Insulin response to glucose is lower in individuals homozygous for the arg64 variant of the beta-3-adrenergic receptor

Type 2 diabetes mellitus (type 2 DM) is a polygenic disorder with a variabl e phenotype that includes both insulin resistance and insulin secretory dys function. The Arg 64 beta -3-adrenergic receptor variant allele is associat ed with an earlier age of onset of type 2 DM. The purpose of this study was to examine the in vivo pathophysiology of this variant allele to determine its contribution to the components of glucose metabolism. We used the freq uently sampled iv glucose tolerance tests, minimal model analysis, and anal ysis of covariance to examine age- and fat-mass-adjusted differences among genotypes. The results demonstrate that individuals homozygous for the Arg 64 allele secrete significantly less insulin in response to a glucose infus ion (562 +/- 116 vs. 962 +/- 94 pmol/muL), have the highest fasting glucose levels (100.4 +/- 1.9 vs. 92.48 +/- 1.60 mg/dL), and have lower glucose ef fectiveness (0.014 +/- 0.003 vs. 0.019 +/- 0.002 min(-1)), compared with th ose homozygous for the Trp 64 allele. This first report of decreased acute insulin release and lower glucose effectiveness in the Arg 64 genotype may help explain the earlier onset of type 2 DM observed in several populations of individuals with the Arg64 beta -3-adrenergic receptor variant allele.