Which of the following health issues is not directly associated with the metabolic syndrome?

Metabolic Syndrome

The clustering of a group of defined metabolic and physical abnormalities is now referred to as the metabolic syndrome.24 Patients with metabolic syndrome commonly have abdominal obesity, reduced levels of high-density lipoprotein (HDL), hyperinsulinemia, glucose intolerance, hypertension, and other characteristic features15 as listed inBox 58.1. Specific criteria for diagnosing metabolic syndrome are included inTable 58.4. The diagnosis requires that at least three of the following be present: abdominal obesity, elevated fasting glucose, hypertension, low HDLs, and hypertriglyceridemia.25 Weight gain with visceral obesity is a major predictor of the metabolic syndrome. The clinical approach uses waist circumference, rather than BMI, to define the adipose mass component contributing to the metabolic syndrome since BMI has been shown to be a relatively insensitive indicator of the risk for obesity-associated metabolic and cardiovascular diseases. Waist circumference, but not BMI, reflects abdominal subcutaneous adipose tissue as well as abdominal visceral adipose tissue and is therefore a better index of central, or truncal, fat mass.

In the United States, approximately 34% of the adult population have metabolic syndrome.26 Of these, more than 83% meet the criterion of abdominal obesity. The incidence of metabolic syndrome increases with age, with more than 40% of the U.S. population affected by the age of 60 years.24 Men are affected more commonly than women, and Hispanics and South Asians appear to be particularly susceptible. Its frequency is lower in African American men than in Caucasians. Metabolic syndrome may result from use of some commonly prescribed drugs, including corticosteroid, antidepressant, and antipsychotic agents. Protease inhibitors used to treat human immunodeficiency virus (HIV) infection can induce metabolic syndrome secondary to insulin resistance.

Patients with metabolic syndrome have an increased risk for cardiovascular disease events and are at increased risk for all-cause mortality. Metabolic syndrome increasesthe risk of type 2 diabetes, which itself is an important risk factor for atherosclerotic disease and may be considered as a coronary heart disease equivalent.17,24 Metabolic syndrome is also associated with a variety of other conditions, such as polycystic ovary syndrome, nonalcoholic fatty liver disease, gallstones, sleep disturbances, sexual impotence, and numerous forms of cancer including breast, endometrial, pancreatic, colon, and liver cancer, as detailed inTable 58.3.27 In multiple trials involving nearly 1900 patients, morbidly obese individuals had much greater weight loss following bariatric surgery than after nonsurgical therapy, with amelioration of most of the diseases associated with morbid obesity in a year’s time.28 Metabolic syndrome is resolved by bariatric surgery in over 95% of patients who achieve the expected weight loss,29 making it clear that bariatric surgery is a metabolic intervention and not simply a weight management procedure.30

Abstract

Metabolic syndrome (MetS) is the commonly observed clustering of obesity, hypertension, dyslipidemia, and insulin resistance. The components of MetS occur together more often than expected by chance and display significant heritability. Investigations into monogenic diseases that model features of the common MetS have uncovered responsible genes. Genome-wide association studies (GWAS) of the components of the MetS have been enormously successful. Meta-analysis of public GWAS data and risk-score analysis are revealing the role of common single-nucleotide polymorphism genotypes in MetS pathophysiology. A pleotropic polygenic architecture underlies MetS, making it a fascinating complex trait. Research will continue to uncover how metabolic pathways interact to form the MetS and its subsequent risk for atherosclerosis and diabetes.

Metabolic Syndrome in Integrative Men's Health

Integrative men's health engenders the need for urologists and their associates to be facile and comfortable when discussing nutrition and exercise. Given the association of obesity with various urologic conditions such as BPH, sexual dysfunction, hypogonadism, and urologic cancer, a more holistic approach is a valuable addition in providing quality care.Obesity, defined as a BMI of at least 30 kg/m2 in adults by the National Institutes of Health, has been associated with a myriad of conditions, including various aspects of metabolic dysfunction such as dyslipidemia, T2DM, hypertension, cardiovascular disease, and stroke (Chu et al., 2015). Downstream consequences of obesity include increased risk of falls and fractures and increased rates of orthopedic surgery on weight-bearing joints (Derman et al., 2014). Between 1980 and 2008 mean global BMI increased by 0.4 to 0.5 kg/m2 per decade in men and women. In 2008 an estimated 1.46 billion adults worldwide had a BMI of 25 kg/m2 or greater, and of these, 205 million men and 297 million women were obese (Finucane et al., 2011).

