Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes

The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.     

Macrovascular complications of metabolic syndrome: an early intervention is imperative

The metabolic syndrome is a widespread clinical condition and an important cluster of atherothrombotic disease risk factors. The inclusion of this syndrome in the recently published Adult Treatment Panel III (ATP III) guidelines focused the attention of the physicians on this entity. Abdominal obesity, PPAR modulation, insulin resistance (with or without glucose intolerance), atherogenic dyslipidemia, elevated blood pressure, prothrombotic and proinflammatory states are the principal factors of this multifaceted syndrome. There are two major pathways of metabolic syndrome progress: (1) With preserved pancreatic beta cells function and insulin hypersecretion, which can recompense for insulin resistance. This pathway leads mostly to the macrovascular complications of metabolic syndrome. (2) With substantial injure of pancreatic beta cells leading to gradually reduced insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads to both microvascular and macrovascular complications. Because macrovascular complications of insulin resistance state precede the onset of hyperglycemia, early intervention in patients with metabolic syndrome is particularly important. Since central obesity (accompanied by insulin resistance even in the absence of hyperglycemia) is the key factor leading to development of metabolic syndrome and its future macrovascular complications, we assume that next logical step is the recognition of central obesity itself as a major risk factor for cardiovascular diseases.     

Insulin resistance and atherosclerosis

The epidemic of obesity in the developed world over the last two decades is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of cardiovascular morbidity and mortality. It is only now being recognized that the major antecedent of type 2 diabetes, insulin resistance with its attendant syndrome, is the major underlying cause of the susceptibility to type 2 diabetes and cardiovascular disease. In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs; other factors such as dyslipidemia and hypertension also arise. In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK); the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. This review addresses the metabolic consequences of the insulin resistance syndrome, its relationship with atherosclerosis, and the impact of insulin resistance on processes of atherosclerosis including insulin signaling in cells of the vasculature.     

Insulin resistance is a cardiovascular risk factor in humans

Diabetes is a common metabolic disorder associated to elevated cardiovascular morbidity and mortality that is not explained by hyperglycemia or traditional cardiovascular risk factors such as smoking or hypercholesterolemia. Intensive glycemic control with insulin that achieves near-normal glycemia does not reduce significantly macrovascular complications compared with conventional glycemic control. Cardiovascular disease continues to develop in patients with diabetes despite adequate glycemic control. In contrast, intensive control with metformin (leading to insulin resistance improvement) reduces diabetes complications, including cardiovascular events, suggesting that enhancement of insulin sensitivity rather than plasma glucose level has a major role improving diabetes outcomes. Accordingly, insulin resistance estimated by glucose tolerance tests is better predictor of future cardiovascular events than fasting glucose level in nondiabetic individuals. Insulin resistance precedes for decades the clinical onset of type 2 diabetes and deteriorates metabolic control of type 1 diabetes. Numerous investigations including cross-sectional and prospective studies, meta-analyses, and systematic reviews provide compelling evidence that insulin resistance by itself is a cardiovascular risk factor in a variety of population groups, including the general population and patients with diabetes. Several estimations of insulin resistance have been consistently associated with elevated rate of cardiovascular events independently of other cardiovascular risk factors and diabetes status. The clinical expression of insulin resistance (the metabolic syndrome or any of its components including obesity, hyperinsulinemia, hypertension, and dyslipemia) has been related to cardiovascular disease as well. An estimation conducted by the Archimedes model confirms that insulin resistance is the most important single cause of coronary artery disease.     

The metabolic syndrome: Insulin resistance

Insulin resistance is the most accepted unifying theory explaining the pathophysiology of the metabolic syndrome. However, epidemiologic studies indicate that a substantial proportion of patients with the metabolic syndrome do not have evidence of insulin resistance, and the correlation between insulin resistance and individual components of the syndrome is weak to moderate. Insulin resistance may play an important role in the development of hyperglycemia and dyslipidemia, which can further aggravate insulin resistance. The implication of insulin resistance in hypertension appears to be less strong than its role in causing hyperglycemia and dyslipidemia. Obesity may be another pathogenic factor in the metabolic syndrome that may help initiate or worsen insulin resistance. However, like insulin resistance, obesity is not universal in the metabolic syndrome, and many obese subjects do not have metabolic abnormalities. This review provides an update on the relationship between insulin resistance and main components of the metabolic syndrome: hyperglycemia, dyslipidemia, hypertension, and obesity.     

