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A.L.M. was supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. T.H. was supported by a research grant from the Novo Nordisk Foundation NNF18OC0034532. The Novo Nordisk Foundation Center for Basic Metabolic Research is also supported by an unrestricted grant from the Novo Nordisk Foundation (NNF18CC0034900). S.B.G was supported by a Juan de la Cierva postdoctoral fellowship (MINECO; FJCI-2017-32090). J.F. was supported by Instituto de Salud Carlos III (PMP21/00067), Wellcome Trust (WT101033), European Research Council Advanced Grant (789055), Spanish Ministry of Science and Innovation (RTI2018-095666-B-I00, PID2021-122522OB-I00) and Departament de Recerca i Universitats de la Generalitat de Catalunya (SGR2021-01371). Work in the Centre for Genomic Regulation was supported by the CERCA Programme, Generalitat de Catalunya and Centro de Excelencia Severo Ochoa (CEX2020-001049) and support from the Spanish Ministry of Science and Innovation to the EMBL partnership. M.G.M. was supported by a research grant from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation, grant number NNF20SA0067242 and the Danish Heart Foundation. T.S.A. was supported by the Novo Nordisk Foundation NNF18OC0052457. The ADDITION-PRO study was funded by an unrestricted grant from the European Foundation for the Study of Diabetes/Pfizer for Research into Cardiovascular Disease Risk Reduction in Patients with Diabetes (74550801), by the Danish Council for Strategic Research and by internal research and equipment funds from Steno Diabetes Center together with Danish Medical Research Council, the Danish Heart Foundation, Danish Health Insurance Foundation, the Foundation of 1870, Fanny Miranda and Willy Rottb & oslash;ll Rokb & oslash;lls Foundation, D.M.Sci Torben Geils Foundation, the grant of 22 July 1959 and Director E. Danielsen and Wife's Foundation. ADIGEN was supported by grants from The Danish Medical Research Council, The Danish National Research Foundation and The Velux Foundation. The Botnia Family Study and the PPP-Botnia Study have been financially supported by grants from Folkhaelsan Research Foundation, the Sigrid Juselius Foundation, The Academy of Finland (grant nos. 263401, 267882, 312063, 336822, 312072 and 336826), University of Helsinki, Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS, MOSAIC FP7-600914), Ollqvist Foundation, Swedish Cultural Foundation in Finland, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Finnish Medical Society, State Research Funding via the Helsinki University Hospital, Perklen Foundation, Naerpes Health Care Foundation and Ahokas Foundation. The PPP-Botnia Study was genotyped by the Finngen project and the Botnia Family Study by Regeneron Pharmaceuticals. The study sponsors had no role in the analysis and interpretation of the data, writing of the manuscript or decision to submit the manuscript for publication. GDM offspring was supported by Copenhagen University, the P. Carl Petersens Foundation, the Danish Medical Research Council, the Copenhagen University Hospital Foundation, the Danish Diabetes Association, Laegeforeningens Forskningsfond/MC and JK Moltums Fond. Health08 was funded by Timber Merchant Vilhelm Bang's Foundation, The Danish Heart Foundation and The Health Insurance Foundation (Helsefonden). Inter99 is supported economically by The Danish Medical Research Council, The Danish Centre for Evaluation and Health Technology Assessment, Novo Nordisk, Copenhagen County, The Danish Heart Foundation, The Danish Pharmaceutical Association, Augustinus Foundation, Ib Henriksen Foundation and Becket Foundation. Metabolic Syndrome in Men (METSIM) was supported by the Academy of Finland (contract no. 124243), the Finnish Heart Foundation, the Finnish Diabetes Foundation, Tekes (contract 1510/31/06), the Commission of the European Community (HEALTH-F2-2007 201681) and the US National Institutes of Health grants DK093757, DK072193, DK062370 and ZIA-HG000024. Analyses of UK Biobank data were performed under application no. 1251 (fat percentage GWAS) and no. 32683 (the rest).

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Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology

Publicated to:Nature Metabolism. - 2024-10-17 (), DOI: 10.1038/s42255-024-01140-6

Authors: Madsen, AL; Bonàs-Guarch, S; Gheibi, S; Prasad, R; Vangipurapu, J; Ahuja, V; Cataldo, LR; Dwivedi, O; Hatem, G; Atla, G; Guindo-Martínez, M; Jorgensen, AM; Jonsson, AE; Miguel-Escalada, I; Hassan, S; Linneberg, A; Ahluwalia, TS; Drivsholm, T; Pedersen, O; Sorensen, TIA; Astrup, A; Witte, D; Damm, P; Clausen, TD; Mathiesen, E; Pers, TH; Loos, RJF; Hakaste, L; Fex, M; Grarup, N; Tuomi, T; Laakso, M; Mulder, H; Ferrer, J; Hansen, T

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Abstract

The genetics of beta-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)(1,2). Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies(3-7), large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants(10-14). Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size(15,16) and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing beta-cells(17,18). We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of beta-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from similar to 26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in beta-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.

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