advanced Glycation End-products (AGEs) was investigated. Resveratrol was found to neutralize both α-dicarbonyls by forming adducts detected by HESI-Orbitrap-MS. This antioxidant action was manifested in a significant reduction of AGEs. However, RES-α-dicarbonyl conjugates oxidized Cys34 and lysine, arginine and/or proline by a nucleophilic attack on SH and ε-NH groups in HSA. The formation of specific semialdehydes in HSA after incubation with GO and MGO at pathological concentrations was reported for the first time in this study, and may be used as early and specific biomarkers of the oxidative stress undergone by diabetic patients. The pro-oxidative role of the RES-α-dicarbonyl conjugates should be further investigated to clarify whether this action leads to positive or harmful clinical consequences. The biological relevance of human protein carbonylation as a redox signaling mechanism and/or as a reflection of oxidative damage and disease should also be studied in future works.

Topics: Antioxidants; Diabetes Mellitus; Glyoxal; Humans; Oxidants; Oxidation-Reduction; Oxidative Stress; Protein Carbonylation; Pyruvaldehyde; Reactive Oxygen Species; Resveratrol; Serum Albumin, Human; Stilbenes

We hypothesized that metabolites of dietary flavonoids attenuate impairments in nitric oxide (NO) bioavailability evoked by glucotoxic conditions mimicking Type 1 or 2 diabetes. To test this, human aortic endothelial cells were treated with either vehicle control, quercetin-3-O-glucoronide, piceatannol or 3-(3-hydroxyphenyl)propionoic acid for 24 h. These are metabolites of quercetin, resveratrol and proanthocyanidin, respectively. Next, cells were exposed to control (5 mM) or high (25 mM) glucose conditions for 48 h, followed by insulin treatment (100 nM, 10 min) to stimulate NO production. In control glucose conditions NO production, phosphorylated to total endothelial nitric oxide synthase (p-eNOS

Topics: Antioxidants; Aorta; Biological Availability; Diabetes Mellitus; Diet; Endothelial Cells; Endothelium, Vascular; Flavonoids; Glucose; Humans; Insulin; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phosphorylation; Plant Extracts; Proanthocyanidins; Proto-Oncogene Proteins c-akt; Quercetin; Resveratrol; Stilbenes

Diabetes mellitus (DM) is one of the major current health problems due to lifestyle changes. Before diagnosis and in the early years of disease, insulin blood levels are elevated. However, insulin generates low levels of reactive oxygen species (ROS) which are integral to the regulation of a variety of intracellular signaling pathways, but excess levels of insulin may also lead to DNA oxidation and DNA damage. Three pharmaceutical compounds, resveratrol, lovastatin and the mTOR-inhibitor RAD-001, were investigated due to their known beneficial effects. They showed protective properties against genotoxic damage and significantly reduced ROS after in vitro treatment of cultured cells with insulin. Therefore, the selected pharmaceuticals may be attractive candidates to be considered for support of DM therapy.

Topics: Animals; Cell Survival; Cells, Cultured; Diabetes Mellitus; DNA Damage; Epithelial Cells; Everolimus; Humans; Insulin; Kidney; Lovastatin; Rats; Reactive Oxygen Species; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

