ANGPTL8调控骨髓脂肪代谢在増龄相关胰岛素抵抗中的作用及机制研究

2型糖尿病（T2D）患病率随年龄增加的机制并不完全清楚。ANGPTL8能促进甘油三酯的合成，导致其循环水平的升高和脂肪肝的形成。这提示ANGPTL8可能也会造成増龄相关性骨髓脂肪化和胰岛素抵抗（IR）。我们发现T2D患者血清ANGPTL8水平明显升高并与年龄及IR呈正相关；在连续传代的骨髓间充质细胞（BMSCs）和不同鼠龄小鼠骨髓冲洗液中ANGPTL8水平均随细胞代数和鼠龄而升高；在小鼠BMSCs中过表达ANGPTL8能促进BMSCs向脂肪细胞分化。本项目拟从以下方面研究ANGPTL8对骨髓脂肪化及増龄相关性IR的作用:（1）ANGPTL8对骨髓脂肪化的调节；（2）ANGPTL8调控骨髓脂肪化所形成的微环境对成骨细胞分化、凋亡和自噬的影响及分子机制。（3）ANGPTL8与骨髓脂肪沉积、骨钙素表达及増龄相关胰岛素抵抗之间的关系。这对于探讨增龄性IR和老年糖尿病的发病机制和防治具有重要意义。

The mechanism of increasing prevalence of type 2 diabetes (T2D) with ageing is not fully understood. It was reported that ANGPTL8 could promote triglyceride synthesis, increase its circulating levels and induce the development of fat liver. This may suggest that ANGPTL8 play an important role in the regulation of ageing-related bone marrow adipogenesis and the development of insulin resistance. Our previous study found that the serum levels of ANGPTL8 in T2D patients was significantly increased and its levels were positively related with age and insulin resistance. The levels of ANGPTL8 in cell culture media and bone marrow rinse were increased with cell passages (bone marrow derived mesenchymal stem cells, BMSCs) and age of mice, respectively. This project intends to investigate the role of ANGPTL8 in the regulation of bone marrow adipogenesis and its role in the development of ageing-related insulin resistance from the following aspects: (1) the effect of ANGPTL8 on bone marrow adipogenesis; (2) the effect of the adipogenesis microenvironment in bone marrow, which was regulated by ANGPTL8, on the differentiation, apoptosis and autophagy of osteoblasts; (3) the interaction of ANGPTL8 with bone marrow fat deposition, the expression of osteocalcin and age-related insulin resistance. The study may reveal the mechanisms of age-related insulin resistance and provide the useful information for prevention of senile diabetes.