Impaired free fatty acid suppression during hyperinsulinemia is a characteristic finding in familial combined hyperlipidemia, but insulin resistance is observed only in hypertriglyceridemic patients

Insulin resistance has been associated with hypertriglyceridemia, combined hyperlipidemia, and familial combined hyperlipidemia (FCHL). Whether all FC HL patients with different types of dyslipidemia have low insulin sensitivi ty has not been evaluated. We measured insulin sensitivity by the hyperinsu linemic euglycemic clamp with indirect calorimetry in 110 healthy controls and in 105 nondiabetic, FCHL family members: in 50 without dyslipidemia, in 19 with hypercholesterolemia (total cholesterol greater than or equal to 7 .7 mmol/L). in 22 with hypertriglyceridemia (total triglycerides greater th an or equal to 2.4 mmol/L in men 2.4 mmol/L in women), and in 14 with combi ned hyperlipidemia. During the hyperinsulinemic clamp, FCHL family members had higher foe fatty acid levels than did controls (0.06+/-0.06 [mean+/-SD] in controls versus 0.16+/-0.11 in relatives without dyslipidemia versus 0. 15+/-0.07 in hypercholesterolemic patients versus 0.29+/-0.14 in hypertrigl yceridemic patients versus 0.27+/-0.17 mmol/L in patients: with combined hy perlipidemia; P<0.001 after adjustment for age, sex, and body mass index). Relatives without dyslipidemia (16.4+/-4.4 mu mol.kg(-1).min(-1), P=0.001) and patients with hypertriglyceridemia (12.8+/-3.8 mu mol.kg(-1).min(-1), P <0.001) and with combined hyperlipidemia (13.7+/-3.1 mu mol.kg(-1).min(-1), P<0.001) had lower rates of insulin-stimulated glucose oxidation than did controls (19.4+/-4.7 mu mol.kg(-1).min(-1)). Also,the rates of nonoxidative glucose disposal were lower in patients with hypertriglyceridemia (P=0.001 ) and combined hyperlipidemia (P=0.011) than in controls. In contrast, subj ects with hypercholesterolemia and control subjects had similar races of in sulin-stimulated glucose uptake. We conclude that a defect in free fatty ac id suppression during hyperinsulinemia, probably located in adipose tissue, is characteristic for all FCHL patients with varying types of dyslipidemia , whereas insulin resistance in skeletal muscle is observed only in FCHL pa tients with elevated triglyceride levels.