The clinical appearance of atherosclerosis represents the authentic end stage in the evolution of the syndrome of diabetes mellitus. Atherosclerosis accounts for 80% or more of total diabetes mortality. Indeed, macrovasculopathy represents the chief threat to life and limb in patients with either insulin-dependent (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Approximately 75% of atherosclerotic mortality results from accelerated coronary artery disease, whereas the remaining 25% results from an admixture of accelerated cerebral and peripheral vascular disease.[1,2] In patients with diabetes mellitus, mortality rates from coronary heart disease are three times the rate seen in comparable patients who do not have diabetes.[3,4] Such an acceleration may not solely be the result of the hyperglycemia of diabetes: There are a number of other well-characterized, independent risk factors for atherosclerosis that also accompany the diabetic state. These risk factors include dyslipidemia, obesity, and the multifaceted syndromes related to insulin resistance.
Although hyperglycemia is generally accepted as an independent risk factor for coronary atherosclerosis, several major prospective cross-sectional cardiovascular studies have failed to demonstrate significant correlations between degrees of fasting hyperglycemia and the appearance of coronary heart disease.[6,7] In other studies, 2-hour postprandial hyperglycemia and fasting hyperglycemia may have at least as important, if not more important, roles in the prediction of coronary atherosclerotic events.[8,9] Moreover, in most studies a strictly proportional, one-to-one relationship between degrees of hyperglycemia, whether fasting or postprandial, and increments in cardiovascular risk cannot be discerned. For this reason, the potential contribution toward accelerated atherosclerosis of other metabolic aberrations--especially dyslipidemia--that are part of the diabetic dysmetabolic state have been investigated.
Dyslipidemia and hyperlipidemia are extremely common in patients with diabetes mellitus. At least 50% of all patients with diabetes have a less than desirable cholesterol level. Moreover, another 25% of all patients with diabetes may have varying degrees of a relatively more ominous diabetic dyslipidemia, which is characterized by elevated very low-density-lipoprotein (VLDL) triglyceride and reduced high-density lipoprotein (HDL) cholesterol content of their blood. This dyslipidemia of diabetes appears both in males and in females with either IDDM or NIDDM and may be associated with or related causally to the insulin resistance of diabetes mellitus. Dyslipidemias and hyperlipidemias, as well as low HDL cholesterol levels, are a more potent predictor of coronary risk than is hyperglycemia alone, at least in the Framingham Study. A diminished activity of lipoprotein lipase is at least one mechanism accounting in part for the dyslipidemia of diabetes, thereby linking this dyslipidemia to the insulin-resistant state that precedes or accompanies clinically overt NIDDM.
Insulin Resistance and Hyperinsulinemia
Insulin resistance begins one to three decades before clinically observable hyperglycemia and may be the most important predictor of the evolution of clinical diabetes mellitus. Insulin resistance may be 1) inherited, usually from one or both parents with NIDDM or 2) an acquired phenomenon secondary to a combination of a sedentary lifestyle, weight gain, and aging.
Resistance to the metabolic action of insulin on target cells results in microscopic hyperglycemia, which in turn causes microscopic hyperinsulinemia. After a number...