Using insulin as a drug rather than as a replacement hormone during acute illness: a new paradigm

The direct correlation between glucose levels and cardiovascular disease in individuals with type 2 diabetes can now be applied to individuals that share an abnormal metabolic milieu similar to that found in central obesity, the metabolic syndrome, and type 2 diabetes. Premature macrovascular complications with a very high morbidity and mortality rate can be found in these nondiabetic populations. The typical phenotype has visceral or central obesity, excess of free fatty acids, insulin resistance, increased insulin secretion, and hypertension. A more complex metabolic-cardiovascular syndrome develops that includes dyslipidemia, abnormal production of cytokines, chronic inflammatory state, and abnormal coagulation. The interplay of all these cardiovascular risk factors is responsible for the accelerated atherosclerotic process. The different terminologies used for populations sharing this common ground for premature cardiovascular disease now generally accepted as the metabolic syndrome, are also discussed. Aggressive insulin treatment during acute illness in individuals with the abnormal metabolic milieu is beneficial. Insulin treatment is changing from using insulin as a hormone to treat only severe hyperglycemia, to a new paradigm using insulin in high doses as a drug. Aggressive insulin regimens should be used to treat only minimal elevations of blood glucose or to prevent hyperglycemia. The newly observed properties of insulin are reviewed which include suppression of inflammatory cytokines and adhesion molecules, improved hemostasis, and other cardiac beneficial effects. The concomitant administration of intravenous glucose and insulin permits the administration of higher insulin doses that can result in improved outcome due to its nonglycemic-related benefits. The use of aggressive insulin therapy requires both better and more cost-effective algorithms to successfully treat this high-risk population during acute illness.     

C肽与动脉粥样硬化的研究进展

以胰岛素抵抗为特征的代谢综合征及2型糖尿病患者倾向于更早期发生弥漫性动脉粥样硬化,甚至出现于高血糖之前,动脉粥样硬化是糖尿病死亡的首要原因。除了传统危险因素外,近年发现一直被认为无生物活性的C肽可能参与了动脉粥样硬化的关键发展步骤,其参与了炎症反应、促进单核巨噬细胞迁移趋化及向泡沫细胞转化、促进血管平滑肌细胞的增殖,几项队列研究提示血清C肽水平升高与全因死亡、心血管疾病、恶性肿瘤死亡相关。文章就C肽的生物学作用从基础研究到临床研究进展做一综述。     

Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis

CONTEXT: Prostate cancer (PCa) is the most common cancer in men. Androgen-deprivation therapy (ADT) is generally employed in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recently, metabolic complications like insulin resistance, diabetes, dyslipidemia, and metabolic syndrome have emerged, which may be responsible for the increased cardiovascular mortality in this population. EVIDENCE ACQUISITION: A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa populations evaluating the association between testosterone and metabolism were also reviewed and briefly mentioned where relevant. EVIDENCE SYNTHESIS: Prospective studies evaluating early (3-6 months) metabolic changes of ADT show development of hyperinsulinemia; however, glucose levels remain normal. Cross-sectional studies of men undergoing long-term (> or =12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. Furthermore, men undergoing ADT also experience higher cardiovascular mortality. CONCLUSION: Long-term prospective studies of ADT are needed to determine the timing of onset of these metabolic complications and to investigate the mechanism behind them. In the meantime, we recommend baseline and serial screening for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT. Glucose tolerance tests and cardiac evaluation may be required in selected cases.     

Insulin resistance, diabetes and cardiovascular risk: approaches to treatment

The prevalence of diabetes is increasing worldwide. Insulin resistance and diabetes mellitus are major predictors of cardiovascular ischaemic disease. Other risk factors for cardiovascular death including hypertension, dyslipidaemia, smoking and visceral obesity are especially lethal in diabetics. C-reactive protein, plasminogen activator inhibitor-1, matrix metalloproteinases and other emerging risk factors and their roles are continually being researched and discovered. Treatment of this syndrome must be aimed at lifestyle modification, glycaemic control and management of concomitant risk factors. Diet and exercise play a vital role in the treatment of diabetes and the metabolic syndrome. Weight reduction and increased physical activity will improve insulin resistance, hyperglycaemia, hypertension and dyslipidaemia. Hypertension management has been shown to be especially important in diabetics to prevent cardiovascular events. Likewise, multiple clinical trials show that reduction of cholesterol is even more vital in diabetics than the general population for risk reduction of coronary disease. There is a great deal of evidence that tight control of glycaemia is essential to treatment of this condition. There are a variety of available pharmacological agents available including metformin, insulin secretagogues, alpha-glucosidase inhibitors, thiazolidinediones and insulin. The mechanisms and side effects of these medications are discussed. As macrovascular disease is the major cause of morbidity and mortality, an early, aggressive, multi-factorial approach to treatment of the metabolic syndrome and diabetes is vital to prevent adverse cardiac outcomes.     

