ESPEYB25 15. Editors' Choice Genetics (9 abstracts)
15.8. Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology
Madsen AL , Bonas-Guarch S , Gheibi S , Prasad R , Vangipurapu J , Ahuja V , Cataldo LR , Dwivedi O , Hatem G , Atla G , Guindo-Martinez 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
Nat Metab 2024; 6:1897-1912. PMID: 39420167 doi: 10.1038/s42255-024-01140-6
In Brief: The authors performed genome-wide association study (GWAS) analyses for 8 OGTT-based measures of β-cell function in ~26,000 individuals of European descent. They integrated the 55 independent genetic signals with pancreatic islet transcriptomic and epigenomic datasets to prioritise 92 candidate genes. Gene silencing in β-cell models highlighted ACSL1 and FAM46C as novel regulators of insulin secretion.
Comment: This paper is an excellent example of integrating expertise in insulin secretion physiology, statistical genetics, bioinformatics informed by molecular data from the exact tissue of interest, together with experimental gene knock-down in cell lines and data from gene knock-out mice. It identifies and characterises many known or expected genes (e.g.GIPR, IGF2BP2, TCF7L2) and also many previously unknown loci, which may represent future drug targets.
In particular, their findings highlight ACSL1, which encodes the long-chain fatty acyl-CoA synthetase 1 and which may impact insulin release by altering the fatty acid composition of insulin granules and mitochondrial function. Also, FAM46C (family with sequence similarity 46, member C), whose expression levels were correlated with glucagon and islet amyloid polypeptide (IAPP, or ‘amylin’), as well as with expression levels of genes involved in insulin exocytosis (SYT13, SYT16, STXBP4), proinsulin processing (PCSK1, CPE) and β-cell differentiation (NEUROD1).
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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