In:
The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 106, No. 1 ( 2021-01-01), p. 80-90
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0021-972X
,
1945-7197
DOI:
10.1210/clinem/dgaa653
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2021
detail.hit.zdb_id:
2026217-6
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