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

Advanced glycation end products (AGEs) by nonenzymatic glycation reactions are extremely accumulated in the diabetic vascular cells, neurons, and glia, and are confirmed to play important role in the pathogenesis of diabetes mellitus -induced cardiovascular complications. Sirt 1, known as mammalian sirtuin, has been recognized to regulate insulin secretion and protect cells against oxidative stress, which is promoted by the accumulated AGEs in cardiovascular cells. In the present study, we treated human endothelial Eahy926 cells with AGEs, and determined the apoptosis induction, caspase activation, the Sirt 1 activity, the expression and acetylation of p53. Then we manipulated Sirt 1 activity with a Sirt 1 activator, Resveratrol (RSV), and a Sirt 1 inhibitor, sirtinol, in the AGE-BSA-treated Eahy926 cells, and then re-evaluated the apoptosis induction, caspase activation, the expression and acetylation of p53. Results demonstrated that AGEs induced apoptosis in the human endothelial Eahy926 cells, by promoting the cytochrome c release, activation of caspase 9/3. Also, the AGE-BSA treatment promoted the total p53 level and acetylated (Ac) p53, but reduced the Sirt 1 level and activity. On the other hand, the Sirt 1 inhibitor/activator not only deteriorated/ameliorated the promotion to p53 level and Ac p53, but also aggravated/inhibited the AGE-induced apoptosis and the promotion to apoptosis-associated signaling molecules. In conclusion, the present study confirmed the apoptosis promotion by AGEs in endothelial Eahy926 cells, by regulating the Sirt 1 activity and p53 signaling, it also implies the protective role of Sirt 1 activator against the AGE-induced apoptosis.

Topics: Acetylation; Apoptosis; Benzamides; Cardiovascular Diseases; Caspases; Cells, Cultured; Cytochromes c; Diabetes Mellitus; Endothelial Cells; Glycation End Products, Advanced; Humans; Insulin; Insulin Secretion; Naphthols; Oxidative Stress; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Tumor Suppressor Protein p53

In this study, resveratrol (RSV) - a potent sirtuin 1 activator - was found to have beneficial effects on glucolipid metabolism and improve inflammatory mediators and markers of oxidative stress. Diabetic (db/db) mice and non-diabetic C57BL/6J mice were used in the study. The db/db mice were treated with or without 0.3% RSV mixed with chow for 8 weeks. Dietary RSV significantly lowered blood glucose, plasma lipid and free fatty acid levels in db/db mice. RSV markedly inhibited the expression of intercellular adhesion molecule-1 (ICAM-1), endothelial vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in the aorta and the blood plasma of db/db mice (p < 0.05). Levels of mac-3-positive macrophages (measure of the infiltration of activated macrophages) were lower in RSV-treated diabetic mice than in their untreated counterparts (p < 0.05). RSV treatment reduced the activity of the transcriptional regulator nuclear factor kappa B (NF-κB) in aortic tissues (p < 0.05). Thus, RSV treatment reduced ICAM-1, VCAM-1 and MCP-1 expression in the aorta and ICAM-1, VCAM-1 and MCP-1 levels in the plasma of diabetic mice. Since dietary supplementation with RSV also reduced NF-κB activities in the aorta, the therapeutic effects of RSV might be associated with the downregulation of NF-κB.

Topics: Animals; Antigens, Differentiation; Blood Glucose; Chemokine CCL2; Diabetes Complications; Diabetes Mellitus; Inflammation; Intercellular Adhesion Molecule-1; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Resveratrol; Signal Transduction; Stilbenes; Vascular Cell Adhesion Molecule-1

This study was designed to investigate the effects of bilateral ovariectomy and fructose diet on obesity-related metabolic parameters in female rats. The potential of resveratrol, alone and in combination with melatonin, to counter ensuing obesity and precipitated metabolic disturbances was explored.. Eight-week-old female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX) or sham operation and randomly assigned to standard diet (SD) or fructose diet (FD) groups (n = 6 rats per group) as follows: Sham; OVX + FD; OVX + SD; OVX + FD + resveratrol 50 mg/kg/day PO (RESV); OVX + SD + RESV; OVX + FD + melatonin 3 mg/kg/day PO in drinking water (M); OVX + SD + M; OVX + FD + RESV + M; OVX + SD + RESV + M. All treatments were given for 7 weeks. Biochemical, dietary, and anthropometrical parameters were estimated, and abdominal fat pads and the liver were examined for histopathological alterations.. Ovariectomy caused an increase in body weight, body mass index, feed efficiency, serum glucose, cholesterol, triglycerides, and free fatty acids, which was further exacerbated by fructose diet. These parameters were significantly decreased by resveratrol, alone and in combination with melatonin. Histopathological examination revealed reduced hypertrophy of adipocytes in adipose tissue and reduced macrophage infiltration in the liver.. Resveratrol/melatonin combination effectively normalizes anthropometrical, biochemical, and histopathological parameters in ovariectomized rats with fructose diet-induced obesity and associated metabolic alterations. The combination should be explored for potential benefits in postmenopausal women.

