Metabolic syndrome and cardiovascular disease: challenges and opportunities

Metabolic syndrome (MetS) has been defined in different ways. However, key components common to most definitions are a constellation of risk factors including abdominal adiposity, impaired fasting glucose, hypertension, and dyslipidemia. A major mediator of MetS appears to be insulin resistance, which relates to the development of the vascular and metabolic dysfunctions that precede overt cardiovascular disease and type 2 diabetes. Evidence suggests that the mechanisms underlying the elevated cardiovascular risk associated with MetS begin with subclinical organ damage. Therapy for MetS targets individual components of the syndrome and includes lifestyle interventions, lipid-modifying therapy, and antihypertensive agents, particularly those that inhibit the renin-angiotensin system. Results of trials of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated reductions in new-onset diabetes and cardiovascular events in a wide range of patients. Clinical trials to investigate further the role of these drugs in the primary prevention of type 2 diabetes in patients with MetS are currently under way. The purpose of this paper is to review the MetS from the perspective of the cardiology workforce with the hope that a better understanding of the links between MetS and cardiovascular disease could lead to improved management of persons at risk.     

Cardiovascular risk in the metabolic syndrome: Fact or fiction?

In population-based studies, a cluster of cardiovascular risk factors comprising the metabolic syndrome (MetS) has been documented as predictive of cardiovascular disease events and type 2 diabetes. Currently, there are several proposed definitions of the MetS, although data support some advantages of using the 2005 National Cholesterol Education Program Adult Treatment Panel III definition, which is considered superior to most others, including the one from the 2005 International Diabetes Federation study. One controversial issue is that some of the conventional cardiovascular risk factors included in the MetS cluster appear to be equally predictive of cardiovascular outcomes as the syndrome itself (eg, the influence of smoking habits). Further observational and intervention studies are needed to explore this issue and target the core problem of the syndrome, which is proposed to be insulin resistance. Useful therapies for the metabolic syndrome include lifestyle modification and drugs that lower conventional cardiovascular risk factors, such as metformin, the "glitazones," and evidence-based drugs.     

Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome.

Insulin resistance is common and plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). Precedents in biomedical research indicate that evaluation of monogenic syndromes can help to understand a common complex phenotype. Monogenic forms of insulin resistance, such as familial partial lipodystrophy, which results from mutations in either LMNA (encoding lamin A/C) or PPARG (encoding peroxisome proliferator-activated receptor gamma), and congenital generalized lipodystrophy, which results from mutations in either AGPAT2 (encoding 1-acylglycerol-3-phosphate O-acyltransferase) or BSCL2 (encoding seipin), can display features seen in the common metabolic syndrome. In addition, insulin resistance is seen in disorders associated with insulin receptor mutations, progeria syndromes and in inherited forms of obesity. Although insulin resistance in such rare monogenic syndromes could simply be secondary to fat redistribution and/or central obesity, the products of the causative genes might also produce insulin resistance directly, and might illuminate new causative mechanisms for insulin resistance in such common disorders as T2DM and obesity.     

Cardiovascular risk associated with the metabolic syndrome

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

北京自然人群代谢综合征发病率及影响因素的研究

目的:探讨北京自然人群代谢综合征(metabolic syndrome,MetS)的发病规律及影响因素。方法:1999年在北京城乡自然人群中采用分层随机抽样方法建立了25~64岁男女两性共1304人的心血管病研究队列。2004年对该人群进行了随访和第2次危险因素调查。2次调查资料完整者893人。本研究对基线时未患MetS的617人5年后MetS的发病情况进行了分析。结果:1.本队列人群1999-2004年5年间MetS的累积年龄标化发病率为12.7%。2.采用多因素Logistic模型调整了年龄、性别等因素的影响后,基线有冠心病家族史、缺乏体育锻炼、胰岛素抵抗和具有MetS的任一组分均可增加MetS的发病危险,其中腹型肥胖对MetS的预测作用最强(OR=5.34,P<0.001)。3.调整其他因素的影响后,基线具有1个和2个MetS组分者5年后发生MetS的危险分别为没有任何组分者的4.39倍和12.48倍。结论:早期预防,特别是肥胖的预防,在MetS及相关的心血管病和糖尿病防治中起着至关重要的作用。     