As with many cancers, numerous risk factors are related to prostate cancer, including age, race, and hormonal and genetic factors.However, there are several modifiable risk factors, such as diet and physical fitness, which may affect incidence and outcomes in men with prostate cancer on numerous levels. Dietary or lifestyle modifications may improve outcomes in many of these urologic diseases. Research has demonstrated that frequent physical exercise reduces the risk of chronic diseases, including T2DM, CVD, and cancers, by a number of mechanisms. First, exercise is well known to increase insulin-mediated glucose uptake. Exercise also decreases inflammation by reducing levels of insulin-like growth factor-1 (IGF-1). A recent study of 26 men with prostate cancer treated with androgen deprivation therapy (ADT) found that IGF-1 levels were reduced (P = 0.019) at month 3 but not month 6 in those who competed in a 24-week home-based aerobic or resistance-based exercise training program versus controls. Modifications in outcomes, including weight and BMI, were also directly correlated with changes in biomarkers, demonstrating physiologic benefit of exercise (Santa Mina et al., 2013).

Exercise is also a universally known practice that helps people reduce excess weight or prevent weight gain; therefore obesity and exercise are interconnected.There is a growing body of data linking obesity, inactivity, and prostate cancer with regard to risk and outcomes such as biochemical recurrence (BR). A large meta-analysis has demonstrated that physical exercise imparts a small benefit with regard to reducing prostate cancer risk. The authors scrutinized 43 articles that met the inclusion criteria and included 19 cohort and 24 case-controlled studies in their analysis (Liu et al., 2011). They confirmed that there was a statistically significant 10% reduction in risk of prostate cancer between men with the highest versus lowest levels of activity (RR 0.90, 95% CI 0.84–0.95,P = 0.001) (Liu et al., 2011). Studies examining the impact of high BMI (25–29 overweight, >30 obese) on prostate cancer risk have also been performed, with a recent meta-analysis incorporating 12 and 13 studies of localized and advanced prostate cancer, respectively. The analysis found an inverse linear relationship between BMI and localized prostate cancer (Ptrend < 0.001, RR 0.94, 95% CI 0.91–0.97 for every 5 kg/m2 increase) and a direct relationship between BMI and advanced prostate cancer (Ptrend = 0.001, RR 1.09, 95% CI 1.02–1.16 for every 5 kg/m2 increase) (D'Amico et al., 2002). This study strongly suggests a twofold effect of adiposity on the development of prostate cancer; however, the cause of this correlation is still unclear. Interestingly, a number of studies have demonstrated the association between low circulating concentrations of free testosterone and aggressive prostate cancer (Dai et al., 2012;Severi et al., 2006), although other studies have showed no relationship between testosterone levels and aggressive prostate cancer (Sher et al., 2009).

What Is Metabolic Syndrome?

Metabolic syndrome (MetS), also called insulin resistance syndrome, is a cluster of various physiological and metabolic abnormalities including hyperinsulinemia, hyperglycemia, hypertension, a decreased plasma concentration of high-density lipoprotein (HDL) cholesterol, an increased plasma concentration of very low density lipoprotein (VLDL) triglyceride, glucose intolerance, and abdominal obesity. Insulin resistance is the primary metabolic defect of this syndrome, with compensatory hyperinsulinemia being the common denominator ultimately responsible for other changes of this constellation. In addition to insulin resistance, abdominal obesity is a key contributor to the development of MetS (see Figure 1).

MetS is a huge public health problem worldwide that is responsible for a growing number of premature deaths throughout the world. Its prevalence is approximately 16% among Caucasians. However, comparison across different countries is difficult as there are different age structures of the population, and even though a World Health Organization (WHO) expert committee published a definition of MetS, there are other, differing definitions available.

