Toggle Main Menu Toggle Search

Open Access padlockePrints

Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Lookup NU author(s): Professor Mark Walker



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Publication metadata

Author(s): Dimas AS, Lagou V, Barker A, Knowles JW, Magi R, Hivert MF, Benazzo A, Rybin D, Jackson AU, Stringham HM, Song C, Fischer-Rosinsky A, Boesgaard TW, Grarup N, Abbasi FA, Assimes TL, Hao K, Yang X, Lecoeur C, Barroso I, Bonnycastle LL, Bottcher Y, Bumpstead S, Chines PS, Erdos MR, Graessler J, Kovacs P, Morken MA, Narisu N, Payne F, Stancakova A, Swift AJ, Tonjes A, Bornstein SR, Cauchi S, Froguel P, Meyre D, Schwarz PEH, Haring HU, Smith U, Boehnke M, Bergman RN, Collins FS, Mohlke KL, Tuomilehto J, Quertemous T, Lind L, Hansen T, Pedersen O, Walker M, Pfeiffer AFH, Spranger J, Stumvoll M, Meigs JB, Wareham NJ, Kuusisto J, Laakso M, Langenberg C, Dupuis J, Watanabe RM, Florez JC, Ingelsson E, McCarthy MI, Prokopenko I, on behalf of the MAGIC Investigators

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2014

Volume: 63

Issue: 6

Pages: 2158-2171

Print publication date: 01/06/2014

Online publication date: 02/12/2013

Acceptance date: 23/11/2013

Date deposited: 04/11/2014

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association


DOI: 10.2337/db13-0949


Altmetrics provided by Altmetric


Funder referenceFunder name
Boston Medical Center
Conseil Regional Nord-Pas de Calais/Fonds europeen de developpement economique et regional
Diabetes Hi Ifs
European Commission under the Marie Curie Intra-European Fellowship
German Diabetes Association
Medical Research Council Centre for Obesity and Related Metabolic Diseases
Royal Swedish Academy of Science
Swedish Foundation for Strategic Research
U.S. Public Health Service
Agence Nationale de la Recherche
Boehringer Ingelheim Foundation
Cambridge Biomedical Research Centre of the U.K. National Institute for Health Research
Danish Diabetes Association
Danish Research Council
Doris Duke Charitable Foundation Clinical Scientist Development Award
European Foundation
Forschungsfonds Deutschland
German Bundesministerium fur Bildung und Forschung (BMBF)
Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention
Mallinckrodt General Clinical Research Program, National Center for Research Resources
Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
Swedish Heart-Lung Foundation
Swedish Research Council
124243Academy of Finland
2 M01 RR000070National Center for Research Resources, NIH
098381Wellcome Trust
1 Z01 HG000024National Human Genome Research Institute
10FTF3360005American Heart Association Fellow
FKZ: 01E01001BMBF
K24 DK-080140NIDDK
LSHM-CT-2004-512013European Community
HEALTH-F4-2007-201413European Community
N02-HL-6-4278Affymetrix Inc.
KFO218/1Clinical Research Group
N01-HC-25195National Heart, Lung, and Blood Institute's Framingham Heart Study
QLG1-CT-2001-01252European Union
R01 DK-078616National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
SF8-1052German Research Council
SP716/2-1Deutsche Forschungsgemeinschaft (DFG)
U54 DA021519NIH
WT098051Wellcome Trust