The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.

转录因子PAX4中的编码变异 (p.Arg192His) 与东亚人群患 2 型糖尿病 (T2D) 的风险改变相关。在小鼠中， Pax4对于 β 细胞的形成至关重要，但其对人类 β 细胞发育和/或功能的作用尚不清楚。在一项横断面研究中，与 p.192Arg 等位基因纯合子相比，携带 PAX4 p.His192 等位基因的参与者表现出胰腺 β 细胞功能下降，在该研究中我们进行了静脉内葡萄糖耐量试验和口服葡萄糖耐量试验。在一名年轻发病的糖尿病患者的家谱中，几位成员携带新发现的 p.Tyr186X 等位基因。在人类 β 细胞模型中，EndoC-βH1、 PAX4敲低会导致胰岛素分泌受损、总胰岛素含量降低以及激素基因表达改变。人诱导多能干细胞 (hiPSC) 衍生的胰岛样细胞中PAX4的缺失会导致 α 细胞基因表达的抑制。携带PAX4 p.His192 和 p.X186 风险等位基因的 hiPSC 的体外分化表现出多激素内分泌细胞形成增加和胰岛素含量减少，这可以通过基因校正来逆转。我们共同证明了 PAX4 在人类内分泌细胞发育、β 细胞功能中的作用及其对 T2D 风险的影响。