Detection of metabolic syndrome features among childhood cancer survivors: A target to prevent disease

Along with the growing epidemic of obesity, the risk of atherosclerosis, cardiovascular disease morbidity, and mortality are increasing markedly. Several risk factors for cardiovascular disease, such as visceral obesity, glucose intolerance, arterial hypertension, and dyslipidemia commonly cluster together as a condition currently known as metabolic syndrome. Thus far, insulin resistance, and endothelial dysfunction are the primary events of the metabolic syndrome. Several groups have recommended clinical criteria for the diagnosis of metabolic syndrome in adults. Nonetheless, in what concerns children and adolescents, there are no unified definitions, and modified adult criteria have been suggested by many authors, despite major problems. Some pediatric disease states are at risk for premature cardiovascular disease, with clinical coronary events occurring very early in adult life. Survivors of specific pediatric cancer groups, particularly acute lymphocytic leukemia, central nervous system tumors, sarcomas, lymphomas, testicular cancer, and following bone marrow transplantation, may develop metabolic syndrome traits due to: hormonal deficiencies (growth hormone deficiency, thyroid dysfunction, and gonadal failure), drug or radiotherapy damage, endothelial impairment, physical inactivity, adipose tissue dysfunction, and/or drug-induced magnesium deficiency. In conclusion, some primary and secondary prevention remarks are proposed in order to reduce premature cardiovascular disease risk in this particular group of patients.     

The metabolic syndrome: a cluster of vascular risk factors

The metabolic syndrome is a cluster of several vascular risk factors (impaired glucose metabolism, dyslipidaemia, hypertension and central adiposity). The prevalence of the metabolic syndrome is high, varying between 10 and 40% depending on age and sex. This prevalence will increase in the years to come due to the increased prevalence of overweight/obesity. To identify the metabolic syndrome, there is a readily applicable definition for daily clinical practice, i.e. the presence of three or more of the following characteristics: hyperglycaemia, hypertension, low plasma HDL cholesterol level, high plasma triglyceride level and central adiposity. The underlying pathophysiology is not fully clarified, but insulin resistance plays an important role in this syndrome. The metabolic syndrome is associated with increased cardiovascular morbidity and mortality and an increased risk for the development of diabetes mellitus type 2. In subjects with one or two components of the metabolic syndrome and in patients with manifest vascular disease, it seems advisable to be alert to the presence of the other components in order to either diagnose or exclude the metabolic syndrome. Although clinical evidence is lacking, from a pathophysiological point of view it seems reasonable to focus the treatment on reducing insulin resistance, which can be achieved by weight reduction and an increase in physical activity. Treatment of the individual risk factors may also be considered, depending on the degree of vascular risk.     

Botanicals and the metabolic syndrome

Metabolic syndrome describes the human condition characterized by the presence of coexisting traditional risk factors for cardiovascular disease, such as hypertension, dyslipidemia, glucose intolerance, and obesity, in addition to nontraditional cardiovascular disease risk factors, such as inflammatory processes and abnormalities of the blood coagulation system. Although the specific etiology for metabolic syndrome is not known, insulin resistance--a clinical state in which a normal or elevated insulin concentration reflects an impaired biological response--is present and is considered a key pathophysiologic abnormality. As such, metabolic syndrome can be considered to be a prediabetic state and contributes greatly to increased morbidity and mortality in humans. Given the public health significance of metabolic syndrome, successful strategies are direly needed to intervene in its development. As such, nutritional supplementation with botanicals that effectively address pathogenic mechanisms, combined with the acceptance and widespread use of botanical supplements by the general public, represents an attractive, novel, and potentially effective approach to the problem. Thus, the overall goal of our botanical research center is to comprehensively evaluate botanicals in addressing the pathophysiologic mechanisms that lead to the development of insulin resistance and metabolic syndrome. Currently, each of the 3 research projects evaluates a specific botanical [Russian tarragon (Artemisia dracunculus L), shilianhua (Sinocrassula indica), and grape (Vitus vinifera) anthocyanins] and assesses the effect on pathogenic mechanisms leading to the development of insulin resistance. With the completion of our research, we anticipate a better understanding of the cellular mechanisms by which insulin resistance develops and the role of botanicals in modulating the progression to metabolic syndrome.     

