DESCRIPTION (adapted from the application) In subjects with diabetes, microalbuminuria predicts end-stage renal disease (ESRD) and cardiovascular disease (CVD). Despite gains, many patients still progress to ESRD and diabetic nephropathy (DN) is the leading cause of ESRD. CVD is the leading cause of death and risk begins to accelerate with microalbuminuria. Central obesity syndrome, which appears to be present in some subjects with type 1 diabetes and many subjects with type 2, increases risk of CVD and elevated albumin excretion rate (AER). This proposal will define the roles of intraabdominal fat (IAF) and the renin-angiotensin system (RAS) in the development of elevated AER and dyslipidemia in subjects with diabetes through an observational cross-sectional study of a subpopulation (three Minnesota cohorts and the Seattle cohort) of the Epidemiology Interventions and Complications Study and an independently-recruited interventional weight loss study of overweight subjects with type 1 diabetes. Additionally, population studies will examine frequencies of the G-6A angiotensinogen variants in subjects with and without hypertension (HTN) and elevated AER. The specific aims of the project are: (1) to characterize the RAS and its relationship to elevated AER, gender, and IAF (as measured by abdominal CT) in subjects with type 1 diabetes; (2) to define the relationship between IAF, central obesity-related dyslipidemia, RAS, and AER in subjects with type 1 diabetes; (3) to determine the frequency of the G-6A haplotype subdivisions in subjects with type 1 diabetes and determine the associations of those haplotypes with HTN and AER; and (4) to compare frequencies of the G-6A AGT genotype in the highest and lowest quartiles of diastolic blood pressures among subjects in the top quartile of weight gain on intensive therapy during the Diabetes Control and Complications Trial. These studies will define mechanisms underlying the relationship between central obesity and the earliest stages of DN, providing insights applicable to some subjects with type 2 diabetes and HTN.