Samples and data are analyzed from a longitudinal population study (1965 to 2007) that allows study of the risk factors and effects of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on development of vascular complications and mortality. 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 regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Findings on risk factors for diabetes are applied to a multicenter randomized clinical trial of prevention of type 2 diabetes that is currently in a long-term outcomes phase (the Diabetes Prevention Program Outcomes Study). Studies of the genetics of type 2 diabetes, obesity, and diabetes complications are described in other projects. Knowledge of diabetes risk factors coming from this and other studies led to the hypothesis that type 2 diabetes could be prevented or delayed in adults at high short-term risk. This hypothesis was confirmed in the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial in which many of the participants and investigators in this project participated. We are now in a long-term follow-up phase, the Diabetes Prevention Program Outcomes Study (DPPOS), to assess long-term success with weight loss, reduction in the incidence of diabetes, and effects on diabetes complications. The DPPOS also began a genetics component to test whether genes with known or suspected effects on type 2 diabetes affected diabetes incidence in the DPP and interacted with study interventions. Treatment guidelines for diabetes have become increasingly stringent as most research shows that more aggressive intervention reduces risks for complications. Community data on the effect of these interventions is lacking. Changes in the pharmacologic treatment of diabetes, blood pressure and cholesterol in adults with diabetes were analyzed in the longitudinal population-based study of American Indians between 1975 and 2004. Major changes in community treatment patterns for diabetes and related conditions coincided with improvements in glycemia, blood pressure and cholesterol. In the Diabetes Prevention Program, metformin produced weight loss and delayed or prevented diabetes. We hypothesized that in the long-term extension of this randomized clinical trial (DPPOS), metformin would have a sustained weight loss effect that would be related to drug-taking adherence. During the DPPOS, the modest weight loss with metformin was durable through 10 years of treatment and was related to the degree of adherence to metformin. HbA1c is the standard measure of glycemic control for managing diabetes but not for diagnosis. Recently HbA1c was proposed for diagnosing diabetes if 6.5%, and at lower levels for identifying high risk persons for preventive interventions. We evaluated these proposals in the Diabetes Prevention Program (DPP) with long-term follow-up for 10 years after randomization (DPPOS). HbA1c at baseline predicted diabetes in all treatment groups. With HbA1c 6.5% as an alternate outcome, the incidence was reduced by 44% by metformin and 49% by lifestyle intervention during the DPP and by 38% by metformin and 29% by lifestyle during long-term follow-up. Unlike the primary findings based on the conventional diabetes definition, metformin and lifestyle were equivalent in preventing rise in HbA1c. The long-term health implications of these differences in treatment effects are unknown.