Different regulation of free fatty acid levels and glucose oxidation by the Trp64Arg polymorphism of the β3-adrenergic receptor gene and the promoter variant (A-3826G) of the uncoupling protein 1 gene in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is characterized by variable expression of dyslipidemias and insulin resistance. Because the genetic background for FCHL is unknown, we investigated the effect of the Trp64Arg polymorphism of the beta 3-adrenergic receptor (beta 3-AR) gene and the promoter variant A --> G (-3826) of the uncoupling protein 1 (UCP1) gene on glucose and lipid metabolism in FCHL families. Both polymorphisms were screened in 228 members from 27 families with FCHL and in 82 control men from a random population sample. The frequency of the polymorphisms of the beta 3-AR and UCP1 genes did not differ between patients with FCHL and controls. Although the rate of insulin-stimulated whole-body glucose uptake evaluated by the euglycemic clamp in family members of patients with FCHL was unaffected by both polymorphisms, subjects with the Trp64Arg genotype of the beta 3-AR gene had higher rates of glucose oxidation (17.6 +/- 4.5 v 15.8 +/- 4.1 mu mol/kg/min, P = .017) and lower levels of free fatty acids (FFAs) in the fasting state (0.56 +/- 0.27 v 0.61 +/- 0.28 mmol/L, P = .027) and during the euglycemic clamp (0.12 +/- 0.10 v 0.21 +/- 0.15 mmol/L, P = .041) than subjects with the Trp64Trp genotype. We conclude that in FCHL families, codon 64 polymorphism of the beta 3-AR gene may influence the rate of glucose oxidation via FFA levels. Copyright (C)o 1998 by W.B. Saunders Company.