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Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study.

Accepted version
Peer-reviewed

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Authors

De Silva, N Maneka G 
Borges, Maria Carolina  ORCID logo  https://orcid.org/0000-0001-7785-4547
Hingorani, Aroon D 
Engmann, Jorgen 
Shah, Tina 

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 to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-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. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

Description

Keywords

Alanine Transaminase, Aspartate Aminotransferases, Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Humans, Insulin Resistance, Liver, Mendelian Randomization Analysis, Risk Factors, gamma-Glutamyltransferase

Journal Title

Diabetes

Conference Name

Journal ISSN

0012-1797
1939-327X

Volume Title

68

Publisher

American Diabetes Association

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_UU_12015/1)
MRC (MC_PC_13046)
Medical Research Council (MC_U106179471)
The Fenland Study is funded by the Wellcome Trust and the Medical Research Council (Grant number: MC_U106179471 and MC_UU_12015/1).