We attempted to identify the pathogenic factors involved in the progression to type 2 diabetes in obese Japanese adolescents. Subjects included 18 nondiabetic obese adolescents, 12 obese adolescents with type 2 diabetes on diet therapy, 10 obese adolescents with type 2 diabetes manifesting ketosis at onset or with a history of treatment with hypoglycemic agents, and 26 non-obese adolescent control subjects. The first-phase insulin response (FPIR), glucose disappearance constant (Kg), glucose effectiveness (Sg), and insulin sensitivity (S(I)) were obtained using an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and a minimal model analysis. The disposition index (DI, by FPIR x S(I)) was determined to assess any endogenous insulin effect. The results showed that Kg was decreased significantly (P = .0006) with the progression to severe diabetes in the obese groups. Although S(I) and Sg did not differ significantly among the 3 obese groups, both parameters were significantly lower in each obese group versus the non-obese controls. As a result of the significant decrease in FPIR (P < .0001), the DI decreased (P = .0006) with the progression to severe diabetes in the obese groups. In conclusion, an early manifestation of type 2 diabetes with occasional ketosis at onset may result from beta-cell dysfunction to glucose stimulation. This finding is demonstrated by the relatively low FPIR to decreased S(I) in obese Japanese adolescents, as well as the low Sg as a synergic role in glucose intolerance. The present findings from a Japanese population for pathogenic factors aside from obesity may help us to gain a better understanding of the progression to adolescent, early-onset, obese type 2 diabetes and its severity.