Chapter 212

Metabolic Syndrome

Donna Jenell Pease

Definition and Epidemiology

Metabolic syndrome is a cluster of disorders that was first introduced by Reaven¹ in 1988. It is characterized by insulin resistance with hyperinsulinemia; hypertension; abdominal (central or visceral) obesity; and dyslipidemia consisting of hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and increased small, dense low-density lipoprotein (LDL) particles. Characteristics that have been added more recently include elevated C-reactive protein (CRP) levels, increased plasminogen activator inhibitor 1 (PAI-1) levels, and microalbuminuria.²

Several organizations have developed simple criteria to diagnose metabolic syndrome.³^–⁶

In 2009, a joint statement was issued by the International Diabetes Federation, the National Heart, Blood, and Lung Institute, the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association for the Study of Obesity to standardize the diagnostic criteria for metabolic syndrome.⁷ It includes the following:

• Elevated waist circumference: population- and country-specific definitions

• Elevated triglyceride levels: 150 mg/dL (1.7 mmol/L) or higher, or specific treatment for this lipid abnormality

• Reduced HDL cholesterol: below 40 mg/dL (1.0 mmol/L) in males and below 50 mg/dL (1.3 mmol/L) in females, or specific treatment for this lipid abnormality

• Elevated blood pressure: systolic 130 mm Hg or higher or diastolic 85 mm Hg or higher, or drug treatment of previously diagnosed hypertension

• Elevated fasting plasma glucose: 100 mg/dL or higher, or drug treatment for elevated glucose

Not all individuals with insulin resistance will develop all of the multiple components of this syndrome, but studies have found that the greater the number of associated characteristics an individual exhibits, the greater his or her risk for development of cardiovascular disease (CVD) or dying young. This syndrome has also been called the insulin resistance syndrome, Reaven syndrome, syndrome X, cardiovascular dysmetabolic syndrome, and deadly quartet.²

Metabolic syndrome often occurs in the general population, mostly in older individuals and in certain ethnicities. It is estimated that metabolic syndrome is present in approximately 22.9% of U.S. adults 20 years of age and older. The National Health and Nutrition Examination Survey (1999 to 2010) found that the prevalence of metabolic syndrome increased with age. Non-Hispanic black males were less likely than non-Hispanic white males to have metabolic syndrome, but non-Hispanic black and Mexican-American females were more likely than non-Hispanic white females to have it. Metabolic syndrome increased dramatically as body mass index (BMI) increased.⁸

Both genetic factors and environmental factors have been found to play a role in the incidence of metabolic syndrome. Studies have found a genetic predisposition to the syndrome and the associated cardiovascular risk factors in first-degree relatives of individuals diagnosed with type 2 diabetes. Researchers have also found that nonobese individuals with a family history of diabetes, hypertension, or obesity are genetically predisposed to the development of metabolic syndrome.⁹

Researchers have recently identified a genetic mutation in the gene DYRK1B that causes obesity related metabolic syndrome. The researchers found that DYRK1B inhibits pathways that keep glucose stable and promotes the production of fat on the body.¹⁰

An environmental factor involved with insulin resistance and obesity is the lifestyle typical of Western civilization, consisting of a high-fat diet and low levels of physical activity. High energy intake and low energy output have led to the increased prevalence of obesity seen today. Tissue sensitivity to insulin declines when an individual becomes overweight. The fat cells found in abdominal obesity are larger and are more insulin resistant. Abdominal fat is also more metabolically active, and fat lipolysis occurs more often, releasing excess free fatty acids that interfere with hepatic insulin clearance, thus resulting in higher levels of circulating insulin. It has been found that visceral or abdominal obesity may be one of the leading causes of insulin resistance. Visceral adipose tissue also releases cytokines, PAI-1, adiponectin, leptin, and resistin, which are potentially pathogenic and associated with higher CVD risk.²

Metabolic syndrome has been recognized as a side effect of several commonly used drugs, such as corticosteroids, antidepressants, and antipsychotics, that can predispose an individual to obesity and glucose intolerance.¹¹

Pathophysiology

Visceral or abdominal obesity leads to insulin resistance. Insulin resistance is defined as the impaired insulin-stimulated glucose uptake by skeletal muscle, adipose tissue, or liver. The mechanisms involved in insulin resistance may consist of abnormal insulin molecules, decreased number of insulin receptors, decreased glucose transporters, and defective postreceptor activity. Impairment at the receptor level is usually associated with decreased sensitivity to insulin, whereas postreceptor or cellular defects are associated with decreased responsiveness to insulin. When the cells become resistant to the insulin, the body compensates by producing more insulin to overcome the resistance and to maintain normal glucose levels. Fasting hyperinsulinemia occurs in response to elevated fasting plasma glucose. This hyperinsulinemia leads to the various other abnormalities associated with metabolic syndrome; they include hypertension, dyslipidemia, atherosclerosis, proinflammatory state, prothrombotic state, and microalbuminuria.²

Hypertension

Insulin resistance and visceral adiposity (central obesity) have been recognized as the main factors in the hypertension seen in metabolic syndrome. Insulin resistance and the resulting hyperinsulinemia induce blood pressure elevation by the activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, which causes urinary sodium excretion to decline. This increased sodium reabsorption causes expansion of the extracellular fluid volume and renal dilation and leads to hypertension, endothelial dysfunction, alteration in renal function, inflammation, and atherogenesis associated with metabolic syndrome.¹²

