Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function

Aims/hypothesis: Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT).

Methods: We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort.

Results: A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10^-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10^-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008).

Conclusions/interpretation: Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.