The metabolic syndrome and cardiovascular disease: Part I

The metabolic syndrome is a constellation of metabolic risk factors and physical conditions that are accompanied by an enhanced propensity toward the development of type 2 diabetes, atherosclerosis, and cardiovascular disease. It presents a combination of atherosclerosis risk including atherogenic dyslipidemia, hypertension, elevated plasma glucose, hypercoagulability, and a proinflammatory state. The 2 major underlying risk factors for the metabolic syndrome are obesity and insulin resistance. Exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors. Associated hyperinsulinemia, hyperglycemia, and elevated adipokine levels (adipose cytokines) lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease. In this 2-part series, the authors present an up-to-date and detailed systematic review of the literature on this important topic.     

Glycemic control in the metabolic syndrome and implications in preventing cardiovascular disease

The metabolic syndrome represents a cluster of cardiovascular risk factors that occur together more commonly than expected from the prevalence of their individual rates. Insulin resistance is widely believed to be the common denominator causing, in susceptible individuals, the development of various cardiovascular risk factor components of the syndrome (e.g., hyperlipidemia, hypertension, and hyperglycemia). The major cause of this insulin resistance appears to be obesity, especially the accumulation of visceral fat. This obesity is due to the combination of excessive caloric intake and inadequate physical activity rather than alterations in energy utilization. In individuals whose beta cells cannot increase their insulin secretion adequately to compensate for insulin resistance, hyperglycemia occurs.     

Are there specific components of the insulin resistance syndrome that predict the increased atherosclerosis seen in type 2 diabetes mellitus?

Cardiovascular disease is often present in patients with newly diagnosed type 2 diabetes. It is hypothesized that both type 2 diabetes and cardiovascular disease arise from an underlying insulin resistance syndrome, including impaired glucose tolerance, hypertension, dyslipidemia, and abdominal obesity. We reviewed the literature using various epidemiologic techniques to evaluate the relation between the insulin resistance syndrome components and incident cardiovascular disease. We found that although insulin resistance is likely important in the development of cardiovascular disease seen in diabetes, lipid and blood pressure abnormalities associated with the syndrome appear to be equally important. Future studies are needed to determine the most effective treatment strategies for preventing cardiovascular disease associated with the insulin resistance syndrome and type 2 diabetes.     

Management of the metabolic syndrome as a strategy for preventing the macrovascular complications of type 2 diabetes: controversial issues

The metabolic syndrome is known to increase cardiovascular morbidity and precede the development of type 2 diabetes. Even before the appearance of hyperglycemia, the components of the metabolic syndrome play a crucial role in the pathogenesis of the macrovascular complications. Thus, the recognition and treatment of the metabolic syndrome may be a strategy to prevent the most likely cause of death (i.e. cardiovascular events) in cases that eventually develop type 2 diabetes. In this review, controversial issues regarding the treatment of the two main components of the metabolic syndrome (i.e dyslipidemia and arterial hypertension) are discussed. Several disparities in the current NCEP-ATPIII recommendations, when applied to patients with the metabolic syndrome, are pointed out. In population-based studies, the number of individuals with the metabolic syndrome who would need LDL cholesterol lowering treatment following these guidelines is remarkably low compared to subjects belonging to the same risk strata (10 year risk 10-20%). Subjects with the metabolic syndrome do not fall into the same risk category, resulting in differing LDL-C targets. Also, the Framingham tables underestimate the cardiovascular risk associated with the metabolic syndrome; hence fewer cases qualify for drug therapy. In addition, LDL-C underestimates the number of atherogenic particles and is therefore not the ideal target for these patients. The selection of antihypertensive medication in the metabolic syndrome is also controversial. Thus, there is sufficient evidence for a review of the current management of the metabolic syndrome as part of a strategy to prevent the macrovascular complications in type 2 diabetes.     

