Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease

Abdominal fat accumulation has been shown to play crucial roles in the development of metabolic syndrome. Visceral fat accumulation particularly is closely correlated to the development of cardiovascular disease and obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension. Given these clinical findings, the functions of adipocytes have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that secrete various bioactive substances termed adipocytokines. Among adipocytokines, tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, which is an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor, and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, particularly adiponectin, is discussed with respect to cardiovascular diseases.     

肝肾综合征的治疗

肝肾综合征(HRS)是严重肝病、肝硬化腹水患者常发生的一种特殊的肾功能衰竭,预后极差。在临床治疗中,尽管对严重肝病和肝硬化腹水患者采取了积极的预防措施,但仍有相当大比例的患者发生HRS。多数在临床诊断后1个月内死亡。因     

The metabolic syndrome in a Congolese population and its implications for metabolic syndrome definitions

AimMetabolic syndrome defined by International cut-off values are limited to detect people at high cardiometabolic risk in Central Africans in comparison with metabolic syndrome defined by ethnic-specific definition. We examined the relationship between metabolic syndromes, diabetes control, abdominal obesity, HDL-cholesterol groups and atherosclerotic complications.Materials and methodsA representative sample of type-2 diabetic central Africans from Kinshasa were studied. Outcome measures included control of diabetes, atherosclerosis, abdominal obesity, insulin resistance, total cholesterol, triglycerides, HDL-cholesterol, metabolic syndromes and atherosclerosis.ResultsOf 1266 type-2 diabetic patients (48.8%), (61.8%), (27.1%) and (81%) had uncontrolled diabetes, atherosclerotics, metabolic syndrome (IDF/Europe), and metabolic syndrome (IDF/local) respectively. There was a significant U-shaped relationship between atherosclerotics complications, insulin resistance, delta postprandial glycaemia and HDL-cholesterol stratification. There was also a significant U-shaped relationship between cardiometabolic risk (P < 0.01) and atherosclerotic complications.ConclusionType-2 diabetic Central Africans exhibit very high rates of uncontrolled diabetes, atherosclerotic complications and metabolic syndrome. Both, abdominal obesity, insulin resistance, low and very high HDL-cholesterol levels are cardiometabolic risk factors.     

The metabolic syndrome

The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.     

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.     

The metabolic syndrome

The "metabolic syndrome" (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.     

Drug-induced metabolic syndrome

The metabolic syndrome is a cluster of risk factors associated with an increased risk for cardiovascular disease and type 2 diabetes. Based on data from 1988 to 1994, it is estimated that 24% of adults in the United States meet the criteria for diagnosis of the metabolic syndrome. The use of certain medications may increase the risk of the metabolic syndrome by either promoting weight gain or altering lipid or glucose metabolism. Health providers should recognize and understand the risk associated with certain medications and appropriately monitor for changes related to the metabolic syndrome. Careful attention to drug choices should be paid in patients who are overweight or have other risk factors for diabetes or cardiovascular disease.     

Current treatment options for the metabolic syndrome

Optional statement The metabolic syndrome is defined as a condition characterized by a set of clinical criteria: insulin resistance, visceral obesity, atherogenic dyslipidemia, and hypertension. The major risk factors leading to the epidemic of this syndrome in the United States are visceral obesity, physical inactivity, and an atherogenic diet. The available current evidence suggests that the first step in management of patients with metabolic syndrome should be focused on lifestyle modifications (eg, weight loss and physical activity). The treatment should be based on two major components: behavioral change to reduce caloric intake and an increase in physical activity. A realistic goal for weight reduction should be 7% to 10% over 6 to 12 months. The general dietary recommendations include low intake of saturated fats, trans fats and cholesterol, and diets with low glycemic index. Soy protein could be more beneficial than animal protein in weight reduction and correction of dyslipidemia. Physical activity is associated with successful weight reduction and these therapeutic lifestyle changes can reduce by half the progression to new-onset diabetes in patients with metabolic syndrome. Physical activity recommendations should include practical, regular, and moderated regimens of exercise, with a daily minimum of 30 to 60 minutes. An equal balance between aerobic exercise and strength training is advised. Medication therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. There is no single best therapy and the treatment should consist of treatment of individual component(s). Atherogenic dyslipidemia should be controlled with statins if there is concomitant increase in low-density lipoprotein cholesterol and if indicated with combination therapy, including fibrates, nicotinic acid, bile acid-binding resins, or ezetimibe. Drugs such as thiazolidinediones and renin-angiotensin system blockers are a few of the available agents in this category. Some evidence suggests that angiotensin-converting enzyme inhibitors and β blockers are more beneficial for treatment of hypertension in patients with metabolic syndrome. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor agonists, will broaden the horizons of the current treatment options in metabolic syndrome.     

Fibrates for treatment of the metabolic syndrome

The National Cholesterol Education Program Adult Treatment Panel III has provided a clinical definition for the metabolic syndrome that is practical for use in an office setting. Identification and treatment of the metabolic syndrome is of enormous public health importance because it is associated with a marked elevation in coronary heart disease risk and affects nearly 25% of adults in the United States. First-line therapy is lifestyle modification, which includes body weight reduction, increased physical activity, and moderation of the dietary glycemic load. Drug treatments focusing on the major components of the syndrome (atherogenic dyslipidemia, hypertension, and a prothrombotic state) have demonstrated efficacy for reducing coronary heart disease events. Fibrates seem to be particularly effective in patients for whom a disturbance of the triglyceride-high-density lipoprotein axis is the primary lipid disorder. Fibrates also appear to influence a number of emerging risk factors, including hemostatic and inflammatory markers and indicators of improved vascular wall biology, which may contribute to their cardioprotective effects.     

Prediction of genetic risk for metabolic syndrome

OBJECTIVES: The aim of the study was to identify gene polymorphisms that confer susceptibility to metabolic syndrome in order to allow reliable assessment of genetic risk for this condition. METHODS AND RESULTS: The study population comprised 1788 unrelated Japanese individuals (1033 men, 755 women), including 1017 subjects with metabolic syndrome (634 men, 383 women) and 771 controls (399 men, 372 women). The genotypes for 158 polymorphisms of 133 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that the -1131T-->C polymorphism of the apolipoprotein A-V gene (APOA5) was significantly associated with the prevalence of metabolic syndrome, with the C allele representing a risk factor for this condition. A stepwise forward selection procedure demonstrated that APOA5 genotype (CC+TC versus TT) significantly affected the prevalence of metabolic syndrome. The C allele of this polymorphism was associated with an increased serum concentration of triglycerides and a decreased concentration of HDL-cholesterol. CONCLUSIONS: Genotype for APOA5 may prove reliable for assessment of genetic risk for metabolic syndrome.