Measurement of insulin, C-peptide, glucagon, and somatostatin are central to epidemiological and metabolic studies which address the role of islet cell function and regulation and insulin resistance in the development and maintenance of obesity and diabetes in the Pima population. In vivo insulin catabolism, assessed by the hyperinsulinemic glucose clamp technique or as fractional extraction of endogenously secreted insulin, was elevated in obese diabetic patients compared to obese nondiabetic controls. The increased insulin clearance rate may contribute to the post-challenge hypoinsulinemia observed in diabetic patients. Secretion of glucagon and glucagon-like-immunoreactivity (GLI) in response to a standard test meal were not altered in obese compared to nonobese subjects in the Pima population. A method was developed for the extraction of somatostatin from untreated human plasma and concentrations of somatostatin in peripheral plasma were not different in diabetic or obese subjects compared to nonobese nondiabetic controls. This method permitted evaluation of the role of endogenous peripheral plasma somatostatin in regulating gastric emptying rates in obese and nonobese subjects. In addition, the cross-sectional differences and longitudinal changes in serum insulin levels in the Pima population were examined in relationship to diabetes and obesity.