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BACKGROUND: Diet and lifestyle factors have been linked to developing diverticulitis. However, it remains largely unknown whether the associations are mediated by metabolic disturbance, such as hyperinsulinemia and corresponding metabolomic perturbations.OBJECTIVE: We investigated associations of the insulinemic potential of diet, lifestyle (diet, physical activity, body weight), and metabolomic patterns with the risk of incident diverticulitis.DESIGN: We conducted a prospective cohort study including participants in three nationwide cohorts of US health professionals. The risk of incident diverticulitis was estimated according to quintiles of the empirical dietary index for hyperinsulinemia (EDIH) and empirical lifestyle index for hyperinsulinemia (ELIH). In a subset of participants with metabolomic measurements, we developed metabolomic dietary index for hyperinsulinemia (MDIH) and metabolomic lifestyle index for hyperinsulinemia (MLIH), metabolite profile scores correlating with EDIH and ELIH, respectively, and tested their associations with subsequent risk of diverticulitis. We also examined whether the associations of EDIH and ELIH with diverticulitis were mediated by the metabolite profile scores.RESULTS: Among 184,508 participants (median age, 51 [IQR, 46-56] years), we documented 9,123 incident diverticulitis cases over 3,419,945 person-years. Compared with those in the lowest quintile, participants with the most hyperinsulinemic diets and lifestyles (highest quintiles of EDIH and ELIH) had a hazard ratio for the risk of diverticulitis of 1.22 (95% CI, 1.13-1.31) and 1.69 (95% CI, 1.57-1.81), respectively. Similarly, the metabolite profile scores were significantly associated with the diverticulitis risk with odds ratio of 1.96 for MDIH (95% CI, 1.47-2.60) and 1.93 for MLIH (95% CI, 1.48-2.51) when comparing extreme quintiles. The explainable proportions of EDIH- and ELIH-related diverticulitis risk by MDIH and MLIH were 70% (95% CI, 6%-99%) and 57% (95% CI, 23%-86%), respectively (P <.0001 for both).CONCLUSIONS: Participants with dietary and lifestyle patterns corresponding to higher insulinemic potential had an increased risk of diverticulitis, which might be mediated by metabolomic profiles.