The Metabolic Syndrome: Pathogenesis, Consequences, and Treatment Strategies

,
Resident & Staff Physician®, January 2005, Volume 0, Issue 0

The last several years have witnessed a heightened interest in the metabolic syndrome, as it has become a health issue of epidemic proportions. Several metabolic abnormalities emerge as key players in the pathogenesis of the syndrome, including insulin resistance, obesity, and inflammation. Individuals with the metabolic syndrome are at increased risk for a variety of clinical conditions, some with serious health implications, particularly diabetes and cardiovascular disease. Treatment should address the causal mediators of the syndrome, such as obesity or insulin resistance. Lifestyle modification is one of the most successful treatments for the prevention of diabetes. Pharmacotherapy for dyslipidemia or hypertension can help prevent cardiovascular complications and the development of diabetes in those at risk.

The last several years have witnessed a heightened interest in the metabolic syndrome, as it has become a health issue of epidemic proportions. Several metabolic abnormalities emerge as key players in the pathogenesis of the syndrome, including insulin resistance, obesity, and inflammation. Individuals with the metabolic syndrome are at increased risk for a variety of clinical conditions, some with serious health implications, particularly diabetes and cardiovascular disease. Treatment should address the causal mediators of the syndrome, such as obesity or insulin resistance. Lifestyle modification is one of the most successful treatments for the prevention of diabetes. Pharmacotherapy for dyslipidemia or hypertension can help prevent cardiovascular complications and the development of diabetes in those at risk.

Ahmad Al-

Mubaslat, MD,

Endocrinology Fellow, Carl T. Hayden VA Medical Center, Banner Good Samaritan Medical Center; Peter Reaven, MD, Associate Professor of Clinical Medicine, University of Arizona, Staff Endocrinologist, Carl T. Hayden VA Medical Center, Phoenix, Ariz

More than 2 decades ago, the concept of "syndrome X" was introduced to describe a cluster of metabolic abnormalities that included obesity, high triglyceride concentration, reduced high-density lipoprotein cholesterol (HDL-C) concentration, hypertension, and glucose intolerance. Since then, our understanding of the pathogenesis and complications of this syndrome has evolved tremendously. This is reflected in the names given to the syndrome throughout this evolution, including the dysmetabolic syndrome, the deadly quartet, the insulin-resistance syndrome, and, more recently, the metabolic syndrome. The latter name has gained acceptance worldwide. This article focuses on the prevalence, pathogenesis, complications, and current treatments of the metabolic syndrome.

Definition

The task of arriving at a universal definition for the metabolic syndrome has been challenging, to say the least. Much debate exists as to what elements need to be included and which cut-off points should be used. As the epidemic scale of the syndrome has become increasingly evident and as its close relationship with various health outcomes, particularly diabetes mellitus and cardiovascular disease (CVD), has been established, a number of health organizations struggled to provide definitions that would enable clinicians and researchers to identify the condition more easily and make it possible to compare its prevalence in different parts of the world.

In 1998, the World Health Organization (WHO) presented its initial definition of the metabolic syndrome.1 It required demonstrating insulin resistance, defined as hyperinsulinemia (in the upper quartile of the nondiabetic population), impaired fasting blood glucose (=110 mg/dL) or impaired glucose tolerance (2-h glucose tolerance test result, =200 mg/dL), in addition to 2 or more of the other abnormalities listed in Table 1. Although this definition was an important step, some argued that it presented clinicians with the cumbersome task of documenting insulin resistance. This issue was addressed in 2001 by the National Cholesterol Education Program Expert Panel Adult Treatment Panel III (ATP III).2 The ATP III definition of the metabolic syndrome offered a tool that could be more readily used in clinical practice, as it only required the presence of 3 or more easily measured abnormalities (Table 2).

Prevalence

A recent study used the ATP III criteria in Americans, aged 30 to 79 years, of different ethnic backgrounds to assess the prevalence of the metabolic syndrome. Prevalence was approximately 25% in white men and 21% in white women; 29% in Mexican American men and 33% in Mexican American women; and 44% in Native American men and 57% in Native American women.3,4 Age plays an important role. An adult aged 60 to 69 years has a 44% risk of having the metabolic syndrome compared with a 7% risk in those aged 20 to 29 years.5 It is interesting that 2 studies from India reported significantly different prevalences for men (36% vs 8%) and for women (47% vs 18%).6,7 This discrepancy may be because the study that found substantially higher prevalences defined obesity by modified ATP III criteria (waist circumference =90 cm in men and =85 cm in women) that may have been more suitable for the generally thinner population of India.7 Prevalence is far lower in some European countries (ie, France, Finland) than in the United States. These variations are undoubtedly due to differences in diet, age structure, and environmental variables, such as daily activity levels. Genetic factors may explain as much as 50% of the variability in metabolic syndrome traits.8 Genetics probably contributes, in part, to the marked differences seen in various ethnic populations in the United States.3