Topics: Administration, Oral; Animals; Antioxidants; Diabetes Mellitus; Diet; Disease Models, Animal; Female; Fructose; Melatonin; Obesity; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

This paper studies the expression of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ and anti-inflammatory cytokines such as IL-10 in diabetic rat aortas, the effects of resveratrol on these cytokines, and the potential epigenetic mechanisms involved. The experiment was performed on rats divided into four groups: normal group (NC), normal interventional group (NB), diabetic group (DM), and diabetic interventional group (DB). The NB and DB groups were treated with resveratrol. After more than 3 months, the rats' aortas were removed and analyzed for cytokines by using immunohistochemistry, Western blotting, real-time PCR, and methylation-specific PCR. Histological localization of these cytokines was mainly found in the arterial intima of diabetic rats. The protein and mRNA expression levels of IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in the DM group than in the NC group (p < 0.05), whereas in the resveratrol-treated groups (NB and DB), the levels were relatively lower than those in the corresponding groups. The DM group showed reduced levels of DNA methylation at the specific cytosine phosphate guanosine sites of IL-1β, IL-6, TNF-α, and IFN-γ, relative to those in the NC group (p < 0.01), and these levels were increased by resveratrol. In contrast, IL-10 was dramatically methylated and showed decreased expression in response to high glucose, and resveratrol reversed this effect. These results demonstrate that the inflammatory response is involved in diabetic macroangiopathy. Resveratrol inhibits the expression of proinflammatory cytokines and thus may have a protective effect on the aorta in hyperglycemia. Thus, DNA methylation, an epigenetic gene silencing signal, may be responsible for these two phenomena.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta; Cytokines; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Angiopathies; DNA Methylation; Gene Expression Regulation; Humans; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Th1-Th2 Balance

Resveratrol (RSV) is a polyphenolic compound suggested to have anti-diabetic properties. Surprisingly, little is known regarding the effects of RSV supplementation on adipose tissue (AT) metabolism in vivo. The purpose of this study was to assess the effects of RSV on mitochondrial content and respiration, glyceroneogenesis (GNG), and adiponectin secretion in adipose tissue from Zucker diabetic fatty (ZDF) rats. Five-week-old ZDF rats were fed a chow diet with (ZDF RSV) or without (ZDF chow) RSV (200 mg/kg body wt) for 6 wk. Changes in adipose tissue metabolism were assessed in subcutaneous (scAT) and intra-abdominal [retroperitoneal (rpWAT), epididymal (eWAT)] adipose tissue depots. ZDF RSV rats showed lower fasting glucose and higher circulating adiponectin, as well as lower glucose area under the curve during intraperitoneal glucose and insulin tolerance tests than ZDF chow. [¹⁴C]pyruvate incorporation into triglycerides and adiponectin secretion were higher in scAT from ZDF RSV rats, concurrent with increases in adipose tissue triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and the phosphorylation of pyruvate dehydrogenase-E1α (PDH) (Ser293) protein content in this depot. Moreover, uncoupled mitochondrial respiration and complex I and II-supported respiration were increased in both scAT and rpWAT, which correlated with increases in cytochrome c oxidase subunit IV (COX4) protein content. In vitro treatment of scAT with RSV (50 μmol/l; 24 h) induced pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) mRNA expression. Collectively, these data demonstrate that RSV can induce adipose tissue mitochondrial biogenesis in parallel with increases in GNG and adiponectin secretion.

