Type 2 diabetes mellitus (type 2 DM) is a polygenic disorder with a variable phenotype that includes both insulin resistance and insulin secretory dysfunction. The Arg 64 beta-3-adrenergic receptor variant allele is associated 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 frequently sampled iv glucose tolerance tests, minimal model analysis, and analysis 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 infusion (562+/-116 vs. 962+/-94 pmol/microL), have the highest fasting glucose levels (100.4+/-1.9 vs. 92.48+/-1.60 mg/dL), and have lower glucose effectiveness (0.014+/-0.003 vs. 0.019+/-0.002 min(-1)), compared with those 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.