THADA调控胰岛β细胞功能和存活参与2型糖尿病发生发展的作用及机制研究

2型糖尿病的发病基础是遗传和环境因素引起的胰岛β细胞功能缺陷及容量不足。THADA是2型糖尿病的重要易感基因，与人群胰岛素分泌的反应性密切相关，且可参与调节果蝇产热。但THADA在血糖稳态维持及2型糖尿病发病中的作用未知。我们前期工作首次发现：THADA全身性敲除小鼠的葡萄糖耐量显著改善，体内外葡萄糖刺激的胰岛素分泌增多且β细胞凋亡减少，伴有胰岛内质网钙含量及CAMKⅡ磷酸化的增加。据此我们提出假设：THADA敲除可通过激活内质网钙-钙调蛋白-CAMKⅡ信号轴引起β细胞功能增强、凋亡减少及活力增加，从而改善小鼠血糖稳态并延缓2型糖尿病的发生。本研究拟利用该基因β细胞特异性敲除小鼠及转录激活的β细胞系，结合高脂高糖饮食诱导的2型糖尿病小鼠模型，系统阐明THADA对糖代谢和胰岛β细胞的调控作用及其分子机制，为揭示2型糖尿病的发病机制提供理论依据，并为研发具有β细胞保护作用的降糖药物提供新靶点。

Genetic and environmental factor-induced defective pancreatic β-cell function and insufficient β-cell mass underlies the pathogenesis of type 2 diabetes mellitus (T2DM). As a key susceptible gene for T2DM，THADA is closely associated with the insulin secretory response of subjects. It is also involved in regulating thermogenesis of Drosophila. However, the role of THADA in the maintenance of glucose homeostasis and the development of type 2 diabetes is unknown. Our preliminary work for the first time uncovered that whole-body THADA-knockout mice exhibited significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion in vivo and ex vivo, as well as decreased β-cell apoptosis. Meanwhile the endoplasmic reticulum (ER) calcium store and CAMKⅡ phosphorylation were increased in islets. In view of the above, we propose that THADA knockout could enhance β-cell function, inhibit β-cell apoptosis and increase β-cell viability by activating the ER calcium-calmodulin-CAMKⅡ signaling axis, leading to improved glucose homeostasis and prevention of T2DM onset in mice. In this study we’ll use the β-cell-specific knockout mice and transcriptionally activated β-cell line, combined with high-fat-high-sucrose diet-induced type 2 diabetes mouse model, to systematically elucidate the regulatory effects of THADA on glucose metabolism and pancreatic β-cell, as well as its molecular mechanism. This will establish the theoretical basis for revealing the pathogenesis of T2DM, also provide new targets for the development of glucose-lowering drugs with β-cell protective effects.