Endothelial dysfunction and the metabolic syndrome

The metabolic syndrome is a highly prevalent multifaceted clinical entity produced through the interaction of genetic, hormonal, and lifestyle factors. A distinctive constellation of abnormalities precedes and predicts the accelerated development of atherogenesis and type 2 diabetes mellitus. Abnormalities of inflammation and coagulation represent emerging risk contributors associated with obesity and insulin resistance, central components of the metabolic syndrome, which act in concert with traditional abnormalities to increase cardiovascular risk. The initiation and progression of atherosclerosis may have its origins in impaired endothelial function that can be detected at the earliest stages of development of the syndrome. The basic elements of the metabolic syndrome and accelerated phase of atherogenesis are often silent partners that present many years before the onset of type 2 diabetes mellitus. The ability to detect and monitor subclinical vascular disease, as a reflection of the multiple factors that contribute to impair arterial wall integrity, holds potential to further refine cardiovascular risk stratification. Noninvasive assessment of vascular health may also aid the clinical decision-making process by guiding therapeutic interventions to optimize vascular protection in the metabolic syndrome.     

Pathophysiology of prediabetes

The term prediabetes refers to subjects with impaired fasting glucose and/or impaired glucose tolerance who are at increased risk for type 2 diabetes mellitus. Although both types of patients are at increased risk for developing type 2 diabetes mellitus and cardiovascular disease, they manifest distinct metabolic abnormalities. In this article, we summarize the metabolic abnormalities that characterize each state and the contribution of these metabolic abnormalities to the increased risk of diabetes and cardiovascular disease.     

The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases

Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations.     

Insulin resistance,diabetes, and atherosclerosis: thiazolidinediones as therapeutic interventions

The insulin resistance syndrome, a cluster of metabolic abnormalities involving dyslipidemia, hypertension, diabetes, impaired glucose tolerance, and hypercoagulability, carries an increased risk of atherosclerosis. Although interventions targeting elements of this syndrome have dramatically reduced cardiovascular risk, the impact of glucose-lowering has been more disappointing. Thiazolidinediones (TZDs) are a new class of insulin-sensitizing agents that activate the nuclear receptor peroxisome proliferators-activated receptor-γ. TZDs may improve not only glucose levels but also other metabolic parameters associated with insulin resistance. The TZD data are reviewed, with a focus on their potential cardiovascular effects.     

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.     

Definition of the Metabolic Syndrome: What's New and What Predicts Risk?

The metabolic syndrome is a clustering of abnormalities that confers an increased risk of cardiovascular disease and type 2 diabetes. Five organizations have proposed definitions of the syndrome. Despite differences in specific criteria among the definitions, there is agreement that the major characteristics of the syndrome include central obesity (except in one definition), elevated blood pressure, dyslipidemia, and impaired glucose metabolism or insulin resistance. Large variations exist in the prevalence of the metabolic syndrome across countries and regions, ethnic groups, and gender. The prevalence is high and increasing, particularly in North and South American countries. The high prevalence, combined with the large number of people at risk for cardiovascular disease, type 2 diabetes, and other related disorders, suggests that the metabolic syndrome may present a major worldwide public health challenge in future.     

The metabolic syndrome

Metabolic syndrome represents a cluster of clinical, biochemical and humoral abnormalities associated with impaired insulin action in glucose metabolism. In the literature also the term syndrome of insulin resistance, dysmetabolic syndrome X, Reaven syndrome or Kaplans dead quartet can be found. Hyperinsulinaemia, central obesity, essential hypertension, dyslipidaemia, impaired glucose homeostasis or type 2 diabetes, hyperuricaemia, hypercoagulable state, endothelial dysfunction and increased markers of inflammation such as C-reactive protein, selectines, adhesion molecules, pro-inflammatory cytokines are the typical components of metabolic syndrome increasing the risk of cardiovascular complications. List of currently recognized clinical and biochemical manifestations continues to expand and include also non-alcoholic steatohepatitis, polycystic ovaric syndrome (PCOS), hyperhomocysteinaemia and others. No standard definition of metabolic syndrome has been routinely used. The WHO initially proposed a definition of metabolic syndrome in 1998, and more recently NCEP-ATP III provided a new working definition in 2001, which is more suitable for clinical practice. Prevalence of metabolic syndrome is very high, about 25-30% in Caucasians, depending on diagnostic criteria used. The clinical significance of metabolic syndrome is augmented by its association with increased and accelerated atherosclerosis. Whether IR predicts cardiovascular disease (CVD) independently of diabetes and other CVD risk factors is still a matter of controversy. Recently there is a growing evidence that metabolic syndrome increases also the risk of all-cause mortality and risk of certain tumors.     

