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 500 individuals have entered into the study and approximately 70 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. Recent analyses indicate that each of these pre-diabetic phenotypes are highly heritable. Sibs who have participated in this study have been genotyped at over 500 random genetic markers and loci linked to insulin resistance, decreased insulin secretory function and obesity are being identified using multi-point linkage analyses. In addition, the expression and function of genes which may contribute to insulin resistance are being examined in skeletal muscle and adipose tissue obtained from selected individuals participating in this protocol.