Pathogenesis

Insulin resistance

Insulin resistance describes impaired insulin-mediated glucose disposal, inhibition of lipolysis, or inhibition of gluconeogenesis, often resulting in hyperinsulinemia as a means of overcoming tissue resistance (eg, in skeletal muscle). It creates a physiologic state that significantly increases the likelihood of developing many of the same metabolic abnormalities that comprise the metabolic syndrome. Among the best documented are glucose intolerance and dyslipidemia (high triglycerides, low HDL-C). However, the metabolic syndrome, particularly as defined by ATP III criteria, does not equal insulin resistance. In fact, the sensitivity of the metabolic syndrome for insulin resistance appears to be 46%, whereas the specificity is 93%.9 In other words, 93% of those with metabolic syndrome actually have insulin resistance, and only 46% of those with insulin resistance actually have the metabolic syndrome, which indicates that individuals without this syndrome may still be at risk for many of the complications associated with it.

Atherogenic lipid profiles associated with insulin resistance include low HDL-C, decreased diameter of low-density lipoprotein (LDL) particles (small, dense LDL) and HDL particles, fasting hypertriglyceridemia, and postprandial accumulation of triglyceride-rich remnants.10 The dyslipidemic criteria set forth by ATP III are therefore common in insulin-resistant individuals.

Insulin resistance is also closely related to hypertension. As a marker of insulin resistance, hyperinsulinemia predicts the development of hypertension in all age-groups. Moreover, up to 50% of hypertensive patients are insulin resistant. Although a complete understanding of the causal relationship is still lacking, enhanced renal sodium retention and increased sympathetic nervous system activity are 2 mechanisms at play in both insulin resistance and hypertension. However, the development of hypertension is a complex process, and it is clear that insulin resistance is just one of many contributors.

Initially, most associations between insulin resistance and metabolic abnormalities were demonstrated in small clinical studies. As the spectrum of abnormalities became more defined, large population studies confirmed the relationship. The San Antonio Heart Study demonstrated that individuals who developed hypertension, high triglyceride levels, low HDL-C levels, high LDL-C levels, or type 2 diabetes were far more likely to have had higher baseline insulin levels.11 The Third National Health and Nutrition Examination Survey (NHANES III) found that, as individuals advanced through the spectrum of glucose intolerance, their chances of developing metabolic syndrome increased significantly.12 Metabolic syndrome occurred in 30% of those with impaired glucose tolerance (IGT), 70% with impaired fasting glucose (IFG), and almost 90% with diabetes. A recent analysis of data from The Veterans Affairs High-Density Lipoprotein Intervention Trial, which included more than 2500 individuals, found that those with higher plasma insulin levels at baseline, who therefore may have been insulin resistant, had lower levels of HDL-C and higher levels of triglycerides.13 At the conclusion of the study, it was this subset of patients that benefited most from gemfibrozil (Lopid) therapy.

Obesity

Our views of adipose tissue have evolved considerably in the past several years. Once perceived as a passive compartment whose sole function was to store fat as an energy source, adipose tissue is now viewed as an active endocrine organ that produces a variety of factors with a vast array of physiologic actions (Figure). Several of these factors, including fatty acids and inflammatory mediators, such as tumor necrosis factor (TNF)-a or interleukin (IL)-6, have been causally implicated in abnormalities with postreceptor insulin signaling and therefore the development of insulin resistance. In contrast, adiponectin increases fatty acid oxidation, decreases gluconeogenesis, and increases insulin-mediated glucose uptake. Although adiponectin is produced in great amounts by fat tissue, its production decreases with increasing weight gain.14

As a result of its over-and under-expression of a variety of bioactive products and its role in the development of insulin resistance, obesity is a key contributor to the development of metabolic syndrome. However, remember that although most people with metabolic syndrome are overweight, some are not. Conversely, not all overweight individuals have the metabolic syndrome, for several reasons. First, not all obese individuals are insulin resistant. Depending on how insulin resistance is defined, as many as 25% of obese persons are relatively insulin sensitive.15 Second, the location of the fat (eg, in muscle and liver) may be as or more important than the overall amount of body fat.