Vascular, metabolic, and inflammatory abnormalities in normoglycemic offspring of patients with type 2 diabetes mellitus

Endothelial dysfunction, insulin resistance, and elevated levels of circulating proinflammatory markers are among the earliest detectable abnormalities in people at risk for atherosclerosis. Accelerated atherosclerosis is a leading contributor to morbidity and mortality in type 2 diabetes mellitus, a complex genetic disorder. Therefore, we hypothesized that normoglycemic offspring of patients with type 2 diabetes mellitus (NOPD) may have impaired vascular and metabolic function related to an enhanced proinflammatory state. We compared NOPD (n = 51) with matched healthy control subjects without family history of diabetes (n = 35). Flow- and nitroglycerin-mediated brachial artery vasodilation were assessed by ultrasound to evaluate endothelium-dependent and -independent vascular function. Each subject also underwent an oral glucose tolerance test to evaluate metabolic function. Fasting levels of plasma adiponectin and circulating markers of inflammation (high-sensitivity C-reactive protein, CD40 ligand, interleukin 1beta, tumor necrosis factor alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule) were measured. Both NOPD and the control group had fasting glucose and insulin levels well within the reference range. However, results from oral glucose tolerance test and quantitative insulin sensitivity check index revealed that NOPD were insulin resistant with significantly impaired flow- and nitroglycerin-mediated dilation compared with the control group. Adiponectin levels were lower, whereas many circulating markers of inflammation were higher, in NOPD compared with the control group. Normoglycemic offspring of patients with type 2 diabetes mellitus have impaired vascular and metabolic function accompanied by an enhanced proinflammatory state that may contribute to their increased risk of diabetes and its vascular complications.     

The operative risk factors in the metabolic syndrome: Is it lipids and high BP or are there direct vascular effects of insulin resistance and obesity?

Increase in patients with central obesity and insulin resistance is an important cause for the worldwide increased incidence of type 2 diabetes. Several risk factors such as glucose intolerance, hyperinsulinemia, obesity, dyslipidemia, and hypertension, but also endothelial dysfunction and inflammation, have been found to cluster and often precede type 2 diabetes mellitus. Seeing the importance of early identification, the US National Cholesterol Education Program created a readily applicable definition of the metabolic syndrome for daily clinical practice. It is assumed that the cardiovascular risk for patients belonging to the metabolic syndrome can just be calculated out of the sum of the separate cardiovascular risk factors dyslipidemia and hypertension. However, there are also data pointing toward a higher risk than expected from these separate cardiovascular risk factors because of possible direct vascular effects of insulin resistance and obesity. Awareness of the underlying disorders of insulin resistance and its associated (non-) traditional risk factors such as endothelial dysfunction and inflammation is important for understanding the pathophysiology and thus coherent treatment.     

Cardiometabolic features of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex disorder comprising both hormonal and metabolic abnormalities that include impaired glucose tolerance, type 2 diabetes, vascular disease, dyslipidemia, and obstructive sleep apnea. Insulin resistance is a central pathogenetic factor in PCOS that seems to result from a post-receptor-binding defect in insulin action. Insulin resistance and the consequent development of hyperinsulinemia contribute to the constellation of cardiometabolic abnormalities noted above. Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented. Attention to the metabolic risks associated with PCOS, starting as early as adolescence, is essential to the medical care of these patients.     

Endothelial dysfunction in metabolic syndrome: Prevalence,pathogenesis and management

The metabolic syndrome (MetS) is characterized by the presence of central obesity, impaired glucose metabolism, dyslipidemia and hypertension. Several studies showed that MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) and vascular events. All components of MetS have adverse effects on the endothelium. Endothelial dysfunction plays a role in the pathogenesis of atherosclerosis and might also increase the risk for insulin resistance and T2DM. We review the prevalence and pathogenesis of endothelial dysfunction in MetS. We also discuss the potential effects of lifestyle measures and pharmacological interventions on endothelial function in these patients. It remains to be established whether improving endothelial function in MetS will reduce the risk for T2DM and vascular events.     

Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA

The insulin resistance syndrome (IRS) is considered to be a new target of risk-reduction therapy. The IRS is a cluster of closely associated and interdependent abnormalities and clinical outcomes that occur more commonly in insulin-resistant/hyperinsulinemic individuals. This syndrome predisposes individuals to type 2 diabetes, cardiovascular diseases, essential hypertension, certain forms of cancer, polycystic ovary syndrome, nonalcoholic fatty liver disease, and sleep apnea. In patients at high risk for cardiovascular diseases, endothelial dysfunction is observed in morphologically intact vessels even before the onset of clinically manifest vascular disease. Indeed, there are several lines of evidence that indicate that endothelial function is compromised in situations where there is reduced sensitivity to endogenous insulin. It is well established that a decreased bioavailability of nitric oxide (NO) contributes to endothelial dysfunction. Furthermore, NO may modulate insulin sensitivity. Activation of NO synthase (NOS) augments blood flow to insulin-sensitive tissues (i.e. skeletal muscle, liver, adipose tissue), and its activity is impaired in insulin resistance. Inhibition of NOS reduces the microvascular delivery of nutrients and blunts insulin-stimulated glucose uptake in skeletal muscle. Furthermore, induction of hypertension by administration of the NOS inhibitor NG-monomethyl-L-arginine is also associated with insulin resistance in rats. Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial vasodilator dysfunction and increased risk of cardiovascular diseases. An intriguing relationship exists between insulin resistance and ADMA. Plasma levels of ADMA are positively correlated with insulin resistance in nondiabetic, normotensive people. New basic research insights that provide possible mechanisms underlying the development of insulin resistance in the setting of impaired NO bioavailability will be discussed.     

Thiazolidinediones-improving endothelial function and potential long-term benefits on cardiovascular disease in subjects with type 2 diabetes

Endothelial dysfunction, which leads to impaired vasodilation, is an early event in the development of atherosclerosis. A number of mechanisms involving, for example, cell adhesion molecules, chemokines, and cytokines, contribute to this inflammatory disease, and insulin resistance plays a cardinal role in accelerating these processes. Hyperglycemia and other metabolic abnormalities that are commonly associated with insulin resistance also contribute to impaired endothelial function. In addition, the important role of the endothelium in damage repair following a cardiovascular event is emerging. The combination of proatherogenic factors in patients with type 2 diabetes results in blunted endothelial function and an increased risk of cardiovascular disease. Insulin-sensitizing agents such as thiazolidinediones have demonstrated a number of clinical benefits, including anti-inflammatory and antithrombotic properties, which may impact on the course of atherosclerosis. Recent studies have demonstrated that thiazolidinediones improve endothelial function in subjects with and without type 2 diabetes.     

Adverse endothelial function and the insulin resistance syndrome

Type 2 diabetes is characterized by impaired endothelial dependent vasodilatation which may contribute to the high prevalence of vascular disease in such patients. Although hyperglycaemia, dyslipidaemia and hypertension can all independently cause a similar defect, recent data suggest that endothelial dysfunction may be intrinsic to the insulin resistance syndrome that commonly precedes type 2 diabetes. Such abnormalities in endothelial function could represent the impact of subclinical disturbance of metabolism or alternatively the presence of a common cellular defect that influences both nitric oxide bioavailability and insulin mediated glucose disposal. Resolution of this puzzle is likely to lead to important advances in our knowledge and ultimately treatment of vascular disease.     

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.     

Preventing diabetes by treating aspects of the metabolic syndrome

The metabolic syndrome often develops into and is usually present in type 2 diabetes in association with premature cardiovascular disease. Treating diabetes can prevent some of its devastating consequences, but it does not eliminate them all. With the goal to eliminate all the adverse consequences of the syndrome, the optimal approach would be through its prevention. Insulin resistance appears to be pivotal to development of the syndrome complex that includes features such as intra-abdominal or visceral obesity, hypertension, impaired glucose homeostasis, dyslipidemia with elevated triglycerides and low highdensity lipoprotein without elevations of low-density lipoprotein, a procoagulant state, and impaired vascular function. Improving the insulin resistance needs to be the primary target of the therapy. Hyperglycemia, which is one feature of the metabolic syndrome, may range from impaired glucose tolerance (IGT) to overt diabetes. The risk of progression of the disease from IGT to diabetes is increased with time and the presence of various risk factors. Diabetes is a disease of serious concern because of the associated complication of the disease and the huge impact on the health care costs. Many short- and longer-term trials have shown promise in the prevention of diabetes and its metabolic and cardiovascular consequences.     

