Sex-specific roles of insulin-like growth factor-1, lean mass and fat mass in type 2 diabetes prevention: Mendelian randomization studies in Western and East Asian populations.

BACKGROUND: Sex-specific effects of body composition and its drivers, including insulin-like growth factor-1 (IGF-1), on type 2 diabetes mellitus (T2DM) are understudied across ethnicity. We assessed the role of IGF-1 in T2DM and mediation by lean or fat mass, by sex in Western and East Asian populations, using Mendelian randomization (MR). METHODS: Genetic predictors of exposure (IGF-1) and mediators (fat or lean mass) were applied to genetic associations with T2DM in Europeans (n = 898,130) and East Asians (n = 433,540). Univariable and multivariable MR (MVMR) were used to obtain total and direct effects of IGF-1 and fat or lean mass on T2DM. Mediation analyses were conducted to obtain indirect effects. RESULTS: In the Western population, genetically predicted higher IGF-1 was positively associated with T2DM in women [odds ratio (OR) 1.21, 95% confidence interval (CI) 1.11 to 1.32] but not men, and in both sexes with lean mass but not fat mass. Lean mass in both sexes decreased and fat mass in women increased T2DM risk. In the East Asian population, genetically predicted higher IGF-1 was positively associated with T2DM in both sexes (1.07, 95% CI 1.02 to 1.12), and with lean mass and fat mass in men. Lean and fat mass were unrelated to T2DM. The association of IGF-1 with T2DM was not mediated by lean or fat mass. CONCLUSIONS: IGF-1 may directly increase T2DM risk, independent of body composition, in Western women and East Asians. Fat mass in women and less lean mass in both sexes may also increase T2DM risk in Western populations.