Management of the metabolic syndrome

The metabolic syndrome (MetS) is strongly associated with insulin resistance and consists of a constellation of factors that raise the risk for cardiovascular diseases and diabetes mellitus. Therefore, the primary goals of treating MetS are prevention of type 2 diabetes and cardiovascular events. Three levels of intervention may be considered for individuals with MetS : 1) management of underlying risk conditions by controlling weight excess, enhancing regular physical exercise and promoting healthy diet; 2) management of individual risk factors such as dyslipidaemia, hypertension, hyperglycaemia and prothrombotic state; and 3) targeting insulin resistance by using specific insulin sensitizers such as thiazolidinediones. The most important therapeutic intervention effective in subjects with MetS should focus on modest weight reduction and regular leisure-time physical activities. Although lifestyle modification is the first-line therapy, drug therapy may be necessary in many patients to achieve recommended goals regarding lipid profile, blood pressure and blood glucose control. Rather than to use a magic bullet that might fully reverse the underlying cause of the syndrome, one appealing alternative would be to use a so-called "polypill" targeting each of the components of MetS. However, such a polypill should ideally contain numerous molecules that all have shown a potential interest for the management of MetS such as metformin, acarbose, a thiazolidinedione, a statin, a fibrate, an inhibitor of the renin-angiotensin system, aspirin. The growing prevalence and high-risk nature of MetS highlights the need to identify individuals with this condition and to treat them with an aggressive multitargeted approach.     

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.     

Intensified screening and treatment of the metabolic syndrome for cardiovascular risk reduction

The metabolic syndrome (MetS), characterized by a clustering of risk factors associated with insulin resistance and abdominal obesity, is associated with an increased risk of coronary heart disease and cardiovascular disease mortality. Persons with MetS have a wide spectrum of coronary heart disease risk and appropriate evaluation of risk using global risk algorithms. Measurement of other risk markers and subclinical disease is potentially needed to best set treatment goals and accompanying treatment regimens. The presence of MetS risk factors should be considered in global risk assessment. Clinical management emphasizes addressing underlying risk factors predisposing to MetS-specifically overweight/obesity and physical inactivity. Further recommendations are given for clinical risk factors, including atherogenic dyslipidemia, elevated blood pressure, insulin resistance/hyperglycemia, prothrombotic state, and proinflammatory state. Clinicians are recommended to assess MetS in their routine practice and to intensify efforts to adequately treat accompanying lifestyle and clinical risk factors.     

Genetics of metabolic syndrome

Metabolic syndrome (MetS) is a cluster of metabolic traits associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Central obesity and insulin resistance are thought to play key roles in the pathogenesis of the MetS. The MetS has a significant genetic component, and therefore linkage analysis, candidate gene approach, and genome-wide association (GWA) studies have been applied in the search of gene variants for the MetS. A few variants have been identified, located mostly in or near genes regulating lipid metabolism. GWA studies for the individual components of the MetS have reported several loci having pleiotropic effects on multiple MetS-related traits. Genetic studies have provided so far only limited evidence for a common genetic background of the MetS. Epigenetic factors (DNA methylation and histone modification) are likely to play important roles in the pathogenesis of the MetS, and they might mediate the effects of environmental exposures on the risk of the MetS. Further research is needed to clarify the role of genetic variation and epigenetic mechanisms in the development of the MetS.     

Metabolic syndrome: its history,mechanisms, and limitations

In late twentieth century, Ruderman and Reaven showed that insulin resistance might be fundamental to metabolic syndrome (MetS) which means a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 2001, user-friendly National Cholesterol Education Program (NCEP) criteria of MetS were proposed. In 2005, the International Diabetes Federation (IDF) and the Examination Committee for Criteria of Metabolic Syndrome in Japan issued different criteria of MetS where abdominal obesity is a necessary component. In 2009, IDF, National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity jointly adopted the revised NCEP criteria, where abdominal obesity is not a necessary component, as worldwide criteria of MetS. In 2010, WHO Expert Consultation warned that MetS is a concept that focuses attention on complex multifactorial health problems but has limited practical utility as a management tool. In animal studies, adipose tissue inflammation characterized by an increased number of crown-like structures in adipose tissue, rather than obesity per se, was shown to be a fundamental mechanism of metabolic derangements.     