MetS is significant because it plays an important role in the etiology of coronary heart disease (CHD) and non-insulin-dependent diabetes mellitus (type II diabetes). Type II diabetes is one of the most prevalent and serious metabolic diseases in the world, and among middle-aged men, CHD is still the leading cause of mortality in Western countries.

Diabetes, Obesity, and Metabolic Syndrome

Metabolic syndrome consists of a cluster of disease states—glucose intolerance, elevated blood pressure, dyslipidemia, and central obesity—that increase the risk for developing type 2 diabetes and coronary vascular disease. All of these issues are frequently found in the obese population. Assessment of the overall rise of type 2 diabetes, obesity, metabolic syndrome, and stone disease suggests potential correlation among these states. A number of investigations have shown an increased risk for stone disease in patients with metabolic syndrome (Kadlec et al., 2012;Sakhaee et al., 2012). Cho et al. reported on the stone composition of patients with metabolic syndrome (Cho et al., 2013). Although the most common stone composition was calcium oxalate, these patients had a significantly higher risk for having a uric acid stone compared with patients without metabolic syndrome.

A number of studies have identified an increased risk for stone disease in diabetics (Lieske et al., 2006;Pak et al., 2003;Taylor et al., 2005;Weinberg et al., 2014). Lieske et al. identified an OR of 1.22 for diabetes among stone formers, whereas Taylor et al. found a relative risk of 1.31 to 1.38 of stone formation in patients with diabetes, depending on age and sex (Lieske et al., 2006;Taylor et al., 2005). These studies confirm the earlier work by Pak et al., in which uric acid stones were identified in a statistically significant predominance for patients with diabetes, indicating innate metabolic abnormalities specific to patients with diabetes.

Recent studies suggest that the increased incidence of uric acid stone formation in obese stone formers may be secondary to the production of more acidic urine than in nonobese patients. Combined data from the two largest stone centers in the United States found that urine pH appears to be directly correlated with body size (Maalouf et al., 2004). Furthermore, patients with type 2 diabetes have been found to have lower urinary pH than nondiabetics independent of the formation of uric acid stones (Cameron et al., 2006). When evaluating patients who form uric acid stones,Sakhaee et al. (2002) identified a much higher incidence of diabetes (both types 1 and 2) compared with other groups. Because individuals with diabetes have impaired ammonium excretion, they have been shown to have an increased incidence of uric acid stone formation (Abate 2004;Pak et al., 2003b). Finally, low urine pH has been shown to directly correlate with the number of metabolic syndrome features (Maalouf et al., 2007). From evaluation of 24-hour urinalyses in 148 non–stone-forming patients, a statistically significant linear relationship was identified in which each additional characteristic of metabolic syndrome portended a decrease in urine pH. Additionally, the degree of insulin resistance was also inversely related to urinary pH.

Basic Information

1 What is the metabolic syndrome?

The metabolic syndrome is a constellation of metabolic derangements that are commonly found in the same patient. The components of the metabolic syndrome are abdominal obesity, dyslipidemias, hypertension, insulin resistance with or without glucose intolerance, and prothrombotic and proinflammatory states. This clustering of cardiovascular risk factors has also been called Syndrome X or the insulin resistance syndrome.

The underlying pathogenesis of the metabolic syndrome remains incompletely understood. Obesity and insulin resistance are two of the most commonly proposed conditions that lead to the other metabolic derangements. Abdominal obesity is a measure of visceral adiposity. Visceral adipose tissue is particularly active as an endocrine organ and produces fatty acids, tumor necrosis factor (TNFα), components of the renin-angiotensin-aldosterone cascade, plasminogen activator inhibitor (PAI-1), and adiponectin. These adipose tissue products can contribute to insulin resistance, hypertension, and proinflammatory and procoagulable states. Insulin resistance is also felt to play a central role, yet its contribution to the other criteria remains poorly defined.

