期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 106, 期 1, 页码 80-90出版社
ENDOCRINE SOC
DOI: 10.1210/clinem/dgaa653
关键词
Glucose intolerance; diabetes progression; beta-cell function; incretin; mathematical model
资金
- Innovative Medicines Initiative Joint Undertaking [115317]
- European Union
- EFPIA companies
- European Union [667191]
- Novo Nordisk Foundation Center for Basic Metabolic Research
- Novo Nordisk Foundation [NNF18CC0034900]
- Danish Diabetes Academy - Novo Nordisk Foundation [NNF17SA0031406]
- Danish Medical Research Council
- Danish National Research Foundation
- Velux Foundation
- University of Copenhagen
- EEC [BMH4CT950662]
- Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction and Care (LUCAMP)
- European Foundation for the Study of Diabetes (EFSD)
- Danish Diabetes Association
- Danish Heart Foundation
- Wellcome Trust [102820/Z/13/Z]
- [ERC-2015-CoG_NASCENT_681742]
Through a genome-wide meta-analysis, we have identified variations in the GIPR-QPCTL and CDKAL1 loci as key determinants of pancreatic beta-cell glucose sensitivity. These results indicate that genetic variations play a significant role in regulating beta-cell glucose sensitivity.
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 x 10(-9)) and rs9368219 in the CDKAL1 (P value = 3.15 x 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.
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