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Lookup NU author(s): Dr Harshal Deshmukh, Dr Ana ViñuelaORCiD, Dr Alison Heggie, Professor Mark Walker
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.CONTEXT: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. OBJECTIVE: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. DESIGN: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. RESULTS: Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10-9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. CONCLUSION: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.
Author(s): Deshmukh HA, Madsen AL, Vinuela A, Have CT, Grarup N, Tura A, Mahajan A, Heggie AJ, Koivula RW, De Masi F, Tsirigos KK, Linneberg A, Drivsholm T, Pedersen O, Sorensen TIA, Astrup A, Gjesing AAP, Pavo I, Wood AR, Ruetten H, Jones AG, Koopman ADM, Cederberg H, Rutters F, Ridderstrale M, Laakso M, McCarthy MI, Frayling TM, Ferrannini E, Franks PW, Pearson ER, Mari A, Hansen T, Walker M
Publication type: Article
Publication status: Published
Journal: The Journal of Clinical Endocrinology & Metabolism
Year: 2021
Volume: 106
Issue: 1
Pages: 80-90
Print publication date: 01/01/2021
Online publication date: 18/09/2020
Acceptance date: 14/09/2020
Date deposited: 19/03/2021
ISSN (print): 0021-972X
ISSN (electronic): 1945-7197
Publisher: Oxford University Press
URL: https://doi.org/10.1210/clinem/dgaa653
DOI: 10.1210/clinem/dgaa653
PubMed id: 32944759
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