Despite advances in the treatment of type 2 diabetes and its Complications, the health impact and economic burden of diabetes continues to expand. The Diabetes Prevention Program (DPP) identified persons at high risk for diabetes and showed that lifestyle and pharmacologic intervention strategies were effective in preventing or delaying the development of diabetes; ongoing studies in the DPP Outcome Study (DPPOS) are examining the long-term impact of these interventions. This proposal is aimed at assessing novel biomarker levels in DPP and DPPOS. These biomarkers reflect pathophysiological pathways considered important in the development of diabetes and its vascular complications in a longitudinal manner, building on the current design of DPP/DPPOS. Using stored blood samples at the baseline and 1-year DPP time points and at entry into DPPOS, the specific aims of this projects are to investigate (1) The effects of interventions on biomarkers (2) Biomarker prediction and intervention effects on development of diabetes, and its co-morbidities (3) Baseline biomarkers and prediction of microvascular and macrovascular complications of diabetes (4) Biomarker levels at diabetes onset and prediction of complications. Biomarkers of inflammation (CRP, IL-6, MCP-1, TNFalpha), coagulant balance (PAI-1, fibrinogen, tPA), endothelial dysfunction (sICAM-1, sVCAM-1, E-selectin) and of metabolic deregulation (adiponectin, apo B, leptin) and cystatin C have been selected for measurement. Change in biomarker levels from DPP baseline to 1 year will assess effects of interventions on biomarkers, and all three biomarker assessments, reflecting pre-intervention, 1-year on-treatment and longer-term on-treatment effects will determine the predictive value of biomarkers on development of diabetes and its complications. Circulating biomarkers of inflammation, coagulation and vascular dysfunction are increasingly being shown to provide a measure of the role of these processes in chronic diseases. This proposal will provide novel information on the disease pathways involved in the development of diabetes and its complications in subjects at high risk for this disease and thereby create improved opportunities for prediction and methods of treatment in the development of type 2 diabetes and its complications. ? ? ?