Alternative complement pathway regulation of beta cell homeostasis

2型糖尿病(T2 DM)已成为一种流行病。这种代谢性疾病的特点是胰岛素抵抗，伴随着β细胞数量和功能的进行性丧失。这种相对的胰岛素减少是由β细胞功能障碍和β细胞质量损失共同作用的结果。我们之前在T2 DM小鼠模型中发现脂肪因子脂肪蛋白，它在肥胖中减少，是胰岛β细胞功能的关键调节因子。Adipsin帮助产生C3a多肽，通过其受体C3aR1影响β细胞上的信号。我们的新数据显示，糖尿病db/db小鼠的慢性脂肪酶治疗可以避免糖尿病并发症--β细胞衰竭。Adipsin下调磷酸酶DUSP26，从而提高β细胞的存活率。在这项建议中，我们寻求对这些研究进行后续研究，并评估慢性脂肪酶治疗保护作用背后的机制。我们将追求以下特定目标：1.通过在小鼠中使用β细胞特异性C3aR1基因敲除来确定C3aR1受体在β细胞上的生理作用。我们将确定在体内维持β细胞稳态所需的C3aR1受体。2.明确磷酸酶DUSP26在调节β细胞特性和存活中的作用。这些研究的总体目标将阐明如何使用脂肪酶/C3a/C3aR1/DUSP26途径来维持长期的β细胞健康，从而治疗T2 DM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.