对胰岛素抵抗在代谢综合征中作用的新认识

代谢综合征(MS)是以中心性肥胖、高血压、脂质代谢异常、微量蛋白尿、葡萄糖耐量受损和(或)糖尿病等为特征的一组临床综合征,是导致糖尿病、心脑血管疾病的危险因素。1999年WHO将其正式命名为MS,并做了工作定义。2005年国际糖尿病联盟(IDF)对其提出了新的工作定义,进而达成全球共识。胰岛素抵抗是指机体对一定量胰岛素的生物学反应低于预计正常水平的一种现象,是导致MS发病的主要机制,其与MS各组分之间密切相关,但机制尚未完全阐明。本文就MS的定义及有关胰岛素抵抗在MS发生中的作用机制的研究的新进展做简要综述。     

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.     

The GH/IGF-1 Axis in Obesity: Physiological and Pathological Aspects

The cluster of cardiovascular risk factors-abdominal obesity, dyslipidaemia, insulin resistance and hypertension-has been recognized as the core of the metabolic syndrome. Adults with severe growth hormone (GH) deficiency have, to a large extent, features of the metabolic syndrome, and there is a strong inverse association between visceral fat accumulation and blunted GH secretion in adults. Hyposomatotropism in abdominal obesity has therefore been suggested to be of importance for its metabolic consequences. However, the underlying pathophysiological mechanisms are poorly understood. Prevalence of the metabolic syndrome is steadily increasing worldwide. Overnutrition and sedentary habits are the stigmata of modern society that predispose genetically susceptible individuals to develop central obesity and other features of the metabolic syndrome including glucose intolerance, hypertension and dyslipidemia. Although there are still no unified definitions of the syndrome, it is clear that this condition is associated with an increased risk for development of cardiovascular disease (CVD) and diabetes mellitus (DM). In this review, we discuss current evidence regarding alterations in the GH-IGF- 1 axis in abdominal obesity and its possible impact on other features of the metabolic syndrome.     

Systemic inflammation and the metabolic syndrome among middle-aged community volunteers

The metabolic syndrome is conceptualized as a clustering of risk factors—including insulin resistance, dyslipidemia, central adiposity, and elevated blood pressure (BP)—that increase the risk for cardiovascular disease and type 2 diabetes mellitus. Recent evidence suggests that markers of systemic inflammation may be included in the definition of the syndrome and play some role in its pathogenesis. In this study, we use a statistical modeling technique, confirmatory factor analysis, to evaluate relationships of systemic inflammation, as measured by plasma concentrations of C-reactive protein and interleukin-6, with the component factors of the metabolic syndrome (insulin resistance, dyslipidemia, central adiposity, and elevated BP) and to examine whether inflammation is a potential common pathway linking established components to the full syndrome. Subjects were 645 community volunteers aged 30 to 54 years (48% male, 82% European American, 18% African American). Consistent with existing literature, structural equation modeling adjusting for age, sex, and race confirmed a higher-order common factor underlying the covariation of insulin resistance, dyslipidemia, adiposity, and BP. Inflammation was positively associated with this common factor, accounting for 54% of its variance and partially mediating statistical aggregation of the component factors comprising the metabolic syndrome. These results were particularly strong for adiposity, raising the possibility that inflammatory processes stimulated by intraabdominal adipose tissue contribute to the development of the metabolic syndrome. The inclusion of inflammatory markers in the clinical definition of metabolic syndrome seems warranted and may improve prognostic assessment of risk of type 2 diabetes mellitus and cardiovascular disease.     