Management of the metabolic syndrome

The metabolic syndrome (MetS) represents the co-occurrence of insulin resistance, hypertension, central adiposity, atherogenic dyslipidemia, and a pro-inflammatory and pro-thrombotic state. Patients with this syndrome are at increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. Epidemiologic studies reveal a prevalence of the MetS that increases with age and obesity. Patients with the MetS should be recognized as being at high risk for cardiovascular complications. Ongoing research focuses on the underlying pathophysiology of this disorder and the use of drug therapy to directly target insulin resistance and endothelial dysfunction. Currently, the standard of care includes active identification and aggressive management of traditional cardiovascular risk factors with an emphasis on healthy lifestyle changes to reduce weight and increase physical fitness.     

Association between the polycystic ovary syndrome and the metabolic syndrome in Puerto Rico

Polycystic ovary syndrome (PCOS) affects mostly young women causing chronic anovulation, hyperandrogenism, hirsutism and obesity with android pattern. The prevalence of the metabolic syndrome (abnormal glucose metabolism, dyslipidemia, hypertension and increased waist circumference) in PCOS is not defined although both have a common etiologic factor: insulin resistance. This retrospective study from medical records examined the presence of obesity and features of the metabolic syndrome in women with PCOS. The metabolic syndrome was defined as presence of two or more of the following signs: abnormal glucose metabolism, hypertriglyceridemia, low HDL, and hypertension. Thirty nine records of patients with PCOS were reviewed. The mean age was 29.4 years and the body mass index was 36 kg/m2. Hypertriglyceridemia was present in 43%, low HDL in 71%, hypertension in 36%, impaired glucose tolerance in 10% and diabetes mellitus type 2 in 37%. The metabolic syndrome was identified in 44% of sampled women with PCOS. These findings indicate that women with PCOS are at increased risk of diabetes mellitus type 2 at a young age. PCOS patients have higher prevalence of the metabolic syndrome than the rest of the population and thus are at increased risk of cardiovascular disease even if they don't develop diabetes mellitus type 2.     

Cardiovascular consequences of cortisol excess

Cushing's syndrome is a consequence of primary or, more commonly, secondary oversecretion of cortisol. Cardiovascular disease is the major cause of morbidity and mortality in Cushing's syndrome, and excess risk remains even in effectively treated patients. The cardiovascular consequences of cortisol excess are protean and include, inter alia, elevation of blood pressure, truncal obesity, hyperinsulinemia, hyperglycemia, insulin resistance, and dyslipidemia. This review analyses the relationship of cortisol excess, both locally and at tissue level, to these cardiovascular risk factors, and to putative mechanisms for hypertension. Previous studies have examined correlations between cortisol, blood pressure, and other parameters in the general population and in Cushing's syndrome. This review also details changes induced by short-term cortisol administration in normotensive healthy men.     

Waist circumference measurement in clinical practice

The obesity epidemic is a major public health problem worldwide. Adult obesity is associated with increased morbidity and mortality. Measurement of abdominal obesity is strongly associated with increased cardiometabolic risk, cardiovascular events, and mortality. Although waist circumference is a crude measurement, it correlates with obesity and visceral fat amount, and is a surrogate marker for insulin resistance. A normal waist circumference differs for specific ethnic groups due to different cardiometabolic risk. For example, Asians have increased cardiometabolic risk at lower body mass indexes and with lower waist circumferences than other populations. One criterion for the diagnosis of the metabolic syndrome, according to different study groups, includes measurement of abdominal obesity (waist circumference or waist-to-hip ratio) because visceral adipose tissue is a key component of the syndrome. The waist circumference measurement is a simple tool that should be widely implemented in clinical practice to improve cardiometabolic risk stratification.     

Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity

OBJECTIVE: The term metabolic syndrome (MS) describes a cluster of cardiovascular risk factors including dyslipidemia, glucose intolerance, insulin resistance, and hypertension. Obesity increases the risk of MS, but as obesity is neither necessary nor sufficient to cause the syndrome, there is considerable interest in identifying obesity-independent pathways. One such pathway may involve the actions of the adipokine leptin, which is associated cross-sectionally with MS and prospectively with coronary heart disease and stroke, independently of obesity. Our goal was to test the hypothesis that leptin predicts the development of the features of MS independently of obesity. RESEARCH METHODS AND PROCEDURES: This study used a prospective population-based cohort of 748 middle-aged whites in whom baseline measures of leptin and repeated measurement of the subcomponents of the MS at 5 and 10 years were available. The features of the MS were characterized as five factors (obesity, dyslipidemia, elevated blood pressure, glucose intolerance, and insulin resistance), which were combined to create an MS summary score. RESULTS: Baseline leptin significantly predicted the development of obesity (p = 0.001) and, after adjustment for BMI, development of glucose intolerance (p = 0.016) and insulin resistance (p < 0.0001). Leptin levels did not independently predict a change in lipids or blood pressure. Leptin levels significantly predicted the development of the MS (p = 0.036), independently of baseline BMI. DISCUSSION: Leptin predicts the development of the MS independently of baseline obesity. This association is specifically related to the development of glucose intolerance and insulin resistance. The extent to which these relationships are explained through residual confounding by obesity remains to be determined.     

Supersize teens: the metabolic syndrome

With obesity and type 2 diabetes on the rise in children and adolescents, there has been recent interest in the study of the metabolic (insulin resistance) syndrome in this population. Characteristics of the syndrome include impaired glucose tolerance, hypertension, dyslipidemia, and abdominal obesity. These features are known to cluster and convey increased cardiovascular risk over time. Screening of children and adolescents is important to the goal of prevention, and therapeutic lifestyle modification is the primary treatment modality. When this fails, pharmacotherapy aimed at the individual risk factors may be indicated.     

Are metabolic risk factors one unified syndrome? Modeling the structure of the metabolic syndrome X

The metabolic syndrome, manifested by insulin resistance, obesity, dyslipidemia, and hypertension, is conceived to increase the risk for coronary heart disease and type II diabetes. Several studies have used factor analysis to explore its underlying structure among related risk variables but reported different results. Taking a hypothesis-testing approach, this study used confirmatory factor analysis to specify and test the factor structure of the metabolic syndrome. A hierarchical four-factor model, with an overarching metabolic syndrome factor uniting the insulin resistance, obesity, lipid, and blood pressure factors, was proposed and tested with 847 men who participated in the Normative Aging Study between 1987 and 1991. Simultaneous multi-group analyses were also conducted to test the stability of the proposed model across younger and older participants and across individuals with and without cardiovascular disease. The findings demonstrated that the proposed structure was well supported (comparative fit index = 0.97, root mean square error approximation = 0.06) and stable across subgroups. The metabolic syndrome was represented primarily by the insulin resistance and obesity factors, followed by the lipid factor, and, to a lesser extent, the blood pressure factor. This study provides an empirical foundation for conceptualizing and measuring the metabolic syndrome that unites four related components (insulin resistance, obesity, lipids, and blood pressure).     

Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease

Obesity, insulin resistance, and endothelial dysfunction closely coexist throughout the natural history of type 2 diabetes. They all can be identified not only in people with type 2 diabetes, but also in various groups at risk for the disease, such as individuals with impaired glucose tolerance, family history of type 2 diabetes, hypertension, dyslipidemia, prior gestational diabetes, or polycystic ovary syndrome. Whereas their evident association cannot fully establish a cause-effect relationship, fascinating mechanisms that bring them closer together than ever before are rapidly emerging. Central or abdominal obesity leads to insulin resistance and endothelial dysfunction through fat-derived metabolic products, hormones, and cytokines. Insulin resistance leads to endothelial dysfunction through the frequent association with traditional cardiovascular risk factors and through some more direct novel mechanisms. Some specific and shared insulin signaling abnormalities in muscle, fat, and endothelial cells, as well as some new genetic and nontraditional factors, may contribute to this interesting association. Some recent clinical studies demonstrate that nonpharmacological and pharmacological strategies targeting obesity and/or insulin resistance ameliorate endothelial function and low-grade inflammation. All these findings have added a new dimension to the association of obesity, insulin resistance, and endothelial dysfunction that may become a key target in the prevention of type 2 diabetes and cardiovascular disease.     

