Mea6基因缺失导致糖尿病的机制研究

Diabetes mellitus is a common metabolic disease with high blood sugar levels over a prolonged period and affects the health of many people. Insulin is the principal hormone that regulates the metabolism of carbohydrate, fat and protein by promoting the uptake of glucose from the blood into most cells of the body and by inhibiting the synthesis of glucose. Insulin is a small peptide hormone produced by β cells in the pancreatic islets. In the ER the proinsulin folds into the correct conformation and is transported to the Golgi where mature insulin is packaged into granules. We have shown recently that MEA6 interacts with components of the ER coat protein complex II (COP II) complex and regulates the formation of COPII. We and others have found that Mea6 is essential for the transportion of large cargos such as Collagen VII and very low density lipoprotein (VLDL). Through the generation of beta-cell-specific conditional knockout mice, we found that Mea6 is critical for insulin secretion and Mea6 deficiency leads to severe diabetes accompanied with low levels of insulin in the blood. In the present study, the physiological function and the underlying molecular mechanism of Mea6 in insulin biogenesis will be explored using gene knockout mouse model in combination with proteomics, cellular and biochemical techniques. This study will not only explore the pathogenesis of diabetes, but also provide a useful animal model and potential theoretical basis for the prevention and treatment of diabetes.

糖尿病是患者的血糖长期高于标准值的一种代谢性疾病，已成为影响人类健康的常见病。胰岛素是由胰岛β细胞分泌的，通过促进葡萄糖的利用和抑制葡萄糖的生成，维持血糖平衡。胰岛素前体—胰岛素原在内质网内进行折叠，通过衣被蛋白复合体II（COPII）从内质网运输到高尔基体。我们和其他研究组的研究表明，Mea6是调控COPⅡ复合物组装的关键因子, 在大分子物质胶原蛋白和极低密度脂蛋白的分泌过程中起作用。我们的延续性工作发现在胰腺的胰岛β细胞中特异敲除Mea6以后小鼠葡萄糖不耐受, 血清胰岛素的水平显著降低, 导致糖尿病的发生。这提示Mea6可能也参与了小分子多肽—胰岛素的分泌。基于以上发现，本研究将利用Mea6基因敲除的小鼠模型，在分子细胞和生理水平研究Mea6在胰岛素生物合成和运输过程中的具体作用及相关分子机制，进一步促进对糖尿病发病机理的了解，并为糖尿病的治疗提供动物模型及潜在的理论依据。

脑脊膜瘤表达性抗原MEA6主要定位在内质网蛋白质分泌泡，并参与大分子物质胶原蛋白和极低密度脂蛋白从内质网到高尔基体的运输过程。我们构建了Mea6在胰腺β细胞中特异性敲除的小鼠模型。结果发现Mea6在胰腺β细胞中特异性敲除后造成了内质网应激反应，胰岛素合成减少，血糖升高，从而导致小鼠严重的葡萄糖不耐受性。通过对分子机制进行探索，我们发现MEA6与Sec22B之间存在相互作用，并且MEA6与Sec22B之间的相互作用在胰岛素原运输过程中起了很重要的作用。除此之外，我们观察到人源MEA6转基因小鼠不仅可以挽救Mea6敲除小鼠中破坏的胰岛结构，还可以很好地挽救Mea6敲除小鼠中胰岛素合成障碍以及葡萄糖不耐受性的表型。总之，我们发现MEA6不仅在大分子物质的运输中起作用，在小分子物质胰岛素原的运输中也起了很重要的作用，使我们进一步地了解了胰岛素原囊泡运输的分子机制。该小鼠可以作为糖尿病模型应用在治疗药物的筛选上。