The genetics of β-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^3,4,5,6,7, large-scale genome-wide association studies (GWAS) of fasting BCF^8,9 or functional islet studies on T2D risk variants^{10,11,12,13,14}. 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 β-cells^17,18. 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.

β细胞功能 （BCF） 的遗传学为 2 型糖尿病 （T2D） 的病因提供了有价值的见解^1,2。以前的研究通过候选基因研究^3,4,5,6,7、空腹 BCF^8,9 的大规模全基因组关联研究 （GWAS） 或 T2D 风险变异^{10、11、12、13、14} 的功能性胰岛研究扩展了 BCF 遗传关联的目录。尽管如此，专注于口服葡萄糖耐量试验 （OGTT） 数据得出的 BCF 性状的 GWAS 样本量有限^{15,16，并且}经常忽视相关性状捕获产生胰岛素的 β 细胞的不同遗传特征的潜力^17,18。我们推断，研究多个 BCF 估计的遗传基础可以提供对 β 细胞生理学的更广泛理解。在这里，我们汇总了来自 ~26,000 名欧洲血统个体的 8 个基于 OGTT 的 BCF 性状的 GWAS 数据，在 44 个基因座确定了 55 个独立的遗传关联。通过检查 BCF 遗传信号对相关表型的影响，我们揭示了 BCF 遗传调控可能影响 T2D 风险的不同疾病机制。将 BCF-GWAS 数据与胰岛转录组学和表观基因组学数据集相结合，揭示了 92 个候选效应基因。β细胞模型中的基因沉默突出了 ACSL1 和 FAM46C 是胰岛素分泌的关键调节因子。总体而言，我们的研究结果深入了解了胰岛素释放的生物学以及将 BCF 与 T2D 风险联系起来的分子过程，从而阐明了 T2D 病理生理学的异质性。