Obesity and Cardiometabolic Risk Factors: From Childhood to Adulthood

Obesity has become a major epidemic in the 21st century. It increases the risk of dyslipidemia, hypertension, and type 2 diabetes, which are known cardiometabolic risk factors and components of the metabolic syndrome. Although overt cardiovascular (CV) diseases such as stroke or myocardial infarction are the domain of adulthood, it is evident that the CV continuum begins very early in life. Recognition of risk factors and early stages of CV damage, at a time when these processes are still reversible, and the development of prevention strategies are major pillars in reducing CV morbidity and mortality in the general population. In this review, we will discuss the role of well-known but also novel risk factors linking obesity and increased CV risk from prenatal age to adulthood, including the role of perinatal factors, diet, nutrigenomics, and nutri-epigenetics, hyperuricemia, dyslipidemia, hypertension, and cardiorespiratory fitness. The importance of ‘tracking’ of these risk factors on adult CV health is highlighted and the economic impact of childhood obesity as well as preventive strategies are discussed.     

Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots

OBJECTIVES: To highlight the clinical and metabolic correlates of abdominal obesity and various abdominal adipose tissue depots. METHODS: We researched the topic using the search terms abdominal obesity, central obesity, visceral obesity, regional obesity, and subcutaneous adipose tissue from MEDLINE (National Library of Medicine, Bethesda, MD), PubMed (National Library of Medicine, Bethesda, MD), Current Contents (Institute for Scientific Information, Thomson Scientific, Philadelphia, PA), and using manual search for the cited references. RESULTS: Abdominal obesity contributes significantly to the metabolic perturbations and cardiovascular risk in human beings. Abdominal adipose tissue depots (intraabdominal and subcutaneous [deep subcutaneous, posterior subcutaneous]) are metabolically active and appear to be important for the pathogenesis of insulin resistance, dyslipidemia, glucose intolerance, hypertension, hypercoagulable state, and cardiovascular risk. Adipocyte anatomy (size), physiology (growth, catecholamine sensitivity, lipolysis, insulin action), and biochemistry (leptin, plasminogen activator inhibitor-1, cytokines, renin-angiotensin system) are reported to be relatively site-specific, highlighting unique roles of regional adipose tissue depots. CONCLUSIONS: Several physiological and metabolic parameters are site-specific in abdominal adipose tissue. The epidemiological, clinical, and prognostic significance and relative importance of the regional adipose tissue depots, however, remain to be ascertained.     

Insulin resistance (metabolic) syndrome in children

The insulin resistance (metabolic) syndrome (IRS), also known as syndrome X, is characterized by a clustering of factors associated with cardiovascular risk (obesity, impaired glucose metabolism, hypertension, and dyslipidemia). As reported from the third National Health and Nutrition Examination survey, the IRS is present in approximately 24% of adults in the United States and is strongly associated with coronary heart disease, stroke, type 2 diabetes, and all-cause mortality. Of equal importance, it is now clear that the origins of the IRS extend back into childhood (the IRS is found in approximately 4-10% of children and adolescents) and that the high prevalence of adult IRS is strongly linked to the development of cardiovascular risk during childhood and tracking of the components of the IRS into adulthood. The goal of this review is to present a summary of the currently available information on the IRS in the pre-adult age group with reference to adult studies only when necessary for clarification. The review will specifically summarize insulin resistance in childhood; the important influence of obesity and, in particular, visceral fat, on insulin resistance and the IRS; differences between ethnic groups; relations to adipocytokines, inflammatory factors and oxidative stress; relations of hypertension and lipids to insulin resistance; familial factors; endocrine complications; and potential therapeutic effects from diet and physical activity. Despite the lesser amount of basic and clinical information on childhood IRS in comparison to information available from adult studies, there can now be little doubt that the adverse associations among risk factors comprising the IRS begin in childhood. The challenge is to identify etiologic relations and develop intervention strategies designed to reduce the increasing prevalence of type 2 diabetes and cardiovascular disease.     