The metabolic syndrome: evolving evidence that thiazolidinediones provide rational therapy

The metabolic syndrome, also known as the dysmetabolic syndrome, syndrome X or the insulin resistance syndrome, refers to the clustering of cardiovascular disease risk factors that are present in many individuals who are at increased risk for both cardiovascular events and type 2 diabetes. Prediabetic subjects typically exhibit an atherogenic pattern of cardiovascular risks that is associated with hyperinsulinaemia. Thus, identification of components of the metabolic syndrome is important if patients are to be treated early enough to prevent cardiovascular events and other complications related to diabetes. Therapies targeted to specific components of the metabolic syndrome such as improving glycaemic control, managing dyslipidaemia and reducing the prothrombotic state should help to minimize cardiovascular risk, particularly if initiated early. Traditional pharmacologic agents used to manage the individual components of the metabolic syndrome do not typically impact the other components. The thiazolidinediones, a new class of agents that improve insulin resistance, have the ability, in addition to their glucose-lowering effects, to exert several powerful anti-atherogenic properties, including anti-inflammatory effects in the vascular endothelium, redistribution of visceral fat and reduction of insulin resistance, hyperinsulinaemia and hyperproinsulinaemia. This makes the thiazolidinediones ideal candidates for the early treatment of many components associated with the metabolic syndrome.     

Insulin resistance syndrome: interaction with coagulation and fibrinolysis

Insulin resistance represents a common metabolic abnormality leading to cardiovascular disease, the major cause of morbidity and mortality in most parts of the world. Insulin resistance is also associated with an increased risk of type 2 diabetes which is strongly associated with obesity. The insulin resistance of obese people and subjects with type 2 diabetes is characterised by defects at many levels, affecting insulin receptor concentration, glucose transport mechanisms and the activities of intracellular enzymes. Around 25% of western populations show some features of the insulin resistance syndrome (often referred to as syndrome X or the metabolic syndrome) ie, a clustering of metabolic, atheromatous risk factors, including hypertriglyceridaemia, hyperinsulinaemia, hyper-tension, hypercholesterinaemia and obesity. However, the known metabolic cardiovascular risk factors associated with the insulin resistance syndrome do not sufficiently explain the excess vascular risk attributed to this syndrome. The observation, that increased plasma plasminogen activator inhibitor 1 (PAI-1) levels were associated with insulin resistance and atherothrombosis added for the first time a pathological basis for an association of the insulin resistance syndrome not only with metabolic, atheromatous (atherosclerotic) risk but also with atherothrombotic risk. It is very likely that not only PAI-1, but also other abnormalities in haemostatic variables contribute to this excess vascular risk. Knowledge of how haemostatic variables cluster with classical metabolic risk factors associated with the insulin resistance syndrome could help to better understand the pathogenesis of cardiovascular diseases. Indeed, many coagulation and fibrinolytic proteins have been shown to be associated with features of the insulin resistance syndrome and these associations suggest that some coagulation and fibrinolytic proteins have a role in atherothrombotic disorders, principally through an association with other established metabolic (atheromatous) risk factors in the presence of underlying insulin resistance. Interestingly, new therapeutic approaches in the prevention and treatment of insulin resistance do show some influence on coagulation and fibrinolysis. The newest drugs are the thiazolidinediones, a totally novel class of insulin sensitisers. They have the potential to offer improvements both in glycaemic control and in cardiovascular events.     

Cardiovascular risk associated with the metabolic syndrome

The term metabolic syndrome refers to a clustering of cardiovascular risk factors, most of which also share insulin resistance as an additional feature. Scientific effort has concentrated on understanding why these diverse cardiovascular risks co-occur in individuals and in determining the presumed common environmental or genetic factors that might underpin this. Clinically important developments include publication of standard definitions of the metabolic syndrome and recommendations for the use of type 2 diabetes and the presence of the metabolic syndrome as critical "risk stratifiers" in cardiovascular disease prevention. The remarkable recent secular increases in the prevalence of type 2 diabetes and obesity in many populations mean that the importance of the metabolic syndrome as a determinant of cardiovascular disease is likely to increase until these trends can be reversed.     

