The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. Beginning in 1982, a subset of this population has been studied to determine the etiologic factors that predispose non-diabetic individuals to develop the disease. Subjects are admitted yearly to the clinical research ward to undergo body composition analysis, an oral glucose tolerance test, an intravenous glucose tolerance test, a standard mixed meal test, and a two-step hyperinsulinemic, euglycemic clamp to measure insulin action in vivo. Over 400 individuals have entered into the study and approximately 42 subjects have developed NIDDM. Obesity, central obesity, fasting hyperinsulinemia, and insulin resistance are each major risk factors for the development of NIDDM. The acute insulin response to an intravenous glucose bolus is an additional, but weaker predictor. Since each of these factors are familial and predictive of diabetes, it is likely that the genetic determinants of these phenotypes contribute to the pathogenesis of NIDDM, which is known to be largely genetically determined. A genomic scan was recently completed which suggested several loci that may harbor genes for diabetes in this population. The expression and function of candidate genes suggests by this scan and on functional criteria are being examined in skeletal muscle and adipose tissue obtained from selected individuals participating in this protocol. In addition, we continue to recruit and study individuals who were previously genotyped, but not fully phenotyped. Finally, individuals who participants in the study several years ago are being restudied to provide valuable longitudinal data to address the sequence of metabolic events leading to diabetes