Format

Send to

Choose Destination
Diabetes. 2017 Aug;66(8):2296-2309. doi: 10.2337/db16-1452. Epub 2017 May 10.

A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.

Author information

1
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K.
2
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.
4
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
5
Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
6
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
7
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC.
8
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
9
Max Planck Institute for Biology of Ageing, Cologne, Germany.
10
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
11
Department of Biological Psychology, VU University, Amsterdam, the Netherlands.
12
Diabetes Center, Internal Medicine Unit, VU University Medical Center, Amsterdam, the Netherlands.
13
Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany.
14
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.
15
German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
16
EMGO+ Institute for Health and Care Research, VU University Medical Center, Department of General Practice, Amsterdam, the Netherlands.
17
Department of Internal Medicine, Utrecht University Medical Center, Utrecht, the Netherlands.
18
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
19
Diabetes & Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
20
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
21
Dasman Diabetes Institute, Dasman, Kuwait.
22
Department of Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria.
23
Saudi Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
24
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
25
Department of Genetics, University of North Carolina, Chapel Hill, NC.
26
Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
27
Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
28
Oxford Biomedical Research Centre, National Institute for Health Research, Churchill Hospital, Oxford, U.K.
29
School of Medicine, University of Dundee, Dundee, U.K.
30
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
31
Institute of Neuroscience, National Research Council, Padova, Italy.
32
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
33
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
34
Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA.
35
Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA.
36
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
37
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
38
Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO.
39
Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
40
Wake Forest School of Medicine, Winston-Salem, NC.
41
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.
42
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.
43
Institute of Cellular Medicine, Newcastle University, Newcastle, U.K. t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.
44
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.
45
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.
46
Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
47
Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
48
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.
49
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K. t.m.frayling@exeter.ac.uk rhanson@phx.niddk.nih.gov lmthart@lumc.nl rwatanab@usc.edu mark.walker@newcastle.ac.uk torben.hansen@sund.ku.dk dbowden@wfubmc.edu.

Abstract

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.

PMID:
28490609
PMCID:
PMC5521867
DOI:
10.2337/db16-1452
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center