Topics: Adipose Tissue, White; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Diabetes Mellitus; Dietary Supplements; Male; Obesity; Rats; Rats, Zucker; Resveratrol; Stilbenes; Treatment Outcome

The aim of this study was to evaluate the effect of smokeless tobacco extract on ovariectomized female rats and to investigate the role of resveratrol in alleviating associated vascular and diabetic complications.. Thirty-six female Wistar rats (8 wk old) were subjected to bilateral ovariectomy (OVX) or sham operation and randomly assigned to six groups: sham operation; OVX; OVX + aqueous extract of smokeless tobacco (AEST); OVX + AEST + 17β-estradiol; OVX + AEST + resveratrol 25 mg/kg/day PO; and OVX + AEST + resveratrol 50 mg/kg/day PO. All treatments were given for 60 days. Various vascular and metabolic markers (such as serum glucose, triglycerides, cholesterol, insulin, estradiol, glycosylated hemoglobin, glucose tolerance), ex vivo vascular reactivity of aortic ring, and aortic collagen levels were estimated after the treatments.. Oral exposure to smokeless tobacco extract in ovariectomized female rats triggered a significant increase in metabolic markers (viz, serum triglycerides, cholesterol, glucose, insulin, glycosylated hemoglobin), and aortic collagen levels. It also led to decreased serum nitrate-nitrite levels and vascular reactivity. Resveratrol 50 mg/kg/day PO attenuated detrimental changes in aortic reactivity and aortic collagen levels, improved glucose tolerance, and reversed the deleterious effects on other serum parameters comparable to 17β-estradiol.. Resveratrol treatment for 60 days abrogates the deleterious effects of smokeless tobacco on ovariectomized female rats. Resveratrol in adequate doses can be effectively used as an alternative to estrogen therapy for smokeless tobacco-induced vascular and diabetic complications.

Topics: Animals; Aorta; Collagen; Diabetes Complications; Diabetes Mellitus; Estradiol; Female; Glucose Tolerance Test; Insulin; Metabolic Diseases; Nitrates; Nitrites; Ovariectomy; Rats; Rats, Wistar; Resveratrol; Stilbenes; Tobacco, Smokeless; Vascular Diseases

The control of blood glucose levels is critical in the treatment of diabetes mellitus. α-Glucosidase inhibitors are of great importance in reducing hyperglycemia, and plants have provided many of these agents. The present study aimed at investigating the effect of two stilbenes, lonchocarpene and 3,5-dimethoxy-4'-O-prenyl-trans-stilbene (DPS), isolated from the Amazonian plant Deguelia rufescens var. urucu, on α-glucosidase activity and on mice postprandial hyperglycemia. Lonchocarpene and DPS inhibited α-glucosidase in vitro, with pIC(50) values of 5.68 ± 0.12 and 5.73 ± 0.08, respectively. In addition, when given orally, DPS produced a significant reduction of hyperglycemia induced by an oral tolerance test, while lonchocarpene did not. Data suggest that DPS may have a potential use as an antidiabetic drug.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Fabaceae; Glycoside Hydrolase Inhibitors; Hyperglycemia; Hypoglycemic Agents; Male; Mice; Phytotherapy; Plant Extracts; South America; Stilbenes

Hypercatabolic syndrome is a biochemical state characterized by a imbalance between catabolism and anabolism in favor of catabolism. Diabetes is an example of hypercatabolic syndrome with presence of decreased insulin level or impaired insulin signaling besides increased inflammatory cytokines. One of the significant outcomes of this state is accelerated protein degradation and muscle wasting. Increased ubiquitin-proteasomal system activity is the major responsible for the muscle wasting. Increase in expression and activities of proteasomal proteins in diabetes had been determined. NF-κB transcription factor mediated inflammation and oxidative stress accompanies proteasomal activity increase. Oxidative stress continuously produces substrate for proteasomes by causing protein oxidation. An intervention that inhibits proteasomal activity, suppressing inflammation and oxidative stress may form a solution in order to prevent muscle wasting. Therefore, I am considering that the combined use of bortezomib, a proteasome inhibitor and an anti-inflammatory with resveratrol, an antioxidant and anti-inflammatory, could prevent diabetes induced muscle wasting. This combination may be a novel therapeutic approach for muscle wasting.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Boronic Acids; Bortezomib; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Humans; Inflammation; Models, Biological; Muscular Atrophy; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Rats; Resveratrol; Stilbenes

