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

The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)<sup>1,2</sup>. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies<sup>3-7</sup>, large-scale genome-wide association studies (GWAS) of fasting BCF<sup>8,9</sup> or functional islet studies on T2D risk variants<sup>10-14</sup>. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size<sup>15,16</sup> and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells<sup>17,18</sup>. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~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 β-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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Journal
Nature Metabolism
Published
2024-10-17
DOI
https://doi.org/10.1038/s42255-024-01140-6
Citations
11
Primary Topic
Genetic Associations and Epidemiology
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article
Field-Weighted Citation Impact
6.05
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article

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

Anne Lundager Madsen, Thorkild I. A. Sørensen, Ruth J. F. Loos, Vineet Ahuja et al.
11 citations
Nature Metabolism
Genetic Associations and Epidemiology
6.05
article

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

Anne Lundager Madsen, Thorkild I. A. Sørensen, Ruth J. F. Loos, Vineet Ahuja, Goutham Atla, Tarunveer S. Ahluwalia, Elisabeth R. Mathiesen, Marta Guindo-Martínez, Rashmi B. Prasad, Om Prakash Dwivedi, Daniel R. Witte, Sahar Hassan, Luis Rodrigo Cataldo, Thomas Drivsholm, Anna Jonsson, Liisa Hakaste, Arne Astrup, Allan Linneberg, Shayesteh Gheibi, Jorge Ferrer, Anders M. Jørgensen, Niels Grarup, Sílvia Bonàs‐Guarch, Oluf Pedersen, Tune H. Pers, Malin Fex, Peter Damm, Irene Miguel-Escalada, Tine D. Clausen, Jagadish Vangipurapu, Hindrik Mulder, Gad Hatem, Torben Hansen, Markku Laakso
article en
11 citations

Abstract

The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)<sup>1,2</sup>. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies<sup>3-7</sup>, large-scale genome-wide association studies (GWAS) of fasting BCF<sup>8,9</sup> or functional islet studies on T2D risk variants<sup>10-14</sup>. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size<sup>15,16</sup> and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells<sup>17,18</sup>. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~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 β-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.

Nature MetabolismVol. 6(10)
University of Copenhagen (DK), University of Helsinki (FI), Steno Diabetes Centers (DK), University of Eastern Finland (FI), Lund University (SE), Aarhus University (DK), Helsinki University Hospital (FI), Novo Nordisk Foundation (DK), Frederiksberg Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), University College Copenhagen (DK), Center for Clinical Research and Prevention (DK), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Institute for Molecular Medicine Finland (FI), Centre for Genomic Regulation (ES), Folkhälsans Forskningscentrum (FI), Hospital District of Helsinki and Uusimaa (FI), Imperial College London (GB), Icahn School of Medicine at Mount Sinai (US)
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