University of Oulu

N. Maneka G. De Silva, Maria Carolina Borges, Aroon Hingorani, Jorgen Engmann, Tina Shah, Xiaoshuai Zhang, Jian’an Luan, Claudia Langenberg, Andrew Wong, Diana Kuh, John C Chambers, Weihua Zhang, Marjo-Ritta Jarvelin, Sylvain Sebert, Juha Auvinen, UCLEB consortium, Tom R Gaunt, Deborah A Lawlor. Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study, Diabetes May 2019, db181048; DOI: 10.2337/db18-1048

Liver function and risk of type 2 diabetes : bidirectional Mendelian randomization study

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Author: De Silva, N. Maneka G.1,2,3; Borges, Maria Carolina1,2; Hingorani, Aroon4,5;
Organizations: 1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
3Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
4UCL Institute of Cardiovascular Science, Research Department of Population Science and Experimental Medicine, Centre for Translational Genomics, University College London, London, United Kingdom
5Farr Institute, University College London, London, United Kingdom
6MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
7Department of Epidemiology and Biostatistics, School of Public Health and Management, Binzhou Medical University, Yantai, Shandong, China
8Department of Biostatistics, School of Public Health, Shandong University, Jinan, Shandong, China
9MRC Unit for Lifelong Health and Ageing at UCL, University College London, London, United Kingdom
10Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
11Imperial College Healthcare NHS Trust, Imperial College London, London W12 0HS, UK
12Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK
13Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK
14Center for Life Course Health Research, University of Oulu, Oulu, Finland
15Biocenter Oulu, Oulu, Finland
16Oulunkaari Health Center, Ii, Finland
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link:
Language: English
Published: American Diabetes Association, 2019
Publish Date: 2019-05-20


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.

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Series: Diabetes
ISSN: 0012-1797
ISSN-E: 1939-327X
ISSN-L: 0012-1797
Volume: 68
Issue: 8
Pages: 1681 - 1691
DOI: 10.2337/db18-1048
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by funds from the U.K. MRC (grant G0801456) and a British Heart Foundation (BHF) grant (AA/18/7/34219). N.M.G.D.S., M.-R.J., and S.S. received support from the European Union’s Horizon 2020 research and innovation programs DynaHEALTH (grant 633595) and LifeCycle (grant 733206). M.C.B., T.R.G., and D.A.L. work in a unit that receives funding from the U.K. MRC (grants MC_UU_00011/6 and MC_UU_00011/4). M.C.B. is supported by a Skills Development Fellowship from the U.K. MRC (grant MR/P014054/1). A.D.H. is a National Institute for Health Research (NIHR) Senior Investigator. X.Z. is supported by a scholarship from the China Scholarship Council (grant 201406220101). A.W. and D.K. are funded by the U.K. MRC (MC UU 12019/1). D.A.L. is a U.K. National Institute for Health Research (NIHR) Senior Investigator (grant NF-0616-10102). The UCLEB consortium is supported by BHF Programme grant RG/10/12/28456 and the UCL Hospitals NIHR Biomedical Research Centre. BRHS is supported by BHF grants (RG/08/013/25942 and RG/13/16/30528). BWHHS is supported by the BHF (PG/13/66/30442). CaPS was funded by the MRC and undertaken by the former MRC Epidemiology Unit (South Wales). The CaPS DNA bank was established with funding from an MRC project grant. The EAS is supported by the BHF and by the Chief Scientist Office of Scotland. ELSA is supported by the National Institute on Aging (NIA)/National Institutes of Health (grant 5 R01 AG017644-16) and a consortium of the U.K. government departments coordinated by the Economic and Social Research Council (ESRC). WHII is supported by grants from the MRC (K013351); BHF (RG/07/008/23674); the Stroke Association; the National Heart, Lung, and Blood Institute (5RO1 HL036310); the NIA (5RO1AG13196); the Agency for Healthcare Research and Quality (HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. NSHD is funded by the U.K. MRC (MC UU 12019/1). The Fenland study is funded by the Wellcome Trust and the MRC (grants MC_U106179471 and MC_UU_12015/1).
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
Copyright information: © 2019 by the American Diabetes Association. The final publication is available at