The metabolic syndrome in a global perspective. The public health impact--secondary publication

The term "metabolic syndrome" refers to the clustering of a number of cardiovascular risk factors (obesity, hypertension, dyslipidemia and hyperglycaemia) believed to be related to insulin resistance. The prevalence of each of these diseases as well as the metabolic syndrome is increasing world wide. Obesity, hypertension, dyslipidemia and diabetes are no longer diseases of the wealthy. By 2025, three out of four people with diabetes will be living in third world countries, and similar trends are likely for the other components of the syndrome. Preventive action is urgently needed, and studies in China and India have proven to be effective.     

Inhibition of postprandial hyperglycemia by acarbose is a promising therapeutic strategy for the treatment of patients with the metabolic syndrome

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular diseases such as visceral obesity, hypertension, diabetes, and atherogenic dyslipidemia. Recently, insulin resistance in the absence of overt diabetes or the metabolic syndrome itself has been associated with endothelial dysfunction, one of the initial steps in the process of atherosclerosis. Postprandial hyperglycemia, one of the characteristic features of insulin resistance, induces oxidative stress generation and elicits vascular inflammation and platelet activation, thus being involved in the pathogenesis of atherosclerosis. A recent multicenter, placebo-controlled randomized trial, STOP-NIDDM trial, revealed that acarbose (Glucobay R), an alpha-glucosidase inhibitor, improved postprandial hyperglycemia and subsequently reduced the risk of development of type 2 diabetes in patients with impaired glucose tolerance (IGT). In this study, acarbose treatment was also found to slow the progression of intima-media thickness of the carotid arteries, a surrogate marker for atherosclerosis, and to reduce the incidence of cardiovascular diseases and newly diagnosed hypertension in subjects with IGT. Acarbose significantly reduced body mass index and waist circumference in these patients over 3 years. Furthermore, a meta-analysis of seven long-term studies has also shown that intervention with acarbose prevents myocardial infarction and cardiovascular diseases in type 2 diabetic patients. In this analysis, glycemic control, triglyceride levels, body weight and systolic blood pressure was also significantly improved during acarbose treatment. These observations suggest that prevention of postprandial hyperglycemia by acarbose may be a promising therapeutic strategy for reducing the increased risk for diabetes, hypertension, dyslipidemia, obesity, and cardiovascular diseases in patients with the metabolic syndrome. Acarbose improves postprandial hyperglycemia by delaying the release of glucose from complex carbohydrates in the absence of an increase in insulin secretion. Therefore, we would like to hypothesize here that this improvement in glucose metabolism could be associated with amelioration in insulin sensitivity, thus explaining the above-mentioned beneficial cardiometabolic actions of acarbose. Large clinical trials will provide us with more definite information whether acarbose treatment can improve insulin sensitivity and resultantly reduce the risk of diabetes, hypertension and cardiovascular diseases in patients with the metabolic syndrome.     

Metabolic syndrome

The Metabolic syndrome is a widely prevalent and multi-factorial disorder. The syndrome has been given several names, including- the metabolic syndrome, the insulin resistance syndrome, the plurimetabolic syndrome, and the deadly quartet. With the formulation of NCEP/ATP III guidelines, some uniformity and standardization has occurred in the definition of metabolic syndrome and has been very useful for epidemiological purposes. The mechanisms underlying the metabolic syndrome are not fully known; however resistance to insulin stimulated glucose uptake seems to modify biochemical responses in a way that predisposes to metabolic risk factors. The clinical relevance of the metabolic syndrome is related to its role in the development of cardiovascular disease. Management of the metabolic syndrome involves patient-education and intervention at various levels. Weight reduction is one of the main stays of treatment. In this article we comprehensively discuss this syndrome- the epidemiology, pathogenesis, clinical relevance and management. The need to do a comprehensive review of this particular syndrome has arisen in view of the ever increasing incidence of this entity. Soon, metabolic syndrome will overtake cigarette smoking as the number one risk factor for heart disease among the US population. Hardly any issue of any primary care medical journal can be opened without encountering an article on type 2 diabetes, dyslipidemia or hypertension. It is rare to see type 2 diabetes, dyslipidemia, obesity or hypertension in isolation. Insulin resistance and resulting hyperinsulinemia have been implicated in the development of glucose intolerance (and progression to type 2 diabetes), hypertriglyceridemia, hypertension, polycystic ovary syndrome, hypercoagulability and vascular inflammation, as well as the eventual development of atherosclerotic cardiovascular disease manifested as myocardial infarction, stroke and myriad end organ diseases. Conversely, treatment and consequent improvement of insulin resistance have been shown to result in better outcomes in virtually all of these conditions.     