Epidemiology of diabetes mellitus and associated cardiovascular risk factors: focus on human immunodeficiency virus and psychiatric disorders

Type 2 diabetes mellitus and obesity have reached epidemic proportions in many developing and developed nations, leading to talk of the "twin epidemics." The latest projections from the International Diabetes Federation suggest that 190 million people worldwide currently have type 2 diabetes. In addition, > or = 300 million people worldwide have impaired glucose tolerance (IGT). These statistics represent an epidemic of major proportions--possibly the largest epidemic in human history--in terms of glucose intolerance and cardiovascular disease (CVD) risk because individuals with IGT are at substantially higher risk for diabetes and CVD than are members of the general population. Along with IGT, the metabolic syndrome comprises other major CVD risk factors, including insulin resistance, central obesity, and dyslipidemia; insulin resistance has been implicated as the single most common cause of the syndrome. Although the exact prevalence of the metabolic syndrome is unknown, the syndrome is widespread among adults in developed nations, becoming more prevalent with age. Epidemiologic data suggest that in patients with schizophrenia or affective disorders, both diabetes and obesity are 1.5 to 2.0 times more prevalent than in the general population. Furthermore, because adverse effects of certain therapies for human immunodeficiency virus (HIV) infection and psychiatric disorders increase the risk for developing diabetes, obesity, and the metabolic syndrome, such therapies should be carefully chosen, particularly considering CVD risk. Appropriate therapy may be determined via screening of patients for levels of fasting blood glucose and lipids, as well as other CVD risk factors, before initiating use of second-generation antipsychotic agents or highly active antiretroviral therapy.     

Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies

Obesity is reaching epidemic proportions with recent worldwide figures estimated at 1.4 billion and rising year‐on‐year. Obesity affects all socioeconomic backgrounds and ethnicities and is a pre‐requisite for metabolic syndrome. Metabolic syndrome is a clustering of risk factors, such as central obesity, insulin resistance, dyslipidaemia and hypertension that together culminate in the increased risk of type 2 diabetes mellitus and cardiovascular disease. As these conditions are among the leading causes of deaths worldwide and metabolic syndrome increases the risk of type 2 diabetes mellitus fivefold and cardiovascular disease threefold, it is of critical importance that a precise definition is agreed upon by all interested parties. Also of particular interest is the relationship between metabolic syndrome and cancer. Metabolic syndrome has been associated with a plethora of cancers including breast, pancreatic, colon and liver cancer. Furthermore, each individual risk factor for metabolic syndrome has also an association with cancer. Our review collates internationally generated information on metabolic syndrome, its many definitions and its associations with life‐threatening conditions including type 2 diabetes mellitus, cardiovascular disease and cancer, providing a foundation for future advancements on this topic.     

Prevalence of metabolic syndrome in urban Pakistan (Karachi): comparison of newly proposed International Diabetes Federation and modified Adult Treatment Panel III criteria

The clustering of central obesity, dyslipidemia, hypertension, and hyperglycemia known as metabolic syndrome has been associated with a two- to three-fold increase in type 2 diabetes (T2DM) and cardiovascular disease (CVD). It is recognized that the features of the metabolic syndrome can be present 10 years preceding T2DM and CVD. The objective of our study was to determine the prevalence of metabolic syndrome in adults aged 25 years and older from an urban population of Karachi, Pakistan, according to the International Diabetes Federation (IDF) definition and modified Adult Treatment Panel III (ATP III) criteria. This study involved a survey conducted from July, 2004, to December, 2004, by generating a computerized random sample of households in Lyari Town using a geographical imaging system (GIS). Out of the 85,520 households, 532 households were randomly selected and 867 adults > or =25 years old consented to take part in the survey; 363 of these subjects gave blood samples. The prevalence of diabetes was 9.4%, whereas 5.6% had impaired fasting glucose (abnormal glucose tolerance 15%). The prevalence of metabolic syndrome according to the IDF definition and modified ATP III criteria was 34.8% and 49%, respectively. Inclusion of modified waist circumference and specific body mass index (BMI) cut offs for Asians may help predict metabolic syndrome at an early stage. High prevalence of metabolic syndrome was identified irrespective of the definition applied in this population. This may call for immediate action to halt the accelerating risk of diabetes and CVD that would lead to a possible unparalleled rise in the cost of health care and human suffering.     

Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance

Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40–50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin–angiotensin–aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance.     

The metabolic syndrome and endothelial dysfunction: Common highway to type 2 diabetes and CVD?

Due to global lifestyle changes, obesity (the main driver of type 2 diabetes [T2D] and cardiovascular disease [CVD]) is reaching pandemic proportions. The metabolic syndrome, which is regarded as a prediabetic state, is characterized by a concurrence of interrelated cardiovascular risk factors, including abdominal obesity, insulin resistance, hypertension, dyslipidemia, and glucose intolerance. Endothelial dysfunction (ED) is common in the metabolic syndrome and is associated with increased risk for T2D and CVD. This review focuses on the mechanisms linking ED to the metabolic syndrome, T2D, and CVD, and the possible therapies that may improve ED and reduce T2D and CVD risk.     

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.     

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.     

Is central obesity a good predictor of carotid atherosclerosis in Japanese type 2 diabetes with metabolic syndrome?

Metabolic syndrome has been revealed to be a major risk factor for cardiovascular disease (CVD) and early mortality in non-diabetic and diabetic patients. In 2005, the International Diabetes Federation (IDF) and the Examination Committee of Criteria for Diagnosis of Metabolic Syndrome in Japan published new definitions of metabolic syndrome in which central obesity was an indispensable factor. However, the significance of this new definition to CVD in type 2 diabetes has not yet been clarified. A cross-sectional study was conducted with 294 Japanese type 2 diabetic patients without known cardiovascular disease to evaluate the association between metabolic syndrome defined by this new definition and carotid atherosclerosis, and the significance of central obesity for the prediction of the development of carotid atherosclerosis. In a multivariate regression analysis, metabolic syndrome but not central obesity was significantly associated with carotid intima-media thickness (IMT) independent of known cardiovascular risk factors (p<0.05). In addition, whereas carotid IMT was significantly increased according to the increase in the number of components of metabolic syndrome, it was not significantly different between the groups with the same number of components of metabolic syndrome with or without central obesity. These findings suggest that the prediction of the development of carotid atherosclerosis in Japanese type 2 diabetic patients could be improved by the assessment of aggregation of components of metabolic syndrome rather than with or without metabolic syndrome by this new definition.     

Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence

A significant proportion of patients with type 2 diabetes mellitus have a low testosterone level relative to reference ranges based on healthy young men. Only a small number of these patients suffer from classical hypogonadism as a result of recognizable hypothalamic–pituitary–gonadal axis pathology. The cut‐off value of the serum testosterone level in men without obvious hypothalamic–pituitary–gonadal axis pathology is controversial. It is unclear to what extent a low serum testosterone level causally leads to type 2 diabetes and/or the metabolic syndrome. From a theoretical standpoint, there can be complex interactions among the hypothalamic–pituitary–gonadal axis, body composition and insulin resistance, which can be further influenced by intrinsic and extrinsic factors to give rise to metabolic syndrome, glucose intolerance, and low‐grade inflammation to increase the risk of cardiovascular disease. Although a low serum testosterone level frequently coexists with cardiometabolic risk factors and might serve as a biomarker, more studies are required to clarify the causal, mediating or modifying roles of low serum testosterone level in the development of adverse clinical outcomes. Currently, there are insufficient randomized clinical trial data to evaluate the effects of testosterone replacement therapy on meaningful clinical outcomes. The risk‐to‐benefit ratio of testosterone therapy in high‐risk subjects, such as those with type 2 diabetes, also requires elucidation. The present article aims to review the current evidence on low serum testosterone levels in patients with type 2 diabetes, and its implications on cardiovascular risk factors, metabolic syndrome and adverse clinical outcomes.     

Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese

The metabolic syndrome is characterized by a clustering of cardiovascular risk factors including type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity. Elevated plasma insulin and urinary norepinephrine (noradrenaline) and reduced urinary epinephrine (adrenaline) excretion are associated with obesity in Caucasian populations. We examined the interrelationships between obesity, plasma insulin, and urinary catecholamine excretion in Chinese subjects with various components of the metabolic syndrome. A total of 577 Chinese subjects (aged 38 +/- 10 years; 68% with type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria and 32% healthy subjects) were studied, all of whom had a plasma creatinine less than 150 micromol/L. The blood pressure, height, weight, waist and hip circumference, and fasting plasma glucose, insulin, lipid, and creatinine levels were measured. A 24-hour urine sample was collected for measurement of albumin and catecholamine excretion. The body mass index (BMI) and waist circumference were used as measures of general and central obesity, respectively. The insulin resistance index was estimated by the calculated product of fasting plasma insulin and glucose concentrations. Patients with an increasing number of components of the metabolic syndrome (type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria) were more obese, hyperglycemic, dyslipidemic, and albuminuric and had higher blood pressure, plasma insulin, insulin resistance indices, and 24-hour urinary norepinephrine excretion but lower urinary epinephrine output (all P < .005). Increasing quintiles of BMI in the whole population or waist circumference in both sexes were associated with increasing trends for adverse lipid profiles, plasma insulin, insulin resistance indices, and urinary norepinephrine excretion but a decreasing trend for urinary epinephrine output (all P < .001). There were close associations between age, obesity, blood pressure, fasting plasma glucose, lipid, insulin, insulin resistance indices, and urinary catecholamine excretion. Using stepwise multiple regression analysis (all P < .001), 34% of the variability of the BMI and 45% of that of the waist circumference were independently related to gender (waist higher in males and BMI higher in females), increased plasma insulin, triglyceride, and urinary norepinephrine excretion, and decreased high-density lipoprotein (HDL) cholesterol and urinary epinephrine output. In Chinese subjects with different manifestations of the metabolic syndrome, hyperinsulinemia, insulin resistance, elevated norepinephrine, and reduced epinephrine excretion were closely associated with general and central obesity. Based on these findings, we postulate that complex interactions between the insulin and sympathoadrenal systems may lead to the development of obesity and the metabolic syndrome.     

Metabolic Syndrome,Androgens, and Hypertension

Obesity is one of the constellation of factors that make up the definition of the metabolic syndrome. Metabolic syndrome is also associated with insulin resistance, dyslipidemia, hypertriglyceridemia, and type 2 diabetes mellitus. The presence of obesity and metabolic syndrome in men and women is also associated with increased risk of cardiovascular disease and hypertension. In men, obesity and metabolic syndrome are associated with reductions in testosterone levels. In women, obesity and metabolic syndrome are associated with increases in androgen levels. In men, reductions in androgen levels are associated with inflammation, and androgen supplements reduce inflammation. In women, increases in androgens are associated with increases in inflammatory cytokines, and reducing androgens reduces inflammation. This review discusses the possibility that the effects of androgens on metabolic syndrome and its sequelae may differ between males and females.     

Challenges in developing drugs for the metabolic syndrome

Metabolic syndrome refers to a clustering of established and emerging cardiovascular disease (CVD) risk factors within a single individual. The established risk factors—such as obesity, diabetes, dyslipidemia, hypertension—and other emerging risk factors are closely related to central obesity (especially intra-abdominal adiposity). Insulin resistance is also an important factor in this syndrome’s etiology. However, despite the potential use of having all the CVD risk factors under an umbrella diagnosis of metabolic syndrome, debate continues about the very existence of the metabolic syndrome. Despite the controversies, many existing therapies and new drugs in development are targeting the metabolic syndrome. To date, no drugs are approved specifically for treating the metabolic syndrome. This article discusses some of the challenges in developing therapies for the metabolic syndrome.     