Arteriosclerotic vascular disease is a major cardiac health problem in westernized countries and the primary cause of mortality in diabetic patients. Recent data have raised serious safety concerns with the antidiabetic rosiglitazone, a thiazolidinedione with peroxisome proliferator-activated receptor γ (PPAR-γ) agonistic activity, in regard to cardiovascular risks. A common feature of atherosclerosis is vascular mineralization. The latter is formed by vascular smooth muscle cells (VSMC) through complex processes that are similar to mineralization in bone. The aim of the current study was to investigate the effect of rosiglitazone on mineralization in cultured human VSMCs. We found that rosiglitazone stimulated mineralization by, at least in part, induction of caspase-dependent apoptosis. Furthermore, rosiglitazone-induced oxidative stress was correlated with stimulated osteoblast-like differentiation of VSMCs. Treatment of rosiglitazone-supplemented VSMC cultures with the caloric restriction mimetic and antioxidant resveratrol diminished rosiglitazone-induced oxidative stress, osteoblast-like differentiation and mineralization. In conclusion, this study reveals novel insights into the relationship of rosiglitazone and cardiovascular events by providing a model that links rosiglitazone-induced osteoblast-like differentiation, oxidative stress and apoptosis with mineralization in VSMCs. In addition, we position resveratrol in this model acting to reduce rosiglitazone-induced oxidative stress, osteoblast-like VSMC differentiation and mineralization.

Topics: Apoptosis; Atherosclerosis; Caspases; Cell Differentiation; Cells, Cultured; Diabetes Mellitus; Humans; Hypoglycemic Agents; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Resveratrol; Rosiglitazone; Signal Transduction; Stilbenes; Thiazolidinediones; Up-Regulation

Methylglyoxal (MGO), the reactive dicarbonyl intermediate generated during the nonenzymatic glycation between reducing sugars and amino groups of proteins, lipids, and DNA, is the precursor of advanced glycation end products (AGEs). Many studies have shown that AGEs play a major pathogenic role in diabetes and its complications. This study found that 2,3,5,4'-tetrahydroxystilbene 2-O-beta-D-glucoside (THSG), the major bioactive compound from Polygonum multiflorum Thunb., can efficiently inhibit the formation of AGEs in a dose-dependent manner by trapping reactive MGO under physiological conditions (pH 7.4, 37 degrees C). More than 60% MGO was trapped by THSG within 24 h, which was much more effective than resveratrol and its methylated derivative, pterostilbene, the two major bioactive dietary stilbenes. The major mono- and di-MGO adducts of THSG were successfully purified and found to be mixtures of tautomers. LC-MS and NMR data showed that positions 4 and 6 of the A ring were the major active sites for trapping MGO. It was also found that THSG could significantly inhibit the formation of AGEs in the human serum albumin (HSA)-MGO assay and both mono- and di-MGO adducts of THSG were detected in this assay using LC-MS. The results suggest that the ability of THSG to trap reactive dicarbonyl species makes it a potential natural inhibitor of AGEs.

Topics: Chromatography, Liquid; Diabetes Complications; Diabetes Mellitus; Glucosides; Glycation End Products, Advanced; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Conformation; Polygonum; Pyruvaldehyde; Resveratrol; Stilbenes

Advanced glycosylation end products (AGE) and its receptor (RAGE) axis is involved in the regulation of lipid homeostasis and is critical in the pathogenesis of diabetic atherosclerosis. We investigated the protective role of resveratrol against the AGE-induced impairment on macrophage lipid homeostasis. In THP-1-derived macrophages, RAGE was dose-dependently induced by AGE and played a key role in the AGE-induced cholesterol accumulation. Resveratrol markedly reduced RAGE expression via peroxisome proliferator-activated receptor (PPAR) gamma but not PPARalpha or AMP-activated protein kinase. Importantly, pretreatment with resveratrol significantly ameliorated AGE-induced up-regulation of scavenger receptor-A (SR-A) and down-regulation of ATP-binding cassette (ABC) A1 and ABCG1 and thus effectively prevented the cholesterol accumulation in macrophages as shown by cellular cholesterol analysis and oil red O staining. Moreover, blockade of PPARgamma abolished all these effects of resveratrol. Collectively, our results indicate that resveratrol prevents the impairment of AGE on macrophage lipid homeostasis partially by suppressing RAGE via PPARgamma activation, which might provide new insight into the protective role of resveratrol against diabetic atherosclerosis.

