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

Andrew R Wood, Anna Jonsson, Anne U Jackson, Nan Wang, Nienke van Leewen, Nicholette D Palmer, Sayuko Kobes, Joris Deelen, Lorena Boquete-Vilarino, Jussi Paananen, Alena Stančáková, Dorret I Boomsma, J.C.N. de Geus, Elisabeth Mw Eekhoff, Andreas Fritsche, Mark H H Kramer, Giel Nijpels, A.M.C. Simonis-Bik, Timon W van Haeften, Anubha MahajanMichael Boehnke, Richard N Bergman, Jaakko Tuomilehto, Francis S Collins, Karen L Mohlke, Karina Banasik, Christopher J Groves, Mark I McCarthy, Ewan R Pearson, Andrea Natali, Andrea Mari, Thomas A Buchanan, Kent D Taylor, Anny H Xiang, Anette P Gjesing, Niels Grarup, Hans Eiberg, Oluf Pedersen, Yii-Derr Chen, Markku Laakso, Jill M Norris, Ulf Smith, Lynne E Wagenknecht, Leslie Baier, Donald W Bowden, Torben Hansen, Mark Walker, Richard M Watanabe, Leen M 't Hart, Robert L Hanson, Timothy M Frayling, Alena Stancáková, Eco J.C. De Geus, Leen M. T'Hart

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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 genomewide 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.

Original languageEnglish
Pages (from-to)2296-2309
Number of pages14
Issue number8
Publication statusPublished - 1 Aug 2017


  • Journal Article

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