Epidemiology of the insulin resistance syndrome

The insulin resistance syndrome consists of the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease, including overall obesity, central obesity, dyslipidemia (characterized by elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol), hyperglycemia, and hypertension. Using criteria proposed by the National Cholesterol Education Program Adult Treatment Panel III, national survey data suggest the insulin resistance syndrome is very common, affecting about 24% of US adults aged greater than 20 years. The syndrome is more common in older people and in Mexican Americans, and will increase in prevalence as populations age and become more obese. Identification of the syndrome warrants aggressive interventions known to prevent type 2 diabetes and cardiovascular disease, including weight reduction, increased physical activity, and control of hypertension and dyslipidemia.     

Statin use in the metabolic syndrome

The metabolic syndrome is a condition associated with obesity, insulin resistance, hypertension, dyslipidemia, hypercoagulability, and chronic inflammation, all of which increase the risk of cardiovascular disease (CVD). The Third National Cholesterol Education Program Adult Treatment Panel extensively discussed the metabolic syndrome because it is a major health issue in the United States due to the national epidemic of obesity. Statins cause significant CVD risk reduction in patients with the metabolic syndrome by alterations in lipid levels and possibly by decreasing inflammation. Because of the increased CVD risk associated with the metabolic syndrome and extensive clinical trial evidence documenting reduction of CVD risk with statin treatment, all patients with the metabolic syndrome should be evaluated as candidates for statin treatment as part of a multidisciplinary approach to reduce CVD risk.     

The emergence of the metabolic syndrome with menopause

Women with the metabolic syndrome (central obesity, insulin resistance, and dyslipidemia) are known to be at especially high risk for cardiovascular disease (CVD). The prevalence of the metabolic syndrome increases with menopause and may partially explain the apparent acceleration in CVD after menopause. The transition from pre- to postmenopause is associated with the emergence of many features of the metabolic syndrome, including 1) increased central (intraabdominal) body fat; 2) a shift toward a more atherogenic lipid profile, with increased low density lipoprotein and triglycerides levels, reduced high density lipoprotein, and small, dense low density lipoprotein particles; 3) and increased glucose and insulin levels. The emergence of these risk factors may be a direct result of ovarian failure or, alternatively, an indirect result of the metabolic consequences of central fat redistribution with estrogen deficiency. It is unclear whether the transition to menopause increases CVD risk in all women or only those who develop features of the metabolic syndrome. This article will review the features of the metabolic syndrome that emerge with estrogen deficiency. A better understanding of these metabolic changes with menopause will aid in the recognition and treatment of women at risk for future CVD, leading to appropriate interventions.     

Metabolic issues and cardiovascular disease in patients with psychiatric disorders

Individuals with psychiatric disorders tend to have excessive morbidity. They typically have high rates of respiratory illnesses, infectious diseases, substance abuse (including smoking), obesity, diabetes mellitus, and cardiovascular disease (CVD). Persons with schizophrenia and affective disorders also have a high prevalence of risk factors for CVD, such as diabetes and obesity, which are on the order of 1.5 to 2.0 times higher than in the general population; this translates into increased mortality rates due to CVD. The use of certain psychotropics results in metabolic sequelae, such as obesity, dyslipidemia, glucose dysregulation, and the metabolic syndrome. These sequelae exacerbate the already elevated risk of CVD and diabetes in this group of people. Therefore, the use of psychotropic agents that result in, for example, excessive weight gain not only add another complication for physicians managing a patient with schizophrenia but also may have serious prognostic and cost implications with respect to treatment-related diabetes and coronary disease incidence. The recent American Diabetes Association (ADA) Consensus Panel concluded that some agents are associated with greater diabetes risk than others. The current review describes the prevalence of the metabolic syndrome in people with affective disorders and schizophrenic populations, its prognostic relevance, and its exacerbation among patients treated with particular psychotropic agents, including certain atypical antipsychotics, selective serotonin reuptake inhibitors, and mood stabilizers. The costs associated with the treatment of the metabolic syndrome, diabetes, and coronary heart disease in populations with schizophrenia are also described.