Role of the β₃-adrenergic receptor locus in obesity and noninsulin- dependent diabetes among members of Caucasian families with a diabetic sibling pair

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the β₃-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the β₃-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp⁶⁴Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg⁶⁴ carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp⁶⁴ homozygotes. Among relatives, Arg⁶⁴ carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp⁶⁴ homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the β₃-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.