Exercise, fitness, and cardiovascular disease risk in type 2 diabetes and the metabolic syndrome

This article highlights research supporting the concept that increased physical activity and cardiorespiratory fitness attenuate risk of cardiovascular disease, type 2 diabetes, and the metabolic syndrome. Increased activity and fitness also attenuate risk of developing cardiovascular disease in persons who have type 2 diabetes or the metabolic syndrome. Although controversial, relationships between physical activity/physical fitness and type 2 diabetes/metabolic syndrome are largely independent of body weight. Thus, physical inactivity and poor cardiorespiratory fitness are not only important determinants of cardiovascular and metabolic diseases, but they can also be considered common features of these conditions, much like traditional risk factors such as obesity and insulin resistance.     

Genetics of metabolic syndrome: Is there a role for phenomics?

Metabolic syndrome (MetS) is a common complex trait consisting of the clustering of abdominal obesity, hypertension, dyslipidemia, and dysglycemia. MetS is found in about 25% of the population in the United States and is associated with increased risk for type 2 diabetes and cardiovascular disease. Despite research into possible genetic influences for MetS, no consistently reproducible genetic markers have been obtained, partially due to lack of agreement on the definition of the phenotype. Because phenotypic precision is essential for genomic interrogation, the evolving discipline of clinical phenomics, which uses objective and systematic acquisition of phenotypic data (ie, “deep phenotyping”), may help evaluate the genetic influences of MetS. This article reviews evidence that MetS has a genetic component and the potential applicability of clinical phenomics for the genetic evaluation of MetS using the example of hierarchical cluster analysis of phenotypic components of lipodystrophy syndromes, which serve as monogenic models of MetS.     

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.     

Galanin peptide family as a modulating target for contribution to metabolic syndrome

Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease.     

The metabolic syndrome, insulin resistance, and cardiovascular risk in diabetic and nondiabetic patients

CONTEXT: The contribution of insulin resistance per se to the vascular risk conferred by the metabolic syndrome (MetS) is not known; conversely, it is uncertain whether insulin resistance confers vascular risk beyond the entity of the MetS. OBJECTIVE: The objective of this study was to investigate the impact of the MetS (Adult Treatment Panel III criteria) and insulin resistance (as estimated by the homeostasis model assessment index) on the incidence of vascular events. DESIGN AND PATIENTS: This was a prospective cohort study enrolling 750 consecutive patients undergoing coronary angiography for the evaluation of coronary artery disease. SETTING: The study was performed at a tertiary care clinical research center. MAIN OUTCOME MEASURE: The main outcome measure was the incidence of vascular events over 2.3 yr. RESULTS: Both the MetS and insulin resistance predicted vascular events after controlling for non-MetS risk factors [hazard ratio (HR), 2.74 (95% confidence interval, 1.71-4.39; P < 0.001) and 1.51 (1.24-1.84; P < 0.001), respectively]. After additional adjustment for insulin resistance, the MetS remained significantly predictive of vascular events [HR, 2.69 (1.57-4.64); P < 0.001], and conversely, insulin resistance remained significantly predictive of vascular events despite adjustment for the MetS [standardized HR, 1.41 (1.14-1.75); P = 0.002]. Additional adjustment for the presence of type 2 diabetes revealed that both the MetS [adjusted HR, 2.57 (1.47-4.51); P = 0.001] and homeostasis model assessment of insulin resistance [standardized adjusted HR, 1.37 (1.09-1.73); P = 0.007] significantly predicted vascular events independent from diabetes status. CONCLUSIONS: Both the MetS and insulin resistance are strong and mutually independent predictors of vascular risk among angiographed coronary patients.     

