Abstract

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from or is merely correlated with T2D due to confounding. We used Mendelian randomization (MR) to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D cases and 607,012 controls. Several biomarkers were used as proxies of liver function [i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT)]. Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetically predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of NAFLD, these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.