Metabolic Syndrome

The metabolic (or insulin resistance) syndrome was first described by J. P. Camus in 1966. Two decades later, Gerald Reaven popularized the concept of the metabolic syndrome. The components of the metabolic syndrome are diabetes (associated with hyperinsulinemia), hypertension, hyperuricemia, coagulation abnormalities, lipid abnormalities, myosteatosis (fatty muscle), and nonalcoholic steatohepatitis (NASH, fatty liver). The lipid abnormalities of the metabolic syndrome include hypertriglyceridemia, decreased high-density lipoprotein (HDL, good cholesterol), and increased low-density lipoprotein (LDL, bad cholesterol). These LDL particles are strongly related to stroke and myocardial infarction. In contrast, HDL particles are associated with increased longevity and are common in centenarians. Recently, it has been suggested that cognitive dysfunction should be added as another component of the metabolic syndrome.

The etiology of the metabolic syndrome has a clear genetic predisposition. Persons with a genetic predisposition who overeat and do not exercise develop visceral obesity, which is highly associated with insulin resistance. Insulin resistance is the most accepted underlying mechanism of the metabolic syndrome. Persons with visceral obesity have an increase in adipokines (peptide hormones derived from fat). This includes cytokines, such as tumor necrosis factor alpha, interleukin 6, leptin, adiponectin, and resistin. Increasing evidence suggests that these adipokines have a crucial role in energy homeostasis by affecting food intake, insulin sensitivity, glucose and lipid metabolism, the coagulation system, and inflammation. Leptin is a peptide hormone that decreases food intake and increases energy metabolism. Thus, its increase in the metabolic syndrome appears to be an attempt to decrease the accumulation of adiposity that occurs as a precursor to the metabolic syndrome. Leptin is under the regulation of testosterone, with higher levels occurring as testosterone levels decline with aging. Resistance to the central effects of leptin occurs in obese persons. The leptin resistance of obesity appears to be due to hypertriglyceridemia, which blocks the ability of leptin to cross the blood–brain [Page 369]barrier. In addition, such persons have a lower than expected level of adiponectin for their level of adiposity. Adiponectin is a hormone that enhances insulin sensitivity by modulating the same intracellular pathway as is modulated by the thiazolidinediones (one type of medication for diabetes) such as rosiglitazone and pioglitazone. In animal models, administration of adiponectin reverses insulin resistance.

Recent studies in muscle have suggested that insulin resistance occurs because of an accumulation of free fatty acids and triglycerides within the cells. This can occur either from high circulating lipid levels or from a defect in mitochondrial oxidative phosphorylation. This latter defect reduces energy metabolism and therefore intracellular use of free fatty acids in the cell. The end result of the process is that the insulin receptor substrate is phosphorylated, blocking its ability to activate the glucose receptor (GLUT-4) on the cell membrane in response to exposure to insulin.

Metabolic syndrome can be considered the classical “couch potato” syndrome. The prevalence of the metabolic syndrome in older persons has been reported to occur in 6.7% of persons 20 to 29 year of age, in 43.5% of persons 60 to 69 years of age, and in 42.0% of persons age 70 years and older. An estimated 47 million persons in the United States have metabolic syndrome. With aging, there is a tendency for muscle to develop a mild insulin resistance. This physiological insulin resistance of aging is a confounding factor in defining insulin resistance in older persons.

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