Hyperinsulinaemia, a key factor of the metabolic syndrome in postmenopausal women

The metabolic syndrome (MetS) is a complex disorder combining obesity, hypertension, atherogenic dyslipidaemia and insulin resistance, a clustering of factors which markedly enhance the risk of developing cardiovascular disease (CVD) and type 2 diabetes. Main features of the MetS, which are found in many postmenopausal women, are increasing prevalence of insulin resistance and obesity (particularly visceral adiposity). Accordingly, a majority of postmenopausal women comply with criteria defining the MetS, and CVD is the first cause of morbidity/mortality in women, occurring even more frequently than in men. Moreover, obesity-related type 2 diabetes approaches pandemic proportions. Simultaneous occurrence of insulin resistance and obesity are most detrimental for metabolic health, and are also associated with increased oxidative stress, inflammatory and prothrombotic processes as well as with postmenopausal alterations in adipocytokine production. Hormone replacement therapy, provided the selected progestin does not antagonize estrogen action, may improve fat mass and distribution, dyslipidaemia and insulin sensitivity in postmenopausal women.     

Resistin,an adipokine,may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin

The metabolic syndrome (MS) is a cluster of metabolic disorders arising from insulin resistance, characterized by the presence of central obesity, impaired fasting glucose level, dyslipidemia and hypertension. As the first-line medication, metformin is commonly used for MS to reduce insulin resistance. Comparing with rosiglitazone, metformin does not increase cardiovascular mortality risk in patients with MS. However, metformin is not good enough in improving insulin sensitivity. Its molecular mechanism is still not clear. Recent studies have demonstrated that resistin, an adipokine, could induce IR by both AMPK-dependent and AMPK-independent pathways. Though there were conflicting findings of resistin in metabolic syndrome or type 2 diabetes mellitus in different studies, resistin was significant decreased in the rosiglitazone treated patients than in the metformin-treated patients in most of studies. Here, we hypothesized that resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin. This hypothesis could explain why rosiglitazone is superior to metformin in enhancement of insulin sensitivity.     

Resistin,an adipokine,may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin

The metabolic syndrome (MS) is a cluster of metabolic disorders arising from insulin resistance, characterized by the presence of central obesity, impaired fasting glucose level, dyslipidemia and hypertension. As the first-line medication, metformin is commonly used for MS to reduce insulin resistance. Comparing with rosiglitazone, metformin does not increase cardiovascular mortality risk in patients with MS. However, metformin is not good enough in improving insulin sensitivity. Its molecular mechanism is still not clear. Recent studies have demonstrated that resistin, an adipokine, could induce IR by both AMPK-dependent and AMPK-independent pathways. Though there were conflicting findings of resistin in metabolic syndrome or type 2 diabetes mellitus in different studies, resistin was significant decreased in the rosiglitazone treated patients than in the metformin-treated patients in most of studies. Here, we hypothesized that resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin. This hypothesis could explain why rosiglitazone is superior to metformin in enhancement of insulin sensitivity.     

Male hypogonadism: The unrecognized cardiovascular risk factor

Normal levels of male sex hormones are essential to men's health. Many studies demonstrate that hypogonadal men are at higher risk for developing a host of metabolic derangements, including dyslipidemia, type 2 diabetes mellitus, obesity, and hypertension. We examined the most recent studies supporting this notion of hypogonadism as a cardiac risk factor by reviewing all relevant PubMed data. Most studies showed an increase in metabolic disorders and cardiac events in hypogonadal men compared to their eugonadal counterparts. Mechanisms explaining this increased risk include adverse cytokine profiles produced by excess adipose tissue, abnormal lipid metabolism by understimulated hormone-sensitive lipase, and abnormal cellular respiration leading to insulin resistance. In contrast, some studies have not demonstrated such an increased cardiac risk. Conflicting data between studies is expected, given the complexity of testosterone and its metabolic effects. Additionally, the interaction of testosterone with the androgen receptor differs based on an individual genome. Hypogonadism will affect individual men differently because of this genomic variance. The literature points toward true hypogonadism as a major cardiac risk factor. Men at risk of being hypogonadal should be screened and brought back to eugonadism with hormone replacement.     

