de Lima Renan Pereira, Li Ang, Gilani Ankit, Lo James C
bioRxiv. 2024 Nov 12:2024.11.11.622969. doi: 10.1101/2024.11.11.622969.
Pancreatic β cell dysfunction is critical to the development of type 2 diabetes (T2D). We show that the complement receptor C3aR1 on β cells plays an essential role in maintaining β cell homeostasis, especially under the metabolic duress of obesity and T2D. Mice with β cell specific deletion of have worse glucose tolerance, lower insulin levels, and decreased β cell mass. Islets from β cell specific knockout (β-C3aR1 KO) mice demonstrate impaired insulin secretion. Disruption of on β cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and β cell-derived C3aR1. Markers of β cell identity were decreased while stress markers were increased in β-C3aR1 KO mice. Islets from β-C3aR1 KO also exhibit increased β cell death to lipotoxicity. Finally, we show that is positively correlated with insulin secretion in human islets. These findings indicate that C3aR1 expression on β cells is necessary to maintain optimal β cell function and preserve β cell mass in T2D.
胰腺β细胞功能障碍对2型糖尿病（T2D）的发生发展至关重要。我们发现β细胞上的补体受体C3aR1在维持β细胞稳态中起关键作用，尤其是在肥胖和T2D的代谢应激情况下。β细胞特异性缺失[此处原文缺失相关基因名称]的小鼠葡萄糖耐量更差、胰岛素水平更低且β细胞量减少。来自β细胞特异性[此处原文缺失相关基因名称]敲除（β-C3aR1 KO）小鼠的胰岛显示胰岛素分泌受损。β细胞上[此处原文缺失相关基因名称]的破坏消除了对C3a的胰岛素分泌反应，确立了C3a与β细胞源性C3aR1之间的信号轴。在β-C3aR1 KO小鼠中，β细胞身份标志物减少而应激标志物增加。来自β-C3aR1 KO的胰岛对脂毒性也表现出β细胞死亡增加。最后，我们表明[此处原文缺失相关基因名称]与人类胰岛中的胰岛素分泌呈正相关。这些发现表明，β细胞上C3aR1的表达对于维持最佳β细胞功能和在T2D中保留β细胞量是必要的。