Inflammation

An ever-growing body of evidence points to the pivotal role of inflammation in the development of the metabolic syndrome and its complications, specifically CVD and type 2 diabetes. It is closely intertwined with obesity, as many of the inflammatory factors that are thought to result in insulin resistance, metabolic syndrome, and CVD are derived in part from adipose tissue. For example, IL-6, approximately 30% of which is produced by adipose tissue, not only predisposes to insulin resistance but enhances the hepatic production of acute phase proteins, such as C-reactive protein (CRP) or fibrinogen. These factors in turn may directly contribute to atherosclerotic plaque progression and rupture. TNF-a is another cytokine produced by adipocytes, in addition to macrophages and endothelial cells, that may contribute to insulin resistance by reducing insulin receptor tyrosine kinase activity and insulin receptor substrate-1 phosphorylation.

Both IL-6 and TNF-a have other adverse effects, including potent proatherogenic effects in the vasculature, as do many of the other factors secreted by fat cells, including angiotensin, free fatty acids, leptin, plasminogen activator inhibitor 1, and various chemokines. Moreover, inflammation and proinflammatory cytokines directly influence lipoprotein metabolism. For example, hypertriglyceridemia; elevated triglyceride- rich lipoproteins; the appearance of small, dense LDL; increased platelet-activating factor acetylhydrolase activity; sphingolipid-enriched lipoproteins; and decreased HDL-C have all been described during infections or in response to cytokines released during other inflammatory events. Cytokines also alter expression or activity of a variety of lipases that can affect lipoprotein metabolism, contributing to the development of hypertriglyceridemia and decreasing HDL-C concentration.

Several large population studies have highlighted the clinical implications of inflammatory factors and documented a strong association between markers of inflammation (eg, CRP, IL-6) and features of the metabolic syndrome as well as the syndrome itself. The Insulin Resistance and Atherosclerosis Study that included 1008 persons without clinical CVD or diabetes showed that CRP levels correlated positively with body mass index (BMI), waist circumference, blood pressure (BP), triglycerides, LDL-C, plasma glucose, and fasting insulin levels and correlated negatively with HDL-C concentration. CRP concentration increased as the number of metabolic abnormalities increased.16 In NHANES III, which included 8814 persons older than 20 years, those with the metabolic syndrome had higher levels of inflammatory markers (eg, CRP, fibrinogen, leukocytes).5 In addition, metabolic abnormalities, particularly central adiposity and insulin resistance, correlated strongly with CRP levels.

Evidence suggests that inflammatory factors are involved in type 2 diabetes and CVD, 2 of the longterm complications of the metabolic syndrome. A study of 27,000 healthy women showed that baseline IL-6 and CRP levels were considerably higher in the 188 women who developed diabetes at 4-year follow-up.17 The relative risk for developing diabetes was nearly 15.7 for CRP and 7.5 for IL-6 in women with elevated baseline levels of these inflammatory markers. CRP level is a strong predictor of future cardiovascular events in essentially all patient groups, including those with metabolic syndrome.18

Consequences of the Metabolic Syndrome

Much of the interest in the metabolic syndrome stems from its close association with a variety of clinical conditions, most important, type 2 diabetes and CVD. A study of 4423 nondiabetic individuals who were followed for 5 years showed that those with metabolic syndrome at baseline were at a 9-to 34-fold increased risk of developing diabetes.19 The degree of risk correlated with the number of metabolic abnormalities. The West of Scotland Coronary Prevention Study (WOSCOPS) showed that the metabolic syndrome increased risk of diabetes by nearly 24-fold among 5974 nondiabetic persons at 5-year followup.20 In a 4-year longitudinal study of 890 nondiabetic Pima Indians, those with the metabolic syndrome were almost 3 times more likely to develop diabetes.21

In 1200 middle-aged Finnish men, cardiovascular mortality was almost 4 times higher in those with the metabolic syndrome diagnosed using the ATP III criteria and almost 3 times higher using the WHO criteria at the end of the 11-year study.22 A recent analysis of data from the Scandinavian Simvastatin Survival Study (4S) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS), involving a total of 11,000 persons, demonstrated that the metabolic syndrome increased risk for major coronary events (ie, fatal and nonfatal myocardial infarction [MI], unstable angina, or sudden cardiac death) by about 1.5-fold.23 Table 3 summarizes results from some key studies.

