Current Understanding of Insulin Resistance
Zachary T. Bloomgarden, MD
At the 12th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists, Gerald M. Reaven, MD, Stanford University School of Medicine, Stanford, California, was honored with the Frontiers in Science award. In his presentation, he reviewed current knowledge about insulin resistance and its links to cardiovascular disease.
In 1988, Dr. Reaven initially suggested the link between what was then termed “Syndrome X” and coronary heart disease (CHD) via insulin resistance, hyperinsulinemia, hypertension, high plasma triglyceride levels, and low plasma HDL cholesterol, with varying degrees of glucose intolerance. Frank diabetes, impaired fasting glucose, and impaired glucose tolerance may be present, but half of the persons with this syndrome have normal glucose tolerance. Abnormalities associated with insulin resistance also include decreased LDL particle diameter and postprandial accumulation of remnant lipoproteins. In addition, decreased endothelium-dependent vasodilation is seen, with increased mononuclear cell adhesion, increased plasma cellular adhesion molecule levels, and increased levels of the endogenous inhibitor of nitric oxide synthase, plasma asymmetric dimethyl arginine. Prothrombotic factors include increased plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Inflammatory markers, including C-reactive protein (CRP) and the leukocyte count, are elevated. Abnormal uric acid metabolism with decreased renal urate clearance and increased plasma uric acid, hemodynamic changes with increased sympathetic nervous system activity, and increased renal sodium retention are also seen.
Women with insulin resistance may have increased ovarian testosterone secretion. Associated illnesses include CHD, type 2 diabetes, hypertension, polycystic ovary syndrome (PCOS), nonalcoholic fatty liver disease, and certain malignancies. PCOS is associated with insulin resistance independent of obesity. Similarly, fat accumulation in the liver — independent of body mass index (BMI) and intra-abdominal and overall obesity — is associated with insulin resistance, hypertension, and hypertriglyceridemia. Insulin resistance is associated with breast cancer with worse outcome, and with colorectal and prostate cancers. Thus, Dr. Reaven said, “what began as a relatively narrow cardiovascular issue…has broad implications.”
He posed the question, “How common is insulin resistance in the population?” Using infusion of somatostatin, insulin, and glucose, the steady-state plasma glucose (SSPG) can be used as a measure of insulin sensitivity. In a study of 490 healthy nondiabetic persons, this level varies from < 50 to > 250 mg/dL in the first through tenth deciles of insulin sensitivity. There is a continuous relationship between SSPG and insulin resistance syndrome disease outcomes such as hypertension, malignancy, heart disease, and stroke, with diabetes seen in the upper third of insulin resistance in the population. There is a linear relationship between BMI and SSPG, with evidence that approximately one quarter of the variability in insulin action is associated with obesity and another quarter is associated with physical inactivity. Obesity has a linear relationship with LDL cholesterol, triglyceride levels, HDL cholesterol, and glucose, but within each BMI subgroup the degree of insulin sensitivity, as measured by the SSPG, adds to the effect of BMI. When comparing weight-matched persons who are insulin sensitive or insulin resistant who lose weight on a hypocaloric diet, the former group shows no further improvement in insulin sensitivity, while the latter group shows improvement in both SSPG and the CRP. However, neither group decreases to the level of the insulin-sensitive group.
Dr. Reaven then discussed the thrifty genotype hypothesis, and asked why diabetes should be so prevalent for such a relatively long period in the history of the human species when one would think there would be a strong genetic selection against the condition. In the early 1960s, Neel suggested the concept that the diabetic genotype is a “thrifty” genotype, allowing greater efficiency of food storage. Around the same time, Cahill suggested that survival depended on the capacity to withstand prolonged periods of deprivation while sparing as much body protein as possible, stating, “If tissues are better able to exclude glucose, which is part of the diabetes syndrome, then gluconeogenesis and in turn protein would be spared.”
Dr. Reaven contrasted the hypotheses of Neel and Cahill; Neel asserting that the diabetes trait would increase energy storage and Cahill asserting that the diabetes trait would decrease energy expenditure. He pointed out that there is no evidence that hyperinsulinemia increases weight gain, as would be implied by a “quick insulin trigger” leading to better energy storage. Furthermore, first-degree relatives of persons with type 2 diabetes themselves have insulin resistance, and both high fasting serum insulin and low increase in insulin relative to glucose 30 minutes after ingesting oral glucose predict IGT. In addition, there is evidence that both reduced muscle glucose uptake and decreased insulin secretory response to glucose predict diabetes.
Dr. Reaven concluded that it is insulin resistance rather than hyperinsulinemia that predicts the development of diabetes, with the former characteristic leading to a trait useful in evolution but now “a major threat to Western civilization.”
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