OBJECTIVE--To identify risk factors for development of non-insulin-dependent diabetes mellitus (NIDDM) during a 5-year longitudinal follow-up of second-generation Japanese-American (Nisei) men. RESEARCH DESIGN AND METHODS--For 5 years, 137 initially nondiabetic Nisei men were followed with 75-g oral glucose tolerance tests at the initial visit and at 2.5- and 5-year follow-up visits. Body fat distribution was assessed by computed tomography (CT) and body mass index (BMI) calculated at each visit. Fasting insulin and C-peptide, the increment of insulin and C-peptide at 30 min after the oral glucose load, intra-abdominal and total subcutaneous fat by CT, and BMI were compared between those who remained nondiabetic (non-DM) and those who had developed NIDDM at 2.5 years (DM-A) and 5 years (DM-B). RESULTS--At baseline, the DM-A group had significantly increased intra-abdominal fat, elevated fasting plasma C-peptide, and lower C-peptide response at 30 min after oral glucose. At the 2.5-year follow-up, this group had markedly increased fasting plasma insulin and decreased 30-min insulin and C-peptide response to oral glucose. The DM-B group also had significantly lower insulin response at 30 min after oral glucose at baseline but no significant difference in intra-abdominal fat or fasting plasma insulin and C-peptide levels. When this group developed NIDDM by 5-year follow-up, however, an increase of intra-abdominal fat was found superimposed on the pre-existing lower insulin response. Fasting plasma insulin and C-peptide remained low. CONCLUSION--In DM-A, lower 30-min insulin response to oral glucose (an indicator of beta-cell lesion) and increased intra-abdominal fat and fasting C-peptide (indicators of insulin resistance) were the risk factors related to the development of NIDDM. DM-B subjects had a lower 30-min insulin response to oral glucose at baseline and increased intra-abdominal fat at 5-years, when they were found to have NIDDM. Thus, both insulin resistance and impaired beta-cell function contribute to the development of NIDDM in Japanese-Americans, and impaired beta-cell function may be present earlier than visceral adiposity in some who subsequently develop NIDDM.