Exercise in aging: its important role in mortality, obesity and insulin resistance

The prevalence of overweight and obesity has increased dramatically over the last several decades. Obesity and physical inactivity increase the risk for cardiovascular disease, Type 2 diabetes mellitus, hypertension, dyslipidemia and certain cancers. Obesity and low levels of physical fitness are also associated with increased risk of all-cause and cardiovascular mortality. Central and total obesity, insulin resistance and inactivity increase with age. Exercise training and increased fitness promote positive changes in body composition and improve insulin sensitivity. This article will describe the effects of exercise training, both aerobic and resistive, on body composition and obesity as well as review studies investigating the effects of exercise training on glucose metabolism and insulin sensitivity in older adults. Adopting a physically active lifestyle should be emphasized in overweight and obese individuals with insulin resistance to reduce the risk for cardiovascular events in the aging population.     

Longitudinal analyses among overweight, insulin resistance, and cardiovascular risk factors in children

OBJECTIVE: It has been questioned whether insulin resistance or obesity is the central abnormality contributing to the cardiovascular risk factors dyslipidemia and hypertension in obesity. RESEARCH METHODS AND PROCEDURES: We studied weight status [SD score (SDS)-BMI], lipids (triglycerides, low-density lipoprotein- and high-density lipoprotein-cholesterol), blood pressure, and insulin resistance index [as homeostasis model assessment (HOMA) model] over a 1-year period in 229 obese white children (median age 12 years). RESULTS: Any degree of decrease in HOMA was associated with significant decreases in triglycerides (p < 0.001), systolic blood pressure (p < 0.001), and diastolic blood pressure (p < 0.001), whereas the children with different changes in HOMA did not differ significantly in their weight changes. Only the children in the highest quartile of weight reduction (decrease in SDS-BMI > 0.5) demonstrated a significant decrease in systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), and triglycerides (p = 0.012), and an increase in high-density lipoprotein-cholesterol (p = 0.023), whereas with a lower degree of weight loss, there were no significant changes in cardiovascular risk factors. In contrast with a lower degree of weight loss, a reduction of >0.5 SDS-BMI was associated with a significant decrease in HOMA (p < 0.001). DISCUSSION: Because blood pressure and triglycerides decreased with any degree of decrease in HOMA, independently of changes in weight status, these findings support the hypothesis that insulin resistance is the central abnormality contributing to these cardiovascular risk factors. Therefore, improving insulin resistance seems more important than reducing overweight to prevent or treat hypertension and dyslipidemia in obese children.     

Exercise and risk factors associated with metabolic syndrome in older adults

BACKGROUND: Older people with elevated blood pressure (BP) often have metabolic syndrome, a clustering of central obesity, insulin resistance, dyslipidemia, and hypertension. Exercise reduces many of these risk factors. This study examined whether the benefits of exercise on cardiovascular and metabolic disease risk factors are mediated by exercise-induced changes in fitness or body composition. METHODS: Randomized controlled trial, comprising 6 months of exercise training, conducted between July 1999 and November 2003. Participants included men and women (n =115) aged 55 to 75 years with untreated systolic blood pressure (SBP) of 130 to 159 or diastolic blood pressure of (DPB) 85 to 99 mm Hg. Fitness measures included BP, lipids, lipoproteins, insulin, and glucose; peak oxygen uptake and muscle strength; and body composition measured by anthropometry, dual-energy x-ray absorptiometry, and magnetic resonance imaging. RESULTS: A total of 51 men and 53 women completed the trial. Exercise significantly increased aerobic and muscle fitness, lean mass, and high-density lipoprotein cholesterol and reduced total and abdominal fat. DBP was reduced more among exercisers. There were no associations among changes in fitness with risk factors. Reductions in total body and abdominal fat and increases in leanness, largely independent of weight loss, were associated with improved SBP, DBP, total cholesterol, very low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and insulin sensitivity. At baseline, 42.3% of participants had metabolic syndrome. At 6 months, nine exercisers (17.7%) and eight controls (15.1%) no longer had metabolic syndrome, whereas four controls (7.6%) and no exercisers developed it (p =0.06). CONCLUSIONS: Although exercise improved fitness, the reductions in total and abdominal fatness and increase in leanness were more strongly associated with favorable changes in risk factors for cardiovascular disease and diabetes, including those that constitute metabolic syndrome.     