The expanding scope of the metabolic syndrome and implications for the management of cardiovascular risk in type 2 diabetes with particular focus on the emerging role of the thiazolidinediones

Over the last decade, new factors including endothelial dysfunction, vascular inflammation, and abnormalities of blood coagulation have joined more established components of the metabolic syndrome, such as hyperglycemia, hypertension, dyslipidemia, and visceral obesity. Many of these factors are known to promote atherosclerosis and the clustering of metabolic abnormalities within the syndrome makes a major contribution to the increased risk of cardiovascular disease and death associated with type 2 diabetes. Given that most patients have multiple cardiovascular risk factors, good glycemic control does not, by itself, adequately reduce the burden of cardiovascular disease associated with diabetes and clinical management needs to address the full profile of cardiovascular risk. The thiazolidinediones have potentially beneficial effects on many components of the metabolic syndrome and so may help to improve cardiovascular outcomes in type 2 diabetes.     

Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus

Type 2 diabetes mellitus, a global epidemic, is largely attributed to metabolic syndrome and its clustering of cardiovascular risk factors including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The two primary approaches to optimally control risk factors associated with metabolic syndrome are lifestyle changes and medications. Although many pharmacological targets have been identified, clinical management of cardiovascular risk factors associated with metabolic syndrome and type 2 diabetes is still dismal. Recent evidence suggests premises of the peroxisome proliferator-activated receptor (PPAR) ligands in the combat against type 2 diabetes and metabolic syndrome including obesity and insulin resistance. Three subtypes of the PPAR nuclear fatty acid receptors have been identified: alpha, beta/delta and gamma. PPARalpha is believed to participate in fatty acid uptake (beta- and omega-oxidation) mainly in the liver and heart. PPARbeta/delta is involved in fatty acid oxidation in muscle. PPARgamma is highly expressed in fat to facilitate glucose and lipid uptake, stimulate glucose oxidation, decrease free fatty acid level and ameliorate insulin resistance. Synthetic ligands for PPARalpha and gamma such as fibric acid and thiazolidinediones have been used in patients with type 2 diabetes and pre-diabetic insulin resistance with significantly improved HbA(1c) and glucose levels. In addition, nonhypoglycemic effects may be elicited by PPAR agonists or dual agonists including improved lipid metabolism, blood pressure control and endothelial function, as well as suppressed atherosclerotic plaque formation and coagulation. However, issues of safety and clinical indication remain undetermined for use of PPAR agonists for the incidence of heart disease in metabolic syndrome and type 2 diabetes.     

Role of Insulin Resistance and Diabetes in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is now a frequent cause of consultation for hepatologists and other health care providers. To a significant extent, this is because the metabolic abnormalities associated with obesity and type 2 diabetes mellitus (T2DM) promote liver disease and are more prevalent than ever before. Clinicians must be aware that insulin resistance and hyperglycemia are believed to worsen the natural history of NAFLD, fueling inflammation, hepatocyte injury (ballooning) and fibrosis. End-stage liver disease and hepatocellular carcinoma (HCC) develop more often in this setting. Interventions that reverse insulin resistance and hyperglycemia, may halt or ameliorate the disease process. Therefore, a comprehensive approach is needed for the successful management of these patients that addresses both, the liver-specific and the associated metabolic conditions. This review focuses on the mechanisms by which insulin resistance, and both lipo- and glucotoxicity, are believed to contribute to the development of NAFLD, and on the treatments tested in obese patients with T2DM and NAFLD, as a means to assist practitioners managing these complex patients.     

Adipose tissue dysfunction and the pathogenesis of metabolic syndrome

Metabolic syndrome is a growing research area. The underlying mechanisms of metabolic syndrome are still not very clear. Insulin resistance, obesity, inflammation and oxidative stress may play an important role in the pathogenesis of metabolic syndrome. The role of adipose tissue dysfunction is emphasized during the development of obesity. Adipose tissue is identified as a complex endocrine organ and its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. Chronic low-grade inflammation activated by the immune system in adipose tissue is a key contributing factor to type 2 diabetes mellitus and cardiovascular diseases. Visceral obesity results in cell autonomous impairment in insulin signaling that leads to insulin resistance. Chronic inflammation in adipose tissue has gained acceptance as a lead promoter of insulin resistance in obesity. Furthermore, obesity creates oxidative stress conditions in adipose tissue that not only correlates with insulin resistance but is also causative in its development. Oxidative stress may be a mechanistic link between several components of metabolic syndrome and cardiovascular diseases, through its role in inflammation and its ability to disrupt insulin-signaling. The study around adipose tissue dysfunction will help to understand the pathogenesis of metabolic syndrome and may bring effective therapy in treatment of metabolic syndrome related diseases. Therefore, this review mainly focuses on the roles of adipose tissue dysfunction in inflammation, insulin resistance, and oxidative stress in the pathogenesis of metabolic syndrome.