肝细胞过度糖异生是Ⅱ型糖尿病(T2D)的关键病理机制，而巨噬细胞M1极化可持久激活肝细胞糖异生。.HSPA12A是HSP70家族新成员。在前1项国家自然基金研究中，我们发现：HSPA12A在T2D病人肝脏巨噬细胞中表达增加，而巨噬细胞HSPA12A基因沉默则减轻高脂喂养诱导的T2D，且该作用可能是通过“抑制肝脏巨噬细胞M1极化、减少其exosome中miR-203a含量，继而旁分泌地增加肝细胞Smile表达、逆转过度糖异生”信号系统而实现的。.本项目将在前期工作基础上，采用巨噬细胞特异性HSPA12A转基因鼠、基因敲除鼠，综合评价巨噬细胞HSPA12A基因沉默对T2D的保护作用；并结合细胞模型，阐明“巨噬细胞M1极化/exosome-miR-203a/肝细胞Smile/糖异生”信号系统在其中的作用，以明确其保护机制。研究结果将从“巨噬细胞-肝细胞”相互影响的角度，为防治T2D提供新的思路。

Over activation of hepatic gluconeogenesis is critical for the development of type 2 diabetes (T2D). Evidence has demonstrated that the hepatic gluconeogenesis is activated by M1 type of macrophages..HSPA12A is a new member of HSP70 family. During the last NSFC (81770854) studies, we observed that HSPA12A was upregulated in liver macrophages of T2D patients, whereas HSPA12A knockout in macrophages attenuated the high fat diet-induced T2D in mice. The pilot studies suggest that the action of HSPA12A deficiency could be mediated by suppressing M1 macrophage polarization to reduce macrophage-derived exosome contained miR-203a, which in turn activates the Smile-mediated suppression of gluconeogenesis in hepatocytes through a paracrine mechanism..To test this possibility, we will comprehensively evaluate the protection of HSPA12A deficiency from T2D using macrophage-specific HSPA12A transgenic and knockout mice. We will also investigate whether the protection of macrophage HSPA12A deficiency against T2D is achieved by suppressing “M1 macrophage polarization/miR-203a/hepatocyte Smile/gluconeogenesis” signaling axis by using both mice and cell culture models. The results will provide novel clues for identifying potential targets of T2D based on the inter-cellular interactions of “macrophage - hepatocyte”.