TIME OF ONSET OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS AND GENETIC-VARIATION IN THE BETA(3)-ADRENERGIC-RECEPTOR GENE

Background. The beta(3)-adrenergic receptor is expressed in visceral a dipose tissue and is thought to contribute to the regulation of the re sting metabolic rate and lipolysis. Methods. To investigate whether mu tations in the gene for the beta(3)-adrenergic receptor predispose pat ients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Associati on studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM). Results. A missense mutation was identified in the ge ne for the beta(3)-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies o f 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 black s, and 0.08 in 48 whites in the United States. Among Pimas, the freque ncy of the Trp64Arg mutation was similar in nondiabetic and diabetic s ubjects. However, in subjects homozygous for the mutation the mean (+/ -SD) age at the onset of NIDDM was significantly lower (36+/-10 years) than in Trp64Arg heterozygotes (40+/-10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation t ended to have a lower adjusted resting metabolic rate (P = 0.14 by ana lysis of covariance). Conclusions. Pima subjects homozygous for the Tr p64Arg beta(3)-adrenergic-receptor mutation have an earlier onset of N IDDM and tend to have a lower resting metabolic rate. This mutation ma y accelerate the onset of NIDDM by altering the balance of energy meta bolism invisceral adipose tissue.