Pereira de Lima Renan, Li Ang, Gilani Ankit, Rubio-Navarro Alfonso, Warren Charles D, Kong Isabella Y, Geri Jacob B, Lo James C
Division of Cardiology, Weill Center for Metabolic Health, Cardiovascular Research Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
Mol Metab. 2025 Jun;96:102134. doi: 10.1016/j.molmet.2025.102134. Epub 2025 Apr 4.
Pancreatic β cell dysfunction is critical to the development of type 2 diabetes (T2D). Our previous studies suggested that C3aR1 on β cells promotes insulin secretion and cell survival. However, as C3aR1 is expressed on many other cell types including within the islets, whole-body C3aR1 knockout models confound the analyses of direct impacts on β cells.
To clarify the role of C3aR1 in β cells under T2D conditions, we generated β cell-specific C3aR1 knockout mice. We assessed glucose homeostasis, focusing on β cell function and mass under metabolic stress conditions, to interrogate the effects of C3aR1 on β cells in a mouse model of T2D. We performed proteomic analyses on islets from control and β cell-specific C3aR1 knockout mice. To determine potential translational relevance, C3AR1 was assessed alongside glucose-stimulated insulin secretion in human islets.
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. Male mice with β cell specific deletion of C3ar1 (β-C3aR1 KO) exhibit worse glucose tolerance and lower insulin levels when fed regular or high fat diet. Under high fat diet, β-C3aR1 KO also have diminished β cell mass. Islets from β-C3aR1 KO mice demonstrate impaired insulin secretion. β cells lacking C3aR1 display increased susceptibility to lipotoxicity-mediated cell death. Markers of β cell identity are decreased in β-C3aR1 KO mice while stress markers are elevated. Disruption of C3ar1 on β cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and β cell-derived C3aR1. Islet proteomic analyses highlight the MAPK pathway and mitochondrial dysfunction with C3aR1 loss in β cells. Finally, we show that C3AR1 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。我们之前的研究表明，β细胞上的C3aR1可促进胰岛素分泌和细胞存活。然而，由于C3aR1在包括胰岛内的许多其他细胞类型上均有表达，全身C3aR1基因敲除模型混淆了对β细胞直接影响的分析。
为阐明T2D条件下C3aR1在β细胞中的作用，我们构建了β细胞特异性C3aR1基因敲除小鼠。我们评估了葡萄糖稳态，重点关注代谢应激条件下的β细胞功能和数量，以探究C3aR1在T2D小鼠模型中对β细胞的影响。我们对对照小鼠和β细胞特异性C3aR1基因敲除小鼠的胰岛进行了蛋白质组学分析。为确定潜在的转化相关性，我们在人胰岛中评估了C3AR1与葡萄糖刺激的胰岛素分泌情况。
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C3ar1（β-C3aR1 KO）的雄性小鼠在喂食常规或高脂饮食时，葡萄糖耐量更差，胰岛素水平更低。在高脂饮食条件下，β-C3aR1 KO小鼠的β细胞数量也减少。β-C3aR1 KO小鼠的胰岛显示胰岛素分泌受损。缺乏C3aR1的β细胞对脂毒性介导的细胞死亡敏感性增加。β-C3aR1 KO小鼠中β细胞身份标志物减少，而应激标志物升高。β细胞上C3ar1的破坏消除了对C3a的胰岛素分泌反应，建立了C3a与β细胞来源的C3aR1之间的信号轴。胰岛蛋白质组学分析突出了β细胞中C3aR1缺失时的丝裂原活化蛋白激酶（MAPK）途径和线粒体功能障碍问题。最后，我们表明C3AR1与人胰岛中的胰岛素分泌呈正相关。
这些发现表明，β细胞上C3aR1的表达对于在T2D中维持最佳β细胞功能和保留β细胞数量是必要的。
