Diabetes Mellitus (DM) is classified into two major categories; type 1 (insulin dependent) and type 2 (non-insulin dependent). A poorly characterized, "atypical" variety of DM is rapidly becoming the predominant form of diabetes among obese, African-American adolescents from the southeastern United States. This atypical diabetes mellitus (ADM) presents with signs of severe insulin deficiency, but evolves into a form of type 2 diabetes, with a persistent predisposition to ketoacidosis. The objective of this proposal is to fully characterize the defects in insulin action and insulin secretion, which constitute ADM at various stages in its progression. The proposed research will explore the hypothesis that ADM results from a primary genetic defect in glucose-insulin coupling, which is complicated by insulin resistance, brought on by puberty and/or obesity. We will attempt to correlate relevant clinical, metabolic and hormonal parameters with the data from a systematic evaluation of insulin secretion and insulin action conducted in the GCRC. A further goal will be to test the effect of various interventions (e.g.; weight loss, insulin sensitizing agents) on the evolution of this diabetes phenotype. As ADM shows very strong familial tendencies, with vertical transmission through three or more generations in the majority of pedigrees, the genetic basis of this disease will be examined. This proposal will examine ADM with genetic linkage studies, using a candidate gene approach. In light of our preliminary data, a number of genes associated with impaired glucose-stimulated insulin secretion will be tested for their association with the ADM phenotype. As this phenotype is distinctive, yet shares many features in common with type 2 diabetes, the study of ADM presents a unique opportunity to explore the genetic basis of one form of non-insulin dependent diabetes.