Alternative complement pathway regulation of beta cell homeostasis

2型糖尿病（T2DM）已成为一种流行病。这种代谢性疾病的特征是胰岛素抵抗，同时伴有β细胞数量和功能的逐渐丧失。这种相对的胰岛素减少是由细胞功能障碍和细胞质量损失共同造成的。我们之前发现脂肪因子脂素在肥胖中减少，是T2DM小鼠模型中胰腺β细胞功能的关键调节因子。Adipsin帮助生成C3a肽，通过受体C3aR1在β细胞上影响信号。我们的新数据表明，慢性脂嘧啶治疗糖尿病db/db小鼠可以避免β细胞衰竭的糖尿病并发症。Adipsin下调磷酸酶DUSP26，从而提高β细胞存活率。在本提案中，我们寻求跟进这些研究并评估慢性脂溶酶治疗保护作用背后的机制。具体目标是：在小鼠中使用β细胞特异性敲除C3aR1来确定C3aR1受体在β细胞上的生理作用。我们将确定C3aR1受体在维持体内β细胞稳态中的需求。2. 确定磷酸酶DUSP26在调节β细胞身份和存活中的作用。这些研究的总体目标将阐明如何利用adipsin/C3a/C3aR1/DUSP26通路来维持长期的β细胞健康以治疗T2DM患者。

Type 2 diabetes mellitus (T2DM) has become an epidemic. This metabolic disease is marked by insulin resistance in conjunction with progressive loss of beta cell number and function. This relative insulinopenia results from a combination of beta cell dysfunction and loss of beta cell mass. We previously identified the adipokine adipsin, which is reduced in obesity, as a critical regulator of pancreatic beta cell function in murine models of T2DM. Adipsin helps to generate the C3a peptide to effect a signal through its receptor C3aR1 on the beta cell. Our new data show that chronic adipsin treatment of diabetic db/db mice staves off the diabetic complication of beta cell failure. Adipsin downregulates the phosphatase DUSP26 which results in improved beta cell survival. In this proposal, we seek to follow up on these studies and assess the mechanisms behind the protective effects of chronic adipsin treatment. We will pursue the following specific aims: 1. Define the physiological role of the C3aR1 receptor on beta cells using a beta cell specific knockout of C3aR1 in mice. We will determine the requirement of the C3aR1 receptor in maintaining beta cell homeostasis in vivo. 2. Define the role of the phosphatase DUSP26 in regulating beta cell identity and survival. The overall goal of these studies will shed light on how the adipsin/C3a/C3aR1/DUSP26 pathway can be used to maintain long term beta cell health to treat patients with T2DM.