脂肪细胞外泌体ANGPTL2蛋白结合胰岛β细胞MIB2介导β细胞功能障碍的机制研究

肥胖与2型糖尿病密切相关，最新研究表明脂肪细胞外泌体在调节β细胞功能中发挥重要作用。我们前期发现ANGPTL2在肥胖糖尿病患者血清外泌体中表达增加，在肥胖小鼠附睾脂肪组织的外泌体中亦表达上调，过表达ANGPTL2的脂肪细胞外泌体与β细胞共培养，可致β细胞分泌功能下降，维持β细胞功能的关键转录因子表达降低。但脂肪细胞外泌体ANGPTL2介导β细胞功能障碍的机制尚不明确。通过免疫共沉淀发现ANGPTL2与泛素连接酶MIB2存在相互作用，胰岛细胞敲除MIB2后可改善ANGPTL2介导的β细胞转录因子表达下调，据此我们提出：肥胖状态下脂肪细胞外泌体ANGPTL2通过与β细胞MIB2结合介导β细胞功能障碍的科学假设。本课题将从分子、细胞及动物水平，明确外泌体ANGPTL2对β细胞功能的影响，阐明ANGPTL2/MIB2如何调控β细胞转录因子介导β细胞功能障碍的分子机制，为防治肥胖糖尿病提供科学依据。

Obesity is closely related to type 2 diabetes. The latest research shows that adipocyte-derived exosomes play an important role in regulating islet β cell function. We previously found that ANGPTL2 was increased in circulating exosomes of obese diabetic patients, and it was also up-regulated in the adipocyte-derived exosome of the epididymal adipose tissue of obese mice. Upregulating ANGPTL2 in adipocyte and extracting exosomes then co-cultured with β cells, resulting in glucose stimulating insulin secretion decreases in βcells. The expression of key transcription factors that maintain β cell function were also decreases. However, the underlying mechanism of adipocyte-derived exosome ANGPTL2 mediates β-cell dysfunction remains unclear. Co-immunoprecipitation found that ANGPTL2 interacts with ubiquitin ligase MIB2. Blocking MIB2 in β-cell can inhibit ANGPTL2-mediated reduction of β-cell transcription factor expression. Based on this, we propose: adipocyte-derived exosome ANGPTL2 might combined with islet β-cell MIB2 mediated β-cell dysfunction in the obesity state. This study will clarify the effect of exosome ANGPTL2 on β-cell function from the molecular, cellular and animal levels, and clarify how ANGPTL2/MIB2 regulates the β-cell transcription factor mediated β-cell dysfunction, and provides scientific data for the prevention and treatment of obesity related diabetes.