胰岛β细胞增殖、代偿性增生是胰岛素抵抗状态等病理状态下维持机体糖调节稳态的重要机制。促进现有β细胞增殖，增加内源性胰岛素分泌水平是糖尿病重要的潜在治疗靶点和研究热点。我们前期研究发现，丙酮酸羧化酶（PC）在高脂饮食，孕期等胰岛素抵抗状态小鼠β细胞表达上调；PC过表达促进体外β细胞增殖；PC通过上调成熟MDM2mRNA表达抑制p53蛋白表达水平；我们还建立了PC胰岛β细胞选择性敲除小鼠模型和p53胰岛β细胞选择性敲除小鼠模型，并初步观察了β细胞功能和糖代谢的特征。因此，PC很可能参与β细胞增殖调控的重要机制。我们将分别从动物、细胞、分子水平，进一步明确PC对β细胞增殖功能的影响作用，确定MDM2-p53通路在其中的作用环节，以及PC作为新型RNA结合蛋白对MDM2进行转录后调控的具体机制。研究结果将阐明PC-MDM2-p53自反馈通路调控胰岛β细胞增殖功能的机制，为防治2型糖尿病提供新靶点。

Type 2 diabetes mellitus (T2DM) and its complications are becoming a major global health burden. β-cell proliferation and compensatory hyperplasia is an important mechanism under the pathological conditions, including insulin resistance, and contributes to maintaining the glucose homeostasis. It is an important potential therapeutic target for diabetes to promote the proliferation of existing β cell, increase the levels of endogenous insulin level, and protect against hyperglycemia. Although β cell proliferation dysfunction has been shown to impair β-cell function, the underlying mechanism remains unclear. A thorough understanding of the pathogenesis of β-cell failure will help to develop more therapeutic strategies against diabetes by relieving metabolic stress in β-cells. Pyruvate carboxylase (PC) is one of the key enzymes from Krebs cycle in mitochondrial, thereby regulates insulin secretion in β cell. Apart from these established roles, recently, we showed that PC is activated in β-cell of high fat diet induced obese mice and female pregnant mice under the insulin resistant condition. Overexpression of PC may induce β cell proliferation, and glucose induced β cell proliferation may blocked by PC knockdown in MIN6 β cell. Such a defect is perhaps due to aberrant effect of PC to MDM2-p53 signaling pathway, especially on the mature MDM2 mRNA level. Based on these findings, we proposed that that a tight control of the PC and its downstream MDM2-p53 axis is important for maintaining β-cell proliferation function. In the early stage of insulin resistance, short term of metabolic stress (eg. obesity or nutrient overload) may induce PC, suppress p53 expression via MDM2, thereby promote β cell proliferation. However, defection of PC may cause β-cell proliferation dysfunction, and result in diabetes in the condition of insulin resistance. In this project, we will test whether genetic deletion of PC in β-cells results in an impaired adaptive β cell proliferation, leads to decreased β cell mass, and causes the onset of severe diabetes phenotype in insulin resistance animal model. In addition, we will investigate the role of PC on β cell proliferation by modulating a novel PC downstream MDM2-p53 signaling pathway. We will also investigate whether inactivation of p53 in β-cells can alleviate PC deletion induced deleterious effects on β-cell proliferation function. The results will provide new insight into the fundamental mechanisms of β-cell function and regulation of β cell mass, and to shed new light on the pathogenesis of glucose dysregulation in diabetes. The unique mouse model established in this study will serve as a useful tool to identify and validate novel drug targets for the development of therapeutics to combat diabetes, one of the major chronic disease in China.