2型糖尿病胰岛β细胞功能调控新靶点IMPACT的功能及作用机制研究

The pancreatic beta cell dysfunction played a key role during the development and outcome of type 2 diabetes, while hyperglycemia and hyperlipidemia are widely involved in this process. A series of studies had shown transcription factor PDX-1, which reduced under hyperglycemia and hyperlipidemia treatment, played important role in pancreatic beta cell maintenance. However, the underlying mechanism of PDX-1 reduction during hyperglycemia and hyperlipidemia is still largely unknown. Our previous study shown that glucose or palmitate stimulation could up-regulate IMPACT and down-regulate PDX-1 level, while interference of IMPACT could reverse PDX-1 level and also improve the pancreatic beta cell function. Therefore, we suppose that IMPACT may involved in the damage process of hyperglycemia and hyperlipidemia on beta cells, and this may act through PDX-1 reduction. So in the present study, we aim to demonstrate the effect of IMPACT on beta cell function maintenance using a series of molecular biology methods. And we will further explore the underlying mechanism of IMPACT-PDX-1 pathway that might be involved, trying to provide a potential target for the treatment of Type 2 diabetes in the furture.

胰岛β细胞功能损伤是影响2型糖尿病发生的主要因素之一，高血糖和高血脂广泛参与了这一过程。高糖和高脂刺激可降低转录因子胰十二指肠同源盒（PDX-1）的表达水平，而PDX-1在胰岛β细胞功能维持中发挥了重要作用。但高糖、高脂引起PDX-1水平降低的调控机制依旧有很多未知。我们的前期研究中发现，原始印记基因（IMPACT）在高糖、高脂刺激胰岛β细胞后表达升高，对其阻断可缓解高糖、高脂引起的PDX-1水平降低及胰岛β细胞功能损伤。由此，我们推测，IMPACT可能介导了高糖、高脂对PDX-1的调控作用，并且直接参与了对胰岛β细胞功能损伤的过程。该项目旨在借助于各种分子生物学的技术手段，研究IMPACT对胰岛β细胞功能的调控作用及潜在的调控PDX-1的作用机制。本项目的完成将有助于阐明高糖、高脂引起胰岛β细胞功能损伤的作用机制，并为2型糖尿病下胰岛β细胞的保护提供一个较为直接的作用靶点。

糖尿病是一类以胰岛功能损伤为特点的代谢性疾病，然而，高糖、高脂诱导的胰岛功能衰退的具体机制尚不完全清楚。前期发现：原始印记基因IMPACT的表达水平与高糖、高脂诱导胰岛β细胞功能损伤具有正相关，而在细胞水平敲低IMPACT可改善胰岛β细胞关键蛋白PDX-1的表达。据此提出假设：高糖、高脂刺激，可能通过升高IMPACT的表达，从而抑制PDX-1，进而抑制胰岛β细胞的功能。本项目在前期研究基础上，从体内和体外实验两个方面，通过GSIS、GTT以及免疫荧光、免疫组化等实验，明确IMPACT可在转录水平抑制Pdx-1基因的表达，而敲低IMPACT可改善高脂刺激导致的胰岛素分泌损伤。此外，我们还首次构建了IMPACT的可诱导的、胰岛β细胞特异性敲除鼠，进一步明确了其对胰岛β细胞功能的调控作用，为相关疾病的基因治疗提供了潜在的靶点。