Insulin resistance is a cardiovascular risk factor in humans

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

The impact of metabolic syndrome on insulin sensitivity, glucose sensitivity, and acute insulin response after glucose load in early-onset type 2 diabetes mellitus: Taiwan Early-Onset Type 2 Diabetes Cohort Study

Diabetic patients with metabolic syndrome (MetS) have higher lifetime risks for cardiovascular disease, especially in early-onset type 2 diabetes mellitus (EODM). Increased insulin resistance (IR) and impaired insulin secretion are important pathophysiologies in diabetic patients. Therefore, the effects of MetS on IR and insulin secretion in EODM were investigated. Forty-eight EODM (mean age, 22.8 ± 0.6 years) patients were enrolled in this study. Two grouping criteria were used: the first was whether the patient had MetS or not (MetS+ or Met−, with 31 and 17 patients, respectively); and the second was the number of MetS components each group had, that is, MetS (1,2) with 1 to 2, MetS (3) with 3, and MetS (4,5) with 4 to 5 components (17, 17, and 14 patients in each group, respectively). A frequently sampled intravenous glucose tolerance test was performed to measure insulin sensitivity, glucose sensitivity, acute insulin response after glucose load, and disposal index. Severe IR was noted with both homeostasis model assessment and frequently sampled intravenous glucose tolerance test both in MetS+ and MetS−. However, significantly higher acute insulin response after glucose load and disposal index were noted in MetS+ and MetS (4,5) than in Met−, MetS (1,2), and MetS (3), respectively. Early-onset type 2 diabetes mellitus patients with MetS had similar IR to those without MetS. This may be due to early deterioration of insulin action in these subjects. In addition, insulin secretion was higher in subjects with more MetS components, suggesting that EODM patients with MetS had better preserved ability of β-cell compensation for IR than those without MetS.     

Underdiagnosis of Metabolic Syndrome in Non-Hispanic Black Adolescents: A Call for Ethnic-Specific Criteria

Childhood obesity is a risk factor for the development of both type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). One marker that can be used to predict T2DM is the metabolic syndrome (MetS). MetS, a cluster of cardiovascular factors associated with insulin resistance, is defined by central obesity, impaired fasting glucose, hypertension, elevated triglycerides (TG), and low levels of high-density lipoprotein cholesterol. Some have advocated using a diagnosis of MetS to trigger increased intervention in children. However, ethnic differences in MetS may hamper identification of at-risk children. For example, non-Hispanic blacks are diagnosed with MetS less frequently than non-Hispanic whites, despite having higher rates of T2DM and CVD. These differences in MetS are predominantly due to a low frequency of hypertriglyceridemia in non-Hispanic blacks. Compared with non-Hispanic whites and Mexican Americans, non-Hispanic blacks have lower TG levels at baseline but exhibit worsening insulin resistance with increasing TG. Therefore “normal” TG levels appear to be falsely reassuring among insulin-resistant non-Hispanic blacks. Ethnic-specific tools may be needed to more accurately predict risk for T2DM and CVD in minorities.     

Atherosclerosis in diabetes and insulin resistance

Atherosclerosis and cardiovascular disease are the major causes of morbidity and mortality in patients with diabetes and those with insulin resistance and the metabolic syndrome. Both conditions profoundly accelerate the development of atherosclerosis and increase the morbidity and mortality of cardiovascular events. The question, therefore, is what are the molecular/biochemical mechanisms that underlie the potentiating influence of diabetes, the metabolic syndrome and/or insulin resistance on the development and progression of atherosclerosis? The following review will focus on the molecular mechanism whereby hyperglycaemia and/or hyperinsulinemia either directly or indirectly promote atherosclerosis.     

Metabolic Syndrome in Blacks: Are the Criteria Right?

Blacks have a lower prevalence of metabolic syndrome (MetS) that can be partly ascribed to the lower prevalent rates of some major components of MetS, namely the lower serum triglycerides and higher high-density lipoprotein cholesterol levels in blacks when compared with whites. Blacks manifest greater insulin resistance, the pivotal lesion underpinning MetS than whites. However, the relationships among insulin resistance and cardiovascular disease (CVD) risk factors are weaker in blacks than whites. The international bodies have recommended the use of European-based cutoff points for MetS for blacks. However, with the emerging inconsistencies in the association of insulin resistance and CVD risk factors in blacks, the use of these definitions and the cutoff points for MetS have become problematic. Therefore, it is important to review the limitations in the use of the current criteria and cutoff points of MetS in blacks to lessen the CVD risk burden in blacks.