Topics: Adenylate Kinase; Animals; Antioxidants; Atherosclerosis; Cholesterol; Diabetes Complications; Diabetes Mellitus; Glycation End Products, Advanced; Homeostasis; Humans; Lipid Metabolism; Macrophages; PPAR gamma; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Resveratrol; Stilbenes

Stilbenediamine is used as derivatizing reagent for methylglyoxal (MGo) and dimethylglyoxal for the gas chromatographic (GC) determination of MGo from the serum of diabetic patients and healthy volunteers. The derivatization is obtained at pH 3. GC elution and separation are carried out on an HP5 column (30 m x 0.32 mm i.d.) at column temperature 150 degrees C with a programmed heating rate of 50 degrees C/min up to 250 degrees C, and a total run time of 7 min. The nitrogen flow rate is 5 mL/min and detection is carried out by flame ionization detection. The linear calibration curves are obtained with a range of 0.076-0.760 microg/mL and the detection limit is 25 ng/mL MGo. The amounts of MGo found in the serum of healthy volunteers and diabetic patients are 0.025-0.065 microg/mL and 0.115-0.228 microg/mL, with coefficient of variation 1.3-3.1% and 1.4-3.3%.

Topics: Adult; Case-Control Studies; Chromatography, Gas; Diabetes Mellitus; Female; Humans; Indicators and Reagents; Male; Pyruvaldehyde; Reference Standards; Stilbenes

Reactive oxygen species (ROS) production has recently been established as an essential contributor in the pathogenesis of obesity-associated insulin resistance. The FoxO1 pathway plays a role not only in nutrient sensing but also in regulating ROS production. We exposed adipocytes to free fatty acids (FFA) and demonstrated that FoxO1 protein levels decrease in a dose-dependent manner. The FoxO1 downregulation correlated with an increase in the production of ROS and a proinflammatory adipokine pattern characterized by a decrease in adiponectin and an increase in IL-6, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1 mRNA expression levels. Similarly, a decrease in FoxO1 protein levels was seen in adipocytes of db/db mice compared with controls. Treatment with the sirtuin agonist resveratrol, which translocates FoxO1 to the nucleus, increased FoxO1 protein levels in adipocytes exposed to FFA. This correlated with a decrease in the generation of ROS and a partial reversal of the proinflammatory adipokine pattern. Together these results indicate that the insulin-resistant adipocyte produced by the exposure to a high concentration of fatty acids is characterized by decreased levels of FoxO1. These data also suggest that modulation of the Sirt1/FoxO1 pathway is a potentially useful therapeutic target for the obesity-induced dysfunctional adipocyte.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Nucleus; Diabetes Mellitus; Fatty Acids, Nonesterified; Forkhead Box Protein O1; Forkhead Transcription Factors; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Reactive Oxygen Species; Resveratrol; Stilbenes

An analytical method has been developed for the separation of glyoxal (Go), methylglyoxal (MGo), and dimethylglyoxal (DMGo) by MEKC using stilbenediamine (SD) as derivatizing reagent, separation time 6.5 min, SDS as micellar medium at pH 8, and sodium tetraborate (0.1 M) as buffer. Uncoated fused-silica capillary, effective length 50 cm x 75 microm id; applied voltage 20 kV and photodiode array detection, were used. Calibration was linear within 0.02-150 microg/mL with detection limits 3.5-5.8 ng/mL. Go and MGo, observed for diabetic and healthy volunteers, were within 0.098-0.193 microg/mL Go and 0.106-0.245 microg/mL MGo with RSD 1.6-3.5 and 1.7-3.4%, respectively, in diabetics against 0.016-0.046 microg/mL Go and 0.021-0.066 microg/mL MGo with RSDs 1.5-3.5 and 1.4-3.6%, respectively, in healthy volunteers. Go and MGo in diabetics were also measured by standard addition and DMGo as an internal standard. Additives do not contribute significantly to Go and MGo matrix.

