INSULIN RESISTANCE

A second category of causation is insulin resistance. Many investigators place a greater priority on insulin resistance than on obesity in pathogenesis. They argue that insulin resistance, or its accomplice, hyperinsulinemia, directly causes other metabolic risk factors. Identifying a unique role for insulin resistance is complicated by the fact that it is linked to obesity. Insulin resistance generally rises with increasing body fat content, yet a broad range of insulin sensitivities exists at any given level of body fat. Most people with categorical obesity (body mass index [BMI] 30 kg/m2) have postprandial hyperinsulinemia and relatively low insulin sensitivity, but variation in insulin sensitivities exists even within the obese population. Overweight persons (BMI 25 to 29.9 kg/m2) likewise exhibit a spectrum of insulin sensitivities, suggesting an inherited component to insulin resistance. In some populations (e.g., South Asians), insulin resistance occurs commonly even with BMI <25 kg/m2 and apparently contributes to a high prevalence of type 2 diabetes and premature CVD. South Asians and others who manifest insulin resistance with only mild-to-moderate overweight can be said to have primary insulin resistance. Even with primary insulin resistance, however, weight gain seems to enhance insulin resistance and metabolic syndrome. Thus, dissociation of obesity and primary insulin resistance in patients with metabolic syndrome is difficult.
This is not to say that insulin resistance per se does not play a significant role in causation of metabolic syndrome. When insulin-resistant muscle is already overloaded with lipid from high plasma NEFA levels, some excess NEFA presumably is diverted to the liver, promoting fatty liver and atherogenic dyslipidemia. Hyperinsulinemia may enhance output of very-low-density lipoprotein triglycerides, raising triglycerides. Insulin resistance in muscle predisposes to glucose intolerance, which can be worsened by increased hepatic gluconeogenesis in insulin-resistant liver. Finally, insulin resistance may raise blood pressure by a variety of mechanisms.