The present study seeks to assess the role of fasting hyperinsulinemia and hyperproinsulinemia as predictors of non-insulin-dependent diabetes mellitus (NIDDM) and of cardiovascular disease (CVD) among women in the Nurses' Health Study. The role of glycohemoglobin levels in women with NIDDM and fructosamine levels in nondiabetic women also will be assessed as determinants of subsequent CVD events, as well as the role of polymorphism of the glyCogen synthase gene as a genetiC marker for NIDDM, insulin resistance, hypertension, and CVD. The proposed investigation to explore biochemical predictors of NIDDM and its CVD complications in women takes advantage of the ongoing large prospective cohort study of 121,700 registered nurses currently aged 47-72 years. At entry in 1976, 2184 prevalent cases of diabetes were reported. Subsequently, from 1976-1990, approximately 3480 incident cases of diabetes have been reported and 2868 have been confirmed as NIDDM (6313 confirmed incident cases of NIDDM projected for 1976-98). We are currently funded to continue to document and classify new diagnoses of NIDDM in this cohort through the 1998 cycle (DK 36798). From blood specimens collected on more than 33,000 participants in 1989-90, glycohemoglobin levels will be measured among the women with NIDDM (in a "nested" case-control design) and fructosamine among nondiabetic women to assess their role in predicting subsequent CVD events. Fasting insulin and proinsulin levels, as well as glycogen synthase genotype, will be examined as predictors of the subsequent diagnosis of NIDDM in nondiabetic women. Further, potentially modifiable determinants of fasting hyperinsulinemia, including physical activity level, diet composition, and other variables will be assessed. The large size of the cohort, the prospective design, the high follow-up rate (>92%), the detailed exposure data, and the availability of blood specimens make this cohort a unique resource to test several etiologic hypotheses related to NIDDM in an extremely cost-efficient manner.