Topics: Calibration; Chromatography, Micellar Electrokinetic Capillary; Diabetes Mellitus; Glyoxal; Humans; Pyruvaldehyde; Reproducibility of Results; Sensitivity and Specificity; Sodium Dodecyl Sulfate; Stilbenes

The purpose of this study was to investigate the effect of pterostilbene and its effect on key enzymes of glucose metabolism. Diabetic rats were orally administered with pterostilbene (10, 20, 40 mg/kg) for 2, 4 and 6 weeks on glucose was determined. Administration of pterostilbene at 40 mg/kg significantly decreases plasma glucose. Based on these data, the higher dose, 40 mg/kg pterostilbene, was selected for further evaluation. Oral administration of pterostilbene for 6 weeks on glucose, insulin levels and hepatic enzymes in normal and streptozotocin (STZ)-nicotinamide-induced diabetic rats. A significant decrease in glucose and significant increase in plasma insulin levels were observed in normal and diabetic rats treated with pterostilbene. Treatment with pterostilbene resulted in a significant reduction of glycosylated hemoglobin and an increase in total hemoglobin level. The activities of the hepatic enzymes such as hexokinase was significantly increased whereas glucose-6-phosphatase, fructose-1,6-bisphosphatase were significantly decreased by the administration of pterostilbene in diabetic rats. A comparison was made between the action of pterostilbene and the antidiabetic drug--metformin.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Fructose-Bisphosphatase; Glucose; Glucose-6-Phosphatase; Glycated Hemoglobin; Hemoglobins; Hexokinase; Hypoglycemic Agents; Insulin; Liver; Male; Niacinamide; Rats; Rats, Wistar; Stilbenes

The methanolic extract of rhizome of Himalayan rhubarb Rheum emodi displayed mild yeast as well as mammalian intestinal alpha-glucosidase inhibitory activity. However, further fractionation of active extract led to the isolation of several potent molecules in excellent yields, displaying varying degrees of inhibition on two test models of alpha-glucosidase. Rhapontigenin, desoxyrhapontigenin, chrysophanol-8-O-beta-d-glucopyranoside, torachrysone-8-O-beta-d-glucopyranoside displayed potent yeast alpha-glucosidase inhibition. However chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin and torachrysone-8-O-beta-d-glucopyranoside displayed potent to moderate mammalian alpha-glucosidase inhibitory activity. Other compounds displayed mild activity on both the tests. Except desoxyrhapontigenin and rhapontigenin that increased Vmax, other compounds including crude extract decreased the Vmax significantly (p<0.02) in yeast alpha-glucosidase test. Further kinetic analysis on mammalian alpha-glucosidase inhibition showed that chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin and torachrysone-8-O-beta-d-glucopyranoside may be classified as mixed-noncompetitive inhibitors. However, desoxyrhapontigenin and rhapontigenin may be classified as modulators of enzyme activity. Presence and position of glycoside moiety in compounds appear important for better inhibition of mammalian alpha-glucosidase. This is the first report assigning particularly, mammalian intestinal alpha-glucosidase inhibitory activity to these compounds. Chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin, desoxyrhapontigenin and rhapontigenin have been isolated in substantial yields from R. emodi for the first time. Therefore, these compounds may have value in the treatment and prevention of hyperglycemia associated diabetes mellitus.

Topics: alpha-Glucosidases; Animals; Binding, Competitive; Diabetes Mellitus; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Hyperglycemia; Intestinal Mucosa; Kinetics; Plant Extracts; Rats; Rheum; Stilbenes; Yeasts