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Lifestyle interventions have been shown to prevent or delay the onset of diabetes; however, inter-individual variability in responses to such interventions makes lifestyle recommendations challenging. We analyzed the Japan Diabetes Outcome Intervention Trial-1 (J-DOIT1) study data using a previously published mechanistic simulation model of type 2 diabetes onset and progression to understand the causes of inter-individual variability and to optimize dietary intervention strategies at an individual level. J-DOIT1, a large-scale lifestyle intervention study, involved 2607 subjects with a 4.2-year median follow-up period. We selected 112 individuals from the J-DOIT1 study and calibrated the mechanistic model to each participant’s body weight and HbA1c time courses. We evaluated the relationship of physiological (e.g., insulin sensitivity) and lifestyle (e.g., dietary intake) parameters with variability in outcome. Finally, we used simulation analyses to predict individually optimized diets for weight reduction. The model predicted individual body weight and HbA1c time courses with a mean (±SD) prediction error of 1.0 kg (±1.2) and 0.14% (±0.18), respectively. Individuals with the most and least improved biomarkers showed no significant differences in model-estimated energy balance. A wide range of weight changes was observed for similar model-estimated caloric changes, indicating that caloric balance alone may not be a good predictor of body weight. The model suggests that a set of optimal diets exists to achieve a defined weight reduction, and this set of diets is unique to each individual. Our diabetes model can simulate changes in body weight and glycemic control as a result of lifestyle interventions. Moreover, this model could help dieticians and physicians to optimize personalized nutritional strategies according to their patients’ goals.