胰岛巨噬细胞极化失衡（抗炎的M2表型减少而促炎的M1表型增加）在β细胞功能紊乱中具有重要的作用，但机制未明。胞葬是机体通过胞葬细胞吞噬、处理死亡细胞并将其清除的过程。作为最主要的胞葬细胞，巨噬细胞对死亡细胞的胞葬可调控其自身的极化：胞葬诱导巨噬细胞极化为抗炎的M2表型。我们前期研究显示，葡萄糖的衍生物糖化终末产物(AGEs)通过其受体RAGE产生氧化应激，诱导胰岛巨噬细胞促炎表型增加，损伤β细胞。我们还发现AGEs在体外可抑制凋亡β细胞的胞葬并使巨噬细胞抗炎标志物减少而促炎标志物增加。我们据此提出如下假说：AGEs可能与巨噬细胞表面的RAGE结合而抑制β细胞胞葬，从而诱导巨噬细胞极化失衡。本项目拟在细胞及动物水平对上述假说予以验证并探讨其分子机制。这些研究将代谢应激、凋亡、胞葬、胰岛炎症联系起来，不仅有助于解析糖尿病状态下胰岛巨噬细胞极化失衡的分子细胞机制，而且对探索新的干预靶点也有裨益。

Imbalanced polarization of islet macrophages (a high M1/M2 ratio of macrophages) plays important roles in islet inflammation and contributes to β cell dysfunction in type 2 diabetes, and the mechanisms have not been completely elucidated. Efferocytosis is the process by which apoptotic cells or dying cells are engulfed and digested by efferocytes. Macrophages are the most important efferocytes, which are largely responsible for efferocytosis of apoptotic cells. Efferocytosis is anti-inflammatory by nature, and induces macrophages reprogramming into anti-inflammatory M2 phenotype. Impaired efferocytosis have been proposed as a potential mechanism for the induction and maintenance of the inflammatory response. Our previous studies have shown that advanced glycation end products (AGEs), the glucose derivatives formed by non-enzymatic glycation, could induce oxidative stress and result in β cells apoptosis and islet inflammation through receptor for advanced glycation end products (RAGE) signaling. The role of RAGE in efferocytosis has been reported. Our recent in vitro studies showed that pretreatment of macrophages with AGEs, which competitively bind to RAGE, inhibited efferocytosis of apoptotic cells and therefore affected macrophages polarization. So, we propose that AGEs-RAGE axis may be involved in modulation of β cells efferocytosis and polarization of islet macrophages. In this project, we will verify the hypothesis at cellular and animal levels.