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OBJECTIVE Insulin response is related to overall health. Diet modulates insulin response. We investigated whether insulinemic potential of diet is associated with risk of all-cause and cause-specific mortality. RESEARCH DESIGN AND METHODS We prospectively followed 63,464 women from the Nurses’ Health Study (1986–2016) and 42,880 men from the Health Professionals Follow-up Study (1986–2016). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using a food-based empirical dietary index for hyperinsulinemia (EDIH), which was predefined based on predicting circulating C-peptide concentrations. RESULTS During 2,792,550 person-years of follow-up, 38,329 deaths occurred. In the pooled multivariable-adjusted analyses, a higher dietary insulinemic potential was associated with an increased risk of mortality from all-cause (hazard ratio [HR] comparing extreme quintiles: 1.33; 95% CI 1.29, 1.38; P-trend &amp;lt;0.001), cardiovascular disease (CVD) (HR 1.37; 95% CI 1.27, 1.46; P-trend &amp;lt;0.001), and cancers (HR 1.20; 95% CI 1.13, 1.28; P-trend &amp;lt;0.001). These associations were independent of BMI and remained significant after further adjustment for other well-known dietary indices. Furthermore, compared with participants whose EDIH scores were stable over an 8-year period, those with the greatest increases had a higher subsequent risk of all-cause (HR 1.13; 95% CI 1.09, 1.18; P-trend &amp;lt;0.001) and CVD (HR 1.10; 95% CI 1.01, 1.21; P-trend = 0.006) mortality. CONCLUSIONS Higher insulinemic potential of diet was associated with increased risk of all-cause, CVD, and cancer mortality. Adopting a diet with low insulinemic potential might be an effective approach to improve overall health and prevent premature death.

Dietary Insulinemic Potential and Risk of Total and Cause-Specific Mortality in the Nurses’ Health Study and the Health Professionals Follow-up Study