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Wood, A.R.* ; Jonsson, A.* ; Jackson, A.U.* ; Wang, N.* ; van Leewen, N.* ; Palmer, N.D.* ; Kobes, S.* ; Deelen, J.* ; Boquete-Vilarino, L.* ; Paananen, J.* ; Stancáková, A.* ; Boomsma, D.I.* ; de Geus, E.J.C.* ; Eekhoff, E.M.W.* ; Fritsche, A. ; Kramer, M.* ; Nijpels, G.* ; Simonis-Bik, A.* ; van Haeften, T.W.* ; Mahajan, A.* ; Boehnke, M.* ; Bergman, R.N.* ; Tuomilehto, J.* ; Collins, F.S.* ; Mohlke, K.L.* ; Banasik, K.* ; Groves, C.J.* ; McCarthy, M.I.* ; Pearson, E.R.* ; Natali, A.* ; Mari, A.* ; Buchanan, T.A.* ; Taylor, K.D.* ; Xiang, A.H.* ; Gjesing, A.P.* ; Grarup, N.* ; Eiberg, H.* ; Pedersen, O.* ; Chen, Y.* ; Laakso, M.* ; Norris, J.M.* ; Smith, U.* ; Wagenknecht, L.E.* ; Baier, L.J.* ; Bowden, D.W.* ; Hansen, T.* ; Walker, M.* ; Watanabe, R.M.* ; 't Hart, L.M.* ; Hanson, R.L.* ; Frayling, T.M.*

A genome-wide association study of IVGTT-based measures of first-phase insulin secretion refines the underlying physiology of type 2 diabetes variants.

Diabetes 66, 2296-2309 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Beta-cell Function; Glycemic Traits; Transcription-factor-7-like-2 Tcf7l2; Genetic Architecture; Mexican-americans; Proinsulin Levels; Common Variants; Iras Family; Glucose; Polymorphisms
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 66, Issue: 8, Pages: 2296-2309 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502400-001
DOI 10.2337/db16-1452
WOS ID WOS:000406014600026
Scopus ID 85025680230
PubMed ID 28490609
Erfassungsdatum 2017-09-07
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