Dyslipidemia

The lipid abnormalities found in metabolic syndrome are elevated triglycerides, low HDL cholesterol, and increased small, dense LDL particles (referred to as pattern B, or atherogenic dyslipidemia). Obesity causes the adipocytes within the abdominal adipose tissue to become insulin resistant, thus impairing the adipocyte’s ability to take up glucose and to store free fatty acids. The adipocytes release large amounts of free fatty acids into the systemic circulation. Muscle cells take up the large amounts of free fatty acid, become saturated with free fatty acids, and become insulin resistant as well. This results in diminished glucose disposal, hyperglycemia, and pancreatic beta cell stimulation to produce larger amounts of insulin (hyperinsulinemia). The free fatty acids that were unable to be absorbed by the muscle cells are diverted to the liver through the portal vein, where they impair normal insulin-mediated suppression of the hepatic glucose output and stimulate the synthesis, assembly, and secretion of lipoproteins that promote atherogenesis (raised triglycerides, low concentrations of HDL cholesterol, increased remnant lipoproteins, elevated apolipoprotein B levels, and small, dense LDL cholesterol). These adverse effects on lipoprotein levels increase the risk of atherosclerosis, ischemic heart disease, CVD, and overall cardiovascular mortality. Individuals with metabolic syndrome are at increased risk for development of CVD and type 2 diabetes mellitus.¹³

Prothrombotic State

Studies have found that levels of PAI-1 correlate significantly with insulin resistance. Elevated levels of PAI-1 reflect impaired fibrinolysis, impaired endothelial function, and increased tendency toward acute arterial thrombosis. Insulin resistance also affects other coagulation factors, including platelet aggregability, platelet adhesion, levels of factor VII and factor VIII, tissue plasminogen activator, and fibrinogen.¹⁴

Proinflammatory State

Obesity is associated with a chronic inflammatory response characterized by abnormal adipokine production and the activation of proinflammatory signaling pathways. Inflammation plays a major role in atherogenesis. CRP is a marker of inflammation that has been found to be an independent CVD risk factor and an independent marker of insulin resistance. It has been found that CRP levels and cytokines (tumor necrosis factor-α and interleukin-6) are increased in patients with metabolic syndrome.¹⁵

Microalbuminuria

An association between microalbuminuria and metabolic syndrome has been found secondary to the effects of insulin on renal hemodynamics. Acute hyperinsulinemia causes renal vasodilation, resulting in increased plasma flow, increased glomerular hydrostatic pressure and gradient, and increased glomerular filtration rate. The localized elevated pressure in the glomerular vessels is involved in increased microalbumin secretion. Microalbuminuria is a strong predictor of cardiovascular morbidity and mortality.¹⁶

Other Pathophysiologic Effects

Several ongoing studies are currently investigating the association between metabolic syndrome and the following medical disorders: cognitive decline, sleep apnea and breathing disorders, polycystic ovary syndrome, low testosterone levels in men, cancer, and nonalcoholic fatty liver disease.

Clinical Presentation

Because it is difficult to accurately measure insulin resistance, the diagnosis is usually clinical, based on a constellation of physical findings and laboratory characteristics. Insulin resistance can be suspected in the individual who is seen with abdominal obesity, increased triglycerides, low HDL cholesterol, and hypertension.

A physical sign that is suggestive of moderate to severe insulin resistance is the hyperkeratotic condition acanthosis nigricans. This is a diffuse, hyperpigmented, velvety thickening of the skin that is found in the neck and axillae. The onset is usually insidious, with the first visible change being darkening of the skin pigmentation so as to appear dirty. As the skin thickens, it becomes velvety, and the skin line is accentuated. The skin eventually becomes rugose and mammillated. The presence of skin tags in conjunction with acanthosis nigricans is also a sign of insulin resistance.¹⁷

Physical Examination

The physical examination consists of accurate measurement of the blood pressure, height and weight, and BMI or waist-to-hip ratio by the techniques described in the Diagnostics section. A patient with the clinical features of metabolic syndrome should be screened annually for hyperglycemia, glucose intolerance, and type 2 diabetes mellitus. Those who have a diagnosis of metabolic syndrome should also be screened for the cardiovascular complications that accompany the syndrome and managed appropriately. It is also important to obtain a thorough history during the assessment to determine whether the patient is at risk for development of insulin resistance secondary to genetic factors or family history.

Diagnostics

Several techniques are available for measurement of insulin resistance and sensitivity. The definitive test (gold standard) for determination of insulin resistance is the euglycemic insulin clamp technique. This technique is costly and performed in the laboratory setting. A more practical way of assessing insulin resistance in the clinical setting is through the measurement of the fasting plasma insulin concentration. High plasma insulin values with normal glucose levels are suggestive of insulin resistance.

A variety of measures of body mass and body fat exist that express different aspects of general obesity, fat distribution patterns, and fat percentage. BMI is calculated as weight divided by height squared and measures percentage of body fat or total adipose tissue. The ratio of waist and hip circumference is highly correlated with visceral adipose tissue. Waist circumference (often measured at the level of the umbilicus or the top of the iliac crest with the patient standing) or waist-to-hip ratio (the ratio of waist circumference to hip circumference measured at the iliac crest) correlates well with insulin resistance and metabolic syndrome. BMI and waist-to-hip ratio are the most routinely used anthropometric indexes because they are easy to use and have a high reliability.

Common laboratory tests can be used to screen for the various other features associated with metabolic syndrome. Impaired fasting glucose (IFG) is measured after an 8- to 12-hour fast; levels between 100 and 126 mg/dL are diagnostic of IFG. Impaired glucose tolerance (IGT) is measured by administration of a 75-g load of oral glucose; after 2 hours, if plasma glucose values are between 140 and 200 mg/dL, IGT can be diagnosed. HDL and triglyceride blood levels are measured after an 8- to 12-hour fast. Microalbumin is measured with a random urine test. An elevated plasma CRP level may indicate inflammation and an emerging risk factor for CVD.³

Diagnostics

Metabolic Syndrome

Laboratory