INSULIN SENSITIVITY IN FAMILIAL HYPERCHOLESTEROLEMIA

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 ± 0.38 v 3.27 ± 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (∼5 mmol/L) hyperinsulinemic (∼340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 ± 2.3 and 31.1 ± 3.0 μmol · kg-1 · min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects. In the whole group, insulin-mediated glucose disposal was inversely related to fasting plasma insulin levels (as expected) and diastolic blood pressure (even after adjusting for body mass), but was unrelated to plasma LDL cholesterol concentrations. We conclude that an isolated, chronic elevation of circulating LDL cholesterol levels-a significant risk for cardiovascular disease-is associated with conspicuously preserved insulin action on carbohydrate, lipid, potassium, and energy metabolism. © 1993.