Diagnosis

Diagnosing metabolic syndrome enables clinicians to identify patients at high risk for developing Type 2 diabetes and CVD and target them for more aggressive risk factor management and disease surveillance. Accordingly, several health organizations have devised diagnostic criteria for this syndrome, including the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program, the World Health Organization (WHO), and the International Diabetes Federation (Box 16-1).2–4 The organizations’ criteria are similar in many respects, although there is a relative emphasis on the presence of abnormal glucose tolerance in the WHO criteria and on waist circumference in the ATP III criteria. The criteria are based on limited empirical data regarding predictive value for future diabetes and CVD, and additional research is needed to refine them. The ATP III and WHO criteria exhibit low sensitivity for identifying patients with insulin resistance, dyslipidemia, and other risk factors, and do not take into account the impacts of age and race or ethnicity.5 For example, the defining levels for elevated waist circumference and body mass index (BMI) should be lower to identify at-risk patients in relatively lean populations such as in India and East Asia. To address these issues, in 2005 the International Diabetes Federation recommended lower thresholds for waist circumference in people of European descent and even lower values for persons of East Asian ethnicity, and a lower threshold for abnormal fasting plasma glucose that matches the American Diabetes Association's definition of impaired fasting glucose (see Box 16-1). Because the formal diagnostic criteria are likely to change further, clinicians should take care to individualize patient evaluations and not overlook patients who may not strictly satisfy published criteria but could benefit from aggressive risk factor management.

Coronary Heart Disease and Type 2 Diabetes

The notion that metabolic syndrome, or its surrogate markers hyperinsulinemia and insulin resistance, antedate and contribute to the pathogenesis of coronary heart disease, diabetes, and at least some cases of hypertension was proposed many years ago.21,35 Coronary heart disease in the setting of metabolic syndrome can to a great extent be attributed to dyslipidemia (increased dense LDL cholesterol, diminished HDL cholesterol, and hypertriglyceridemia)231 as well as to elevations in blood pressure and blood glucose and the presence of a procoagulant, proinflammatory state.22,228 In addition, some studies suggest that hyperinsulinemia and insulin resistance, as well as hyperglycemia, may be independent risk factors.51 Whether elevated FFA levels or a dysregulation of intracellular fatty acid metabolism contribute to atherosclerosis by directly altering the function of endothelium (see the section entitled “Vascular Endothelial Cells and Atherogenesis”) or other cells in the vascular wall remains to be determined. Relevant to this discussion, low levels of adiponectin are associated with an increased risk for coronary heart disease in humans,155 whereas, as noted earlier, overexpression of adiponectin or its globular subunit diminishes the severity of atherosclerosis in ApoE–/– mice.232,233

More definitive evidence that metabolic syndrome per se predisposes to coronary heart disease and cerebrovascular disease has been reported. Thus a twofold to fourfold increase in subsequent cardiovascular events has been described in men and women with metabolic syndrome (modified WHO criteria) even in the absence of type 2 diabetes or impaired glucose tolerance.234-236 Qualitatively, similar results have been obtained when metabolic syndrome was defined by ATP III criteria237,238 (Fig. 43-9). In a compilation of multiple studies, the presence of metabolic syndrome had a greater impact on the risk for developing diabetes (fivefold) than ASCVD (twofold).22,182,199 In addition, where studied, the rate of cardiovascular events was higher in patients who had diabetes and metabolic syndrome than in individuals with only metabolic syndrome.22,239

Conclusions

Knowledge that the circulating FBG in the normal range has a physiological continuum pattern concerning the insulin resistance syndrome could provide a guide for preventing and/or ameliorating present and approaching major health problems.5,6 Other measures such as HbA1c and/or insulin levels that correlate with FBG could have replaced the latter as the estimate of insulin resistance, but the former is most convenient (Figs. 18.1 and 18.2). The findings imply that maintaining FBG at the lowest safe levels may afford the most healthful outlook in the prevention of obesity, diabetes, elevated BP, dyslipidemias like high triglycerides and low HDL-cholesterol, and NAFLD. In addition, because inflammation plays such an important role in so many maladies, lowering FBG could ameliorate many more potential health disturbances. In conclusion, I believe that maintaining FBG in the lower normal range, say in the 80s instead of the 90s in terms of mg/dL, could be most helpful to maintain long-term good health.