Several other clinical conditions seem to share a close association with the metabolic syndrome. Studies have shown that 88% of patients with nonalcoholic steatohepatitis have the metabolic syndrome,24 and up to 98% have insulin resistance.25 Of note, the association with insulin resistance appears to be independent of obesity; this finding was corroborated in a study that showed hepatic fat content, a hallmark of nonalcoholic steatohepatitis, correlated most strongly with fasting insulin levels and plasma triglyceride concentration.26

Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders in premenopausal women, occurs more frequently in metabolic syndrome patients. This may be because insulin resistance is critical in the pathogenesis of both disorders. A recent study showed that fasting blood glucose and insulin levels were significantly higher in both lean and obese PCOS patients compared with a control group.27 Obese, but not lean, PCOS patients were more insulin resistant.

There may also be an association between insulin resistance and obesity and cancer. Several case-control studies in postmenopausal women have shown that risk of breast cancer increases by about 40% in women with BMI in the highest quartile.28 Although some of this increased risk is explained by a higher production of endogenous estrogen, insulin and or insulin-like growth factors may also contribute to this risk.

A study of 860 patients with prostate cancer showed that those who were obese at a younger age (and presumably more likely to be insulin resistant) had a higher grade and more advanced prostate cancer.29 Increasing evidence also implicates insulinlike growth factors in the evolution of prostate and colorectal cancer. Liver cancer, perhaps as a result of nonalcoholic steatohepatitis and subsequent inflammation and cirrhosis, also appears to be more common in metabolic syndrome patients.

Treatment

The chances that patients with the metabolic syndrome will develop common complications, such as diabetes or CVD, appear to be a function of the number of individual risk factors. Thus, there does not appear to be a unique synergistic risk associated with having 3 or more metabolic syndrome features. This implies that therapies that address each risk factor should successfully reduce complications. Conceptually, treatment of potential underlying causes, such as insulin resistance, obesity, or inflammation, may have broader efficacy and improve several risk factors simultaneously. Until large trials with metabolic syndrome patients are available, we must often extrapolate from studies of individuals with abnormalities in glucose regulation. Individuals with IGT usually have many of the other metabolic syndrome features, and most (but not all) individuals with type 2 diabetes also have the metabolic syndrome.

Prevention of type 2 diabetes

Weight reduction with diet and exercise shows promise in preventing progression from IGT to frank diabetes. This was first demonstrated in the Finnish Diabetes Prevention study, where 522 middle-aged, overweight individuals with IGT were randomized to a control or lifestyle intervention group.30 At baseline, participants had high triglycerides (approximately 156 mg/dL), high systolic BP (approximately 138 mm Hg), and were overweight (mean BMI, >31 kg/m2). Thus, one can safely conclude that the majority had the metabolic syndrome. Counseling about weight loss through dietary changes (ie, less saturated-fat intake, more fiber) and increased exercise in the intervention group resulted in 43% of subjects losing more than 5% body weight compared with only 13% of the control group. In addition, 86% of those in the intervention group were exercising more than 4 hours weekly compared with 71% of the controls. Such modest weight-loss and exercise interventions translated into a 58% reduced risk of diabetes at 4- year follow-up.

The Diabetes Prevention Research Group followed 3234 nondiabetic individuals with IFG and postoral glucose load plasma glucose concentration.31 Losing more than 7% of body weight combined with a minimum of 150 minutes of physical activity weekly reduced the chances of developing diabetes by 58%. The number needed to treat to prevent 1 case of type 2 diabetes was 7, suggesting that this approach, despite the added resources, may also be cost-effective.

Pharmacologic prophylaxis

A number of medications have been used with some success to prevent type 2 diabetes in patients at risk for the metabolic syndrome. Thiazolidinediones (TZDs) are strong candidates thanks to their ability to modify a number of the metabolic aberrations that comprise the metabolic syndrome. Their multi-action profile includes increased insulin sensitization, thus improving fasting and postprandial hyperglycemia; reduced triglyceride levels and increased HDL levels; and possibly reduced BP. An added benefit is their ability to shift visceral fat toward the periphery, thus modifying central obesity that may be contributing to the pathogenesis of the metabolic syndrome.

In the Troglitazone in the Prevention of Diabetes (TRIPOD) study, nondiabetic women who had previously had gestational diabetes were randomized after delivery to receive either troglitazone (which is no longer marketed in the United States) or placebo.32 After a mean follow-up of 30 months, treatment with the TZD reduced new-onset diabetes by 56%. The greatest benefit occurred in women whose insulin resistance was significantly decreased by troglitazone and who still had moderately good beta-cell insulin secretory capacity. Several larger ongoing studies are trying to confirm the effects of TZDs on the development of diabetes, as well as their ability to decrease the progression of atherosclerosis.

