The purpose of this project is to identify the determinants of non- insulin-dependent diabetes (NIDDM), various types of arthritis, and gallbladder disease, and elucidate the natural history of the diseases. Genetic and environmental risk factors for NIDDM have been studied in the Pima Indians. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and cholelithiasis are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose tolerance, occupational and leisure-time physical activity and diabetes in relatives are assessed. The prevalence of diabetes in offspring or siblings of diabetic subjects was higher if the index case was less rather than more obese. This may indicate that a greater "load" of familial determinants of diabetes is present in leaner diabetic persons and should be taken into account in familial and genetic investigations of NIDDM. NIDDM is highly prevalent in Pima Indians; the disorder is familial, but its prevalence has increased in recent years. Segregation analysis was conducted to determine whether, accounting for the cohort effect, familial aggregation of NIDDM in this population could reflect the action of a single major gene. The findings are consistent with the hypothesis that a major gene influences the risk for NIDDM in Pima Indians by affecting age at onset. The expression of this gene may depend on environmental factors that have become more prevalent in recent birth cohorts.