Background. Because visceral obesity predicts insulin resistance, we studied whether alterations in the gene encoding for the β3-adrenergic receptor in visceral fat are associated with insulin resistance. Methods. We studied the frequency of a cytosine-to-thymidine mutation that results in the replacement of tryptophan by arginine at position 64 (Trp64Arg) of the β3- adrenergic receptor by restriction-enzyme digestion with BstOI in 335 subjects from western Finland, 207 of whom were nondiabetic and 128 of whom had non-insulin-dependent diabetes mellitus (NIDDM). We also determined the frequency of the mutation in 156 subjects from southern Finland. Sensitivity to insulin was measured by the hyperinsulinemic-euglycemic clamp technique in 66 randomly selected nondiabetic subjects. Results. In the subjects from western Finland, the frequency of the mutated allele was similar in the nondiabetic subjects and the subjects with NIDDM (12 vs. 11 percent). The mean age of the subjects at the onset of diabetes was lower among those with the mutation than those without it (56 vs. 61 years, P=0.04). Among the nondiabetic subjects, those with the mutation had a higher ratio of waist to hip circumference (P=0.02), a greater increase in the serum insulin response after the oral administration of glucose (P=0.05), a higher diastolic blood pressure (82 vs. 78 mm Hg, P=0.01), and a lower rate of glucose disposal during the clamp study (5.3 vs. 6.5 mg [29 vs. 36 μmol] per kilogram of body weight per minute; P=0.04) than the subjects without the mutated allele. In an analysis of sibling pairs, the siblings with the mutation generally had higher waist:hip ratios (P=0.05) and higher responses of blood glucose and serum insulin after the oral administration of glucose than their siblings without the mutation (P=0.02 and P=0.005, respectively). Conclusions. The Trp64Arg allele of the β3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM.
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