Other agents have also shown benefit. In the Diabetes Prevention Program, patients assigned to metformin HCl (Glucophage) were 31% less likely to develop diabetes during the 3-year study period.31 The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus randomized 412 adults with IGT to placebo or acarbose (Precose).33 After a 3.9-year follow-up, the incidence of diabetes in the intervention group was reduced by 25%.

Prevention of CVD

A number of studies have demonstrated that reduction of LDL-C in individuals with a history of diabetes or new-onset diabetes is beneficial. Perhaps the best data come from the Heart Protection Study, which followed more than 20,000 individuals for 5 years.34 Participants with diabetes (5963) who were randomized to simvastatin (Zocor) had a 22% reduced risk of MI or stroke. In the subset of 2912 diabetic patients who did not have CVD when the study began, risk of MI or stroke was reduced by at least 33%. All groups appeared to benefit, regardless of baseline clinical characteristics. Even in the 2426 diabetic patients with pretreatment LDL-C levels less than 116 mg/dL, risk was reduced by 27%.

Although persons with the metabolic syndrome are at increased risk for CVD, they are not in the same risk category as those with diabetes. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), which specifically addressed nondiabetic individuals with insulin resistance, included 2531 men with coronary artery disease and low HDL-C concentration.35 Among the 627 participants with diabetes, those who received gemfibrozil therapy had a 24% reduced risk of cardiovascular death, nonfatal MI, and stroke compared with the placebo group at 5-year follow-up. Similarly, risk was reduced by 35% in the 1449 patients who had 3 or more of the metabolic syndrome criteria.35

In the AFCAPS/TexCAPS study, 46% of the participants appeared to meet the diagnostic criteria for the metabolic syndrome after excluding those with diabetes.36 This group had a 37% reduced risk of an acute coronary event (first fatal or nonfatal MI, unstable angina, or sudden cardiac death) with lovastatin therapy compared with a 43% reduced risk in those with diabetes. Although dyslipidemia is only one aspect of the metabolic syndrome, large population studies have consistently shown that the successful correction of lipid abnormalities in patients diagnosed with or very likely to have the metabolic syndrome translates into a significantly lower risk of CVD.

Many studies have shown that BP control lowers the risk of CVD in hypertensive patients with IGT, diabetes, or those who are likely to have the metabolic syndrome. The Heart Outcomes Prevention Evaluation (HOPE) trial included 9297 individuals; 65% had dyslipidemia, 48% had hypertension, and 39% had diabetes.37 Thus, a significant proportion probably had the metabolic syndrome. Treatment with ramipril (Altace) significantly reduced the risk for the composite end point of MI, stroke, or cardiovascular death compared with placebo at 4.5-year follow-up. In the 3577 participants with diabetes, risk was reduced by 25%.38

Conclusion

The metabolic syndrome is a health issue of epidemic proportions. Its prevalence in the United States continues to increase, hand in hand with that of obesity. Diabetes and CVD are occurring at alarming rates in patients with the metabolic syndrome, adding a tremendous burden to the health care system. Even though we lack a single treatment, several therapeutic interventions that target the individual metabolic abnormalities have shown efficacy in interrupting or slowing the development of diabetes and CVD. Lifestyle changes remain one of the more successful strategies for preventing diabetes. As our understanding of the metabolic syndrome evolves, it is likely that more comprehensive therapeutic options will become available. n

Self-Assessment Test

1. Which of these diagnostic criteria is NOT included in the ATP III definition of metabolic syndrome?

  • BMI >30 kg/m2
  • BP = 130/85 mm Hg

2. All these statements about the metabolic syndrome are true, except:

  • It is more common in the United States than in France
  • All patients with the metabolic syndrome are overweight/obese

3. Increases in CRP level are associated with increases in all of these metabolic features, except:

  • Waist circumference
  • HDL-C concentration

4. The metabolic syndrome has been associated with all the following conditions, except:

  • Sudden cardiac death
  • Osteoporosis

5. Which of these treatments has NOT been used to prevent the development of type 2 diabetes in patients with IGT or the metabolic syndrome?

  • Metformin
  • Troglitazone

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Answers:

1. B; 2. D; 3. D; 4. D; 5. A