Weight excess and abdominal fat in the metabolic syndrome among Japanese-Brazilians

OBJECTIVE: Obesity, especially abdominal, has been associated with cardiovascular risk factors such as dyslipidemia, hypertension and diabetes mellitus (DM). The importance of these risk factors among Japanese-Brazilians was previously shown, although obesity is not a typical characteristic of Japanese migrants. In this study the prevalence of weight excess and central adiposity (CA) among Japanese-Brazilians and their association with metabolic disorders was evaluated. METHODS: A sample of 530 1st and 2nd generation Japanese-Brazilians (aged 40 - 79 years) went through anthropometric and blood pressure measurements, lipid profile and oral glucose tolerance tests. The prevalence rate (point and confidence interval) of overweight was calculated using a cut-off value of >26.4 kg/m2. CA diagnosis was based on waist-to-hip circumference ratio (WHR): greater-than-or-equal 0.85 and 0.95 in women and men, respectively. RESULTS: The prevalence of weight excess was 22.4% (CI 95% 20.6 - 28.1), and CA was 67.0% (95% CI 63.1 - 70.9). In addition to higher prevalence of DM, hypertension and dyslipidemia, stratifying by BMI and WHR, people with weight excess and CA revealed a poorer metabolic profile: blood pressure levels were significantly higher among those with weight excess with or without CA; CA individuals had higher glucose, triglycerides, total and LDL cholesterol, and lower HDL than those without weight excess or CA; fasting insulinemia was significantly higher among subjects with weight excess (with or without CA) than among those without weight excess or CA. CONCLUSION: Comparing subgroups with and without CA supports the hypothesis that abdominal fat accumulation represents a risk factor for insulin resistance-related diseases, even among Japanese descendants. The increased prevalence of metabolic syndrome among Japanese migrants could be attributed to visceral fat deposition, which has been implicated in the genesis of insulin resistance.     

Non-alcoholic fatty liver disease and cardiovascular risk

Non-alcoholic fatty liver disease is present in 15-25% of the general population. The fundamental derangement in non-alcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, dyslipidemia, hypertension, and obesity. The natural history of non-alcoholic fatty liver disease is not always benign, and causality for chronic liver disease and cirrhosis is well known in clinical practice and sometimes it is accompanied by hepatocellular carcinoma. Non-alcoholic fatty liver disease is likely to be associated with increased cardiovascular disease risk, and it raises the possibility that non-alcoholic fatty liver disease may be not only a marker but also an early mediator of atherosclerosis. Therapy is currently directed at treating components of the metabolic syndrome which may be beneficial also for the liver.     

The obesity epidemic: pathophysiology and consequences of obesity

Obesity has reached epidemic proportions in the United States: more than 20% of adults are clinically obese as defined by a body mass index of 30 kg/m(2) or higher, and an additional 30% are overweight. Environmental, behavioral, and genetic factors have been shown to contribute to the development of obesity. Elevated body mass index, particularly caused by abdominal or upper-body obesity, has been associated with a number of diseases and metabolic abnormalities, many of which have high morbidity and mortality. These include hyperinsulinemia, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, coronary heart disease, gallbladder disease, and certain malignancies. This underscores the importance of identifying people at risk for obesity and its related disease states.