The role of sirtuin proteins in obesity.

Although the progressive metabolic changes associated with obesity are complex, it is well-recognized that obesity is a risk factor for the development of insulin resistance and type 2 diabetes. Because both obesity and type 2 diabetes are associated with insulin resistance, there is significant interest in defining the mechanistic basis for insulin resistance. Recent studies involving SIRT1, the most intensely studied sirtuin family member, have shown that it regulates many metabolic adaptations linked with obesity. SIRT1 has been shown to regulate the expression of adipokines, repress the activity of factors required for maturation of fat cells, regulate insulin secretion, modulate plasma glucose levels and insulin sensitivity and alter mitochondrial capacity. Moreover, some investigators have suggested that altering SIRT1 activity may be a promising new therapy for type 2 diabetes. In this review we focus on the role of sirtuins in obesity with particular emphasis on the contribution of SIRT1.     

Should visceral fat be reduced to increase longevity?

Several epidemiologic studies have implicated visceral fat as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and death. Utilizing novel models of visceral obesity, numerous studies have demonstrated that the relationship between visceral fat and longevity is causal while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. Specific recommended intake levels vary based on a number of factors, including current weight, activity levels, and weight loss goals. It is discussed the need of reducing the visceral fat as a potential treatment strategy to prevent or delay age-related diseases and to increase longevity.     

代谢性核受体及其与代谢综合征的关系

代谢性核受体是一组与代谢调节相关的配体激活核受体转录因子,主要包括脂质过氧化物体增殖物激活受体(PPARs)、肝X受体(LXRs)和法尼酯衍生物X受体(FXRs)3种。它们在胰岛素敏感性、脂肪生成、脂质代谢、能量代谢、血压调节、炎症、细胞生长和分化等过程中起着关键的调节作用,因而近年来倍受关注。越来越多的研究表明这3种核受体不仅与代谢综合征,包括胰岛素抵抗、糖耐量受损2、型糖尿病、肥胖、高脂血症、高血压和微白蛋白尿之间存在密切的关系,也在动脉粥样硬化的发生及发展中有重要的作用。本文就代谢性核受体的生物学活性和生理功能作一简述,并对其在代谢综合征发病机制中的作用进行重点讨论。     

The altered homeostatic theory: A hypothesis proposed to be useful in understanding and preventing ischemic heart disease, hypertension, and diabetes--including reducing the risk of age and atherosclerosis

Evidence will be presented to support the usefulness of the altered homeostatic theory in understanding basic pathogenetic mechanisms of ischemic heart disease (IHD), hypertension, and diabetes, and in improving prevention of these disorders. The theory argues that: IHD, hypertension, and diabetes share the same basic pathogenesis; risk factors favor a sympathetic homeostatic shift; preventative factors favor a parasympathetic homeostatic shift; risk and preventative factors oppose each other through a dynamic risk/prevention balance; and prevention should be based on improving the risk/prevention balance. Prevention based on improving the risk/prevention balance should be more effective, as this method is regarded as reflecting more accurately basic pathogenetic mechanisms. As example, the theory argues that the risk of supposedly nonmodifiable risk factors as age and the risk of relatively nonmodifiable atherosclerosis can be reduced significantly. The possible validity of the altered homeostatic theory was tested by a study based on multiple associations. Findings support a common pathogenesis for IHD, hypertension, and diabetes based on a sympathetic homeostatic shift, and the usefulness of prevention based on improving the risk/prevention balance by using standard pharmaceutical and lifestyle preventative measures. The same set of multiple and diverse risk factors favored IHD, hypertension, and diabetes, and the same set of multiple and diverse pharmaceutical and lifestyle preventative measures prevented these disorders. Also, the same set of preventative agents generally improved cognitive function and bone density, and reduced the incidence of Alzheimer's disease, atrial fibrillation, and cancer. Unexpectedly, evidence was developed that four major attributes of sympathetic activation represent four major risk factors; attributes of sympathetic activation are a tendency toward thrombosis and vasoconstriction, lipidemia, inflammation, and hyperglycemia, and corresponding risk factors are endothelial dysfunction (which expresses thrombosis/vasoconstriction and epitomizes this tendency), dyslipidemia, inflammation, and insulin resistance. These findings, plus other information, provide evidence that dyslipidemia acts mainly as a marker of risk of IHD, rather than being the basic mechanism of this disorder. However, prevention generally is based solely on improvement of dyslipidemia; basing prevention on dyslipidemia relatively underemphasizes the importance of other significant risk factors and, by certifying its validity, discourages alternate pathogenetic approaches. Also, development of myocardial infarction is approached differently. It seems generally accepted that dyslipidemia results rather automatically in infarction through the sequence of atherosclerosis, atherosclerotic complications, and thrombosis. In contrast, distinction is made between development of atherosclerosis and acute induction of infarction--where atherosclerosis is only one of multiple risk factors.     

