A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.
Wood, AR; Jonsson, A; Jackson, AU; et al.Wang, N; van Leewen, N; Palmer, ND; Kobes, S; Deelen, J; Boquete-Vilarino, L; Paananen, J; Stančáková, A; Boomsma, DI; de Geus, EJ; Eekhoff, EM; Fritsche, A; Kramer, M; Nijpels, G; Simonis-Bik, A; van Haeften, TW; Mahajan, A; Boehnke, M; Bergman, RN; Tuomilehto, J; Collins, FS; Mohlke, KL; Banasik, K; Groves, CJ; McCarthy, MI; Pearson, ER; Natali, A; Mari, A; Buchanan, TA; Taylor, KD; Xiang, AH; Gjesing, AP; Grarup, N; Eiberg, H; Pedersen, O; Chen, Y-D; Laakso, M; Norris, JM; Smith, U; Wagenknecht, LE; Baier, L; Bowden, DW; Hansen, T; Walker, M; Watanabe, RM; 't Hart, LM; Hanson, RL; Frayling, TM
Date: 10 May 2017
American Diabetes Association
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 ...
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 non-diabetic individuals from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycaemic 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, IGFBP2, 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 glycaemic traits.
Institute of Biomedical & Clinical Science
College of Medicine and Health
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