Impaired insulin-stimulated glucose oxidation and free fatty acid suppression in patients with familial combined hyperlipidemia: a precursor defect for dyslipidemia?

Familial combined hyperlipidemia (FCHL) is characterized by hyperlipidemia and insulin resistance, but intracellular defect in insulin action is unknown. Therefore, we investigated insulin action by applying the hyperinsulinemic euglycemic clamp technique with indirect calorimetry in 58 FCHL family members (28 with FCHL; 30 without dyslipidemia; aged 49+/-12 years; body mass index [BMI], 25. 2+/-4.0 kg/m2) and in 72 healthy control subjects (aged 54+/-6 years; BMI, 26.3+/-3.1 kg/m2). In the fasting state, FCHL patients had higher levels of total cholesterol, total triglycerides, and apolipoprotein B than control subjects (P<0.001 after adjustment for gender, age, and BMI). During the euglycemic clamp, FCHL patients had lower rates of glucose oxidation (15.93+/-3.55 versus 19.65+/-4. 60 micromol/kg/min; P=0.001) and higher rates of lipid oxidation (0. 15+/-0.13 versus 0.01+/-0.25 mg/kg/min; P=0.024), as well as higher levels of serum-free fatty acids (FFA) (0.24+/-0.17 versus 0.06+/-0. 06 mmol/L; P<0.001) compared with those of control subjects. Relatives without dyslipidemia differed similarly from control subjects with respect to rates of glucose and lipid oxidation and FFA suppression during the hyperinsulinemic clamp. In FCHL family members, during the euglycemic clamp FFAs correlated negatively with the rates of glucose oxidation (P<0.001) but not with the rates of glucose nonoxidation (P=0.408). In FCHL family members without dyslipidemia and in control subjects, FFAs during the clamp correlated positively with levels of total triglycerides (P<0.001) and very low density lipoprotein cholesterol (P=0.008). We conclude that in patients with FCHL, and also in their first-degree relatives, insulin's suppressive effect on FFA levels is impaired, which may precede dyslipidemia in FCHL.