Insulin resistance and endothelial cell dysfunction: studies in mammalian models

Type 2 diabetes and obesity are major risk factors for the development of cardiovascular atherosclerosis. Resistance to the metabolic effects of insulin on its traditional target tissues (muscle, liver and adipose tissue) is a central pathogenic feature of these disorders. However, the role of insulin resistance in non-canonical tissues, such as the endothelium, is less clear. Several large studies support a role for insulin resistance in the development of premature cardiovascular atherosclerosis independent of type 2 diabetes and obesity. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived nitric oxide. Nitric oxide is a signalling molecule which has a portfolio of potential antiatherosclerotic effects. The presence of insulin receptors on endothelial cells is well documented, and the endothelium has now emerged as a potentially important target tissue for insulin, with insulin-stimulated production of nitric oxide a feature of the action of insulin on endothelial cells. The role of insulin resistance at the level of the endothelial cell in vascular pathophysiology is unclear. A number of studies in humans and gene-modified mice have demonstrated a close association between insulin resistance and nitric oxide bioactivity. In this review, we discuss the link between insulin resistance and endothelial cell function in humans and demonstrate the complimentary information provided by murine models of obesity and insulin resistance in our understanding of the vasculopathy associated with type 2 diabetes and obesity.     

Risk factors for diabetes,but not for cardiovascular disease,are associated with family history of Type 2 diabetes in subjects from central Mexico

Background: Independent of obesity, family history of type 2 diabetes mellitus (FHT2DM) is another important risk factor for developing diabetes.

Aim: To establish the association among FHT2DM, risk factors for diabetes and cardiovascular disease in subjects from central Mexico.

Subjects and methods: Clinical and biochemical studies were performed in 383 first-degree relatives of patients with type 2 diabetes and 270 subjects unrelated to patients with type 2 diabetes—all subjects were from the city of Puebla in central Mexico. Logistic regressions were used to assess the association between FHT2DM and metabolic parameters. Cardiovascular risk was classified by dyslipidemia and the Framingham Risk Score (FRS).

Results: FHT2DM was associated with risk factors for diabetes, such as increased fasting insulin levels (OR = 1.731, 95% CI = 1.041–2.877), decreased insulin sensitivity (OR = 1.951, 95% CI = 1.236–3.080) and pre-diabetes (OR = 1.63, 95% CI = 1.14–2.33). FHT2DH was not associated with risk factors for cardiovascular disease, such as dyslipidemia (OR = 1.12, 95% CI = 0.70–1.79) and FRS (OR = 0.74, 95% CI = 0.40–1.36) when adjusted for gender, age, smoking and obesity.

Conclusion: Diabetic risk factors, but not cardiovascular disease risk factors, are associated with a positive family history of diabetes in subjects from central Mexico, independent of the presence of obesity.     

An approach to the etiology of metabolic syndrome

Increased prevalence of obesity in the world, especially accumulation of abnormal amounts of visceral fat predisposes to insulin resistance, which is the central role of metabolic syndrome (MS). Obesity can deregulate the intracellular signaling of insulin due to the production of inflammatory substances, chemoattractant proteins, adipokines and molecules that trigger hormonal mediator potentials for destabilization of signal transduction, leading to metabolic disorders such as hyperglycemia, hypertension, and dyslipidemia. The complexity of the MS and of the genetic mechanisms involved in its etiology derives from the combination of variants on genes involved and environmental factors that predispose it. The purpose of this paper is to review the effects of obesity in molecular and biochemical responses that trigger insulin resistance and its relation to some candidate genes and the ancestral component of the population.     

Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors

Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G-protein-coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men.     

Mechanisms of endothelial dysfunction in obesity-associated hypertension

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.     

