Metabolome contribution to sex differences in the link between alcohol consumption and type 2 diabetes: a prospective analysis in the Hispanic Community Health Study/Study of Latinos

BACKGROUND: Light-to-moderate alcohol consumption has been linked to improved insulin resistance and lower type 2 diabetes (T2D) risk predominantly in females but not males. Potential mechanisms underlying this sex difference remain unclear. OBJECTIVES: This study evaluated associations of sex-specific alcohol-associated metabolomic signatures (AMSs) with insulin resistance and T2D risk in United States Hispanic/Latino adults. METHODS: We analyzed serum metabolome data in the Hispanic Community Health Study/Study of Latinos, a prospective, multicenter, community-based study of Hispanics/Latinos, aged 18 to 74 y old, enrolled from 4 United States metropolitan areas between 2008 and 2011. Sex-specific AMSs were developed using an elastic net to identify serum metabolites uniquely associated with alcohol consumption in females (n = 2747) and males (n = 1737) without diabetes at baseline, respectively, excluding heavy drinkers. Poisson regression was used to examine the cross-sectional associations of AMSs with insulin resistance (homeostasis model assessment of insulin resistance >/=2.5) and the prospective associations of AMSs with T2D risk in females (n = 2265) and males (n = 1290) over approximately 6 y, adjusting for demographic, socioeconomic, and behavioral factors. RESULTS: We identified 40 and 54 metabolites uniquely associated with light-to-moderate alcohol consumption in females and males, respectively. Cross-sectionally, female-specific AMS (FAMS) was inversely associated with insulin resistance and various T2D-related metabolic traits in females, whereas male-specific AMS was positively associated with insulin resistance and metabolic traits in males. Prospectively, females in the highest quartile of FAMS had approximately 82% (95% confidence interval: 70%, 89%) lower T2D risk compared with those in the lowest quartile. The favorable association between alcohol consumption and risk of T2D was attenuated after adjusting for FAMS. In males, there was no statistically significant association between male-specific AMS and T2D risk. CONCLUSIONS: Our results suggested distinct blood metabolomic signatures associated with alcohol consumption in females and males, which might contribute to sex differences in the relationship between alcohol consumption and T2D.