本课题组前期研究发现：呈现高甘油三酯血症（HTG）的脂蛋白脂酶基因敲除杂合子（LPL+/-）小鼠通过脂毒性直接诱发了糖代谢紊乱；28周龄LPL+/-小鼠不同组织由脂质累积引起的胰岛素抵抗（IR）程度由重到轻为内脏脂肪>肝脏>骨骼肌，同时发现不同组织IR的脂毒性机制具有差别。因此LPL+/-小鼠各组织IR、全身IR和胰岛β细胞损伤的出现具有怎样的时间顺序？同一周龄LPL+/-小鼠各组织IR的程度差异如何？哪些脂毒性机制参与了LPL+/-小鼠糖代谢异常的发生过程？本课题在分子学水平上全面评价不同周龄LPL+/-小鼠全身IR、各组织IR、以及β细胞损伤情况，并分析相关的脂毒性机制，从而进一步探讨LPL+/-小鼠由脂毒性引发糖代谢异常的时间、空间特异性及其相关作用机制，动态观察LPL+/-小鼠由HTG进展为2型糖尿病的病理生理过程，并且探索贝特类药物能否延缓该小鼠发生糖代谢紊乱的病情进展。

Preliminary studies of our group have found that, lipoprotein lipase gene knockout heterozygous (LPL+/-) mice with hypertriglyceridemia (HTG) was directly induced disordered glucose metabolism by lipotoxicity; insulin resistance (IR) severity of different tissues caused by lipid accumulation of 28-week-old LPL+/- mice was visceral fat> liver> skeletal muscle followed by; and also there was not the same of lipotoxicity mechanism of IR in different tissues. Therefore, how is IR of different tissues, IR of the whole body, and β cell injury in chronological sequence of LPL+/- mice? For the same week-old LPL+/- mice, how is severity of IR in different tissues? What are the mechanisms of lipotoxicity involved in the process of abnormal glucose metabolism of LPL+/- mice? This subject evaluates IR of the whole body, IR of different tissues ,and β cell injury comprehensively on the molecular level, and also analyzes relevant lipotoxicity mechanisms to further discuss temporal and spatial characteristics and mechanisms of abnormal glucose metabolism caused by lipotoxicity and dynamically observe pathophysiological process to type 2 diabetes started with HTG of LPL+/- mice. And also we explore if fibrates can slow the progress of disordered glucose metabolism of LPL+/- mice.