The metabolic syndrome, diabetes and lung dysfunction

Sleep-disordered breathing and sleep apnoea are conditions frequently associated with comorbidity, including obesity, diabetes, hypertension, insulin resistance (metabolic syndrome) and cardiovascular disease. The diabetic state (type 1 and type 2 diabetes) may be associated to diminished lung function and, in particular, decreased vital capacity, and the association between chronic obstructive pulmonary disease (COPD) and type 2 diabetes may be due to a shared inflammatory process. Also, the alteration in circulating endothelial progenitor cells found in respiratory disease, the metabolic syndrome and cardiovascular disease reflect a common condition of endothelial dysfunction.     

The importance of diagnosing the polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is an extremely common disorder that occurs in 4% to 7% of women of reproductive age. Although PCOS is known to be associated with reproductive morbidity and increased risk for endometrial cancer, diagnosis is especially important because PCOS is now thought to increase metabolic and cardiovascular risks. These risks are strongly linked to insulin resistance and are compounded by the common occurrence of obesity, although insulin resistance and its associated risks are also present in nonobese women with PCOS. Women with PCOS are at increased risk for impaired glucose tolerance, type 2 diabetes mellitus, and hypertension. Cardiovascular disease is believed to be more prevalent in women with PCOS, and it has been estimated that such women also have a significantly increased risk for myocardial infarction. Many lipid abnormalities (most notably low high-density lipoprotein cholesterol levels and elevated triglyceride levels) and impaired fibrinolysis are seen in women with PCOS. Early diagnosis of the syndrome and close long-term follow-up and screening for diabetes and cardiovascular disease are warranted. An opportunity exists for preventive therapy, which should improve the reproductive, metabolic, and cardiovascular risks.     

New concepts in dyslipidemia in the metabolic syndrome and diabetes

Trials have revealed that cardiovascular risk is not uniform in the population, but is distributed in a "risk pyramid." Diabetic patients with prior cardiovascular disease (CVD) are at greatest risk. Nondiabetic patients with CVD, diabetic patients without CVD, and subjects with the metabolic syndrome form the next three risk categories. The presence of insulin resistance-related metabolic abnormalities is a common denominator in this risk pyramid. Insulin resistance is a core defect in type 2 diabetes and the metabolic syndrome. Because insulin resistance may cause the atherogenic dyslipidemia that is commonly associated with these conditions, therapeutic strategies that combat insulin resistance could substantially reduce cardiovascular risk. Evidence suggests that defects in mitochondrial oxidative phosphorylation (which may be inherited, age related, or lifestyle acquired) may play a critical role in the pathogenesis of insulin resistance. Reduced mitochondrial oxidative phosphorylation can be partially reversed by improved diet, increased exercise, and administration of peroxisome proliferator-activated receptor-alpha agonists (omega-3 fatty acids and fibrates). Statin therapy has demonstrated clinical benefits in insulin-resistant patients but residual cardiovascular risk remains elevated. Fibrates also improve the lipid profile and reduce cardiovascular risk in a variety of insulin-resistant populations. Affected individuals should be targeted for therapeutic lifestyle intervention. Patients with atherogenic dyslipidemia who have developed insulin resistance, the metabolic syndrome, or type 2 diabetes should receive more intensive interventions including, where appropriate, statin-fibrate combination therapy, to comprehensively modify the lipid profile together with aggressive control of blood pressure and glucose to minimize risk in this very high-risk population.     

Metabolic syndrome: no internationally defined standard cut-off value for waist circumference

The metabolic syndrome (MS) is a cluster of interrelated risk factors of metabolic origin - metabolic risk factors that appear to directly promote the development of atherosclerotic cardiovascular disease and increase the risk of development of type 2 diabetes.……