干细胞：代谢综合征治疗的新资源

背景：代谢综合征是以糖、脂等代谢紊乱及向心性肥胖、高血压为特征的系列症候群,传统的治疗尚不能从根本上改善、治愈代谢综合征。 目的：综述干细胞移植治疗代谢综合征的研究进展,并提出干细胞使用方面许多亟待解决的问题。 方法：使用计算机检索Pubmed数据库及中国学术期刊全文数据库(CNKI)2002至2011年有关干细胞移植治疗代谢综合征胰岛素抵抗、高血糖、高血脂、高血压等组分的研究文献。英文检索词为“stem cells,metabolic syndrome,insulin resistance,diabetes,hyperlipidemia,hypertension,stem cells transplantation”,中文检索词为“干细胞、代谢综合征、胰岛素抵抗、糖尿病、高脂血症、高血压、干细胞移植”。排除陈旧性和重复性研究,收集到43篇相关文献纳入综述。 结果与结论：干细胞是机体组织细胞的起源,具有自我复制、高度增值和多向分化的能力,干细胞治疗可促进各种损伤修复和衰老死亡细胞的更新,从而改善组织器官的结构与功能,促进代谢产物的利用及排泄。相关研究证实干细胞可通过各种机制治疗代谢综合征的脂代谢紊乱、胰岛素抵抗、高血压、高血糖、动脉粥样硬化等病变。关于干细胞移植治疗代谢综合征,目前还有很多尚待解决的问题,但现有研究资料已经证实,干细胞移植治疗代谢综合征是一个充满希望的新途径。     

Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome

Metabolic syndrome (MetS) is characterized by accumulation of visceral fat associated with the clustering of metabolic and pathophysiological cardiovascular risk factors: impaired glucose tolerance, dyslipidemia, and hypertension. Although the definition of MetS is different among countries, visceral obesity is an indispensable component of MetS. A growing body of evidence suggests that increased oxidative stress to adipocytes is central to the pathogenesis of cardiovascular disease in MetS. Increased oxidative stress to adipocytes causes dysregulated expression of inflammation-related adipocytokines in MetS, which contributes to obesity-associated vasculopathy and cardiovascular risk primarily through endothelial dysfunction. The purpose of present review is to unravel the mechanistic link between oxidative stress and cardiovascular risk in MetS, focusing on insulin resistance, hypertension, and atherosclerosis. Then, therapeutic opportunities translated from the bench to bedside will be provided to develop novel strategies to cardiovascular risk factors in MetS.     

Poor vitamin D status may contribute to high risk for insulin resistance, obesity, and cardiovascular disease in Asian Indians

Asian Indians are highly prone to insulin resistance syndrome, obesity, diabetes, and coronary disease. At any given BMI, they tend to have more body fat and more central fat than other groups – yet their insulin resistance is disproportionately high relative to their body composition. They are also tend to have very poor vitamin D status, even in UV-drenched India, primarily owing to highly pigmented skin and a cultural tendency to avoid direct sun exposure. The resulting up-regulation of parathyroid hormone (PTH) arguably may play a role in their high risk for insulin resistance and associated pathologies. There is suggestive evidence that moderate elevations of PTH may promote insulin resistance, weight gain, hypertension, left ventricular hypertrophy, and the acute phase response, while increasing risk for ischemic arrhythmias and cardiovascular mortality. Controlled studies should assess the impact of optimal vitamin D supplementation, with or without added calcium, on risk factors associated with insulin resistance in Asian Indians, as well as in other highly pigmented urbanized ethnic groups that are at high risk for insulin resistance and obesity.     

Familial partial lipodystrophy: a monogenic form of the insulin resistance syndrome

Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) is a rare monogenic form of insulin resistance characterized by loss of subcutaneous fat from the extremities, trunk, and gluteal region. FPLD recapitulates the main metabolic attributes of the insulin resistance syndrome, including central obesity, hyperinsulinemia, glucose intolerance and diabetes, dyslipidemia, and hypertension. Through the use of focused DNA sequencing of positional candidate genes on chromosome 1q21, we discovered that FPLD results from mutations in LMNA (R482Q; OMIM 150330.0010), which is the gene that encodes nuclear lamins A and C. By stratifying members of extended FPLD pedigrees according to LMNA genotype, we found that hyperinsulinemia is present early in the course of the disease and that dyslipidemia (characterized by high triglycerides and depressed HDL cholesterol) precedes the development of glucose abnormalities. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. The findings in FPLD indicate that defective structure of the nuclear envelope produces a phenotype of insulin resistance. The findings may have relevance for common insulin resistance and for drug-associated lipodystrophies, whose molecular basis is unknown at present.