Trp⁶⁴Arg variant of the β₃-adrenoceptor and insulin resistance in obese postmenopausal women

There is controversy regarding the role of the Trp₆₄Arg variant of the β₃-adrenergic receptor (β₃AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 ± 6 yr old) heterozygous for the β3AR variant and in 14 women (57 ± 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in β₃AR heterozygotes (241 ± 135 mg/min) vs. normal homozygotes (379 ± 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 ± 27 mg/min) and normal homozygotes (164 ± 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 ± 57 mg/min) and normal homozygotes (56 ± 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 ± 111 mg/min) than for normal homozygotes (441 ± 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp⁶⁴Arg variant in the β₃AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.