Context: Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies leading to diabetes. Objective: We investigated effects of weight loss, an intensive lifestyle intervention (ILS), and metformin on the relationship between insulin secretion and sensitivity using repository data from 2931 participants in the Diabetes Prevention Program clinical trial in adults at high risk of developing type 2 diabetes. Methods: Insulin secretion and sensitivity were estimated from insulin and glucose concentrations in fasting and 30-minute postload serum samples at baseline and 1, 2, and 3 years after randomization, during the active intervention phase. The nonlinear relationship of secretion and sensitivity was evaluated by standardized major axis regression to account for variability in both variables. Insulin secretory demand and compensatory insulin secretion were characterized by distances along and away from the regression line, respectively. Results: ILS and metformin decreased secretory demand while increasing compensatory insulin secretion, with greater effects of ILS. Improvements were directly related to weight loss; decreased weight significantly reduced secretory demand (b=?0.144 SD; 95% CI (?0.162, ?0.125)/5 kg loss) and increased compensatory insulin secretion (b=0.287 SD, 95% CI (0.261, 0.314)/5 kg loss). In time-dependent hazard models, increasing compensatory insulin secretion (hazard ratio [HR]=0.166 per baseline SD, 95% CI 0.133, 0.206) and weight loss (HR=0.710 per 5 kg loss, 95% CI 0.613, 0.819) predicted lower diabetes risk. Conclusion: Diabetes risk reduction was directly related to the amount of weight loss, an effect mediated by lowered insulin secretory demand (due to increased insulin sensitivity) coupled with improved compensatory insulin secretion.