GPR120调控PDX1表达影响2型糖尿病胰岛β细胞功能的机制研究

胰岛素由胰岛β细胞合成并分泌，对机体血糖稳态的维持起着决定性作用。2型糖尿病的发生发展与胰岛β细胞功能障碍密切相关。研究发现，胰十二指肠同源盒1（PDX1），又称胰岛素转录因子1，对胰岛β细胞的功能和存活极为关键。我们前期研究发现激活G蛋白偶联受体120(GPR120)可提升PDX1的表达，促进胰岛素的转录和分泌，改善高脂诱导的胰岛β细胞功能障碍，但分子调控机制尚不清楚。项目拟采用小鼠胰岛细胞系、人胰岛细胞系、鼠原代胰岛，从细胞水平研究转录因子PPARγ和FoxO1在GPR120调控胰岛β细胞PDX1表达中的作用和机制，并选用GPR120敲除小鼠和db/db 2型糖尿病小鼠，施加GPR120激动剂与PPARγ激动剂或FoxO1抑制剂，在动物水平明确GPR120-PPARγ/FoxO1-PDX1因子网络对糖尿病胰岛β细胞功能的影响和机制，为临床上改善胰岛β细胞功能障碍提供理论依据。

Insulin is synthesized and secreted by pancreatic β cells, and plays a critical role in maintaining glucose homeostasis. The occurrence and development of type 2 diabetes is closely related to the dysfunction of pancreatic β cells. Previous studies have found that the insulin transcription factor pancreatic duodenal homeobox 1 (PDX1) is critical to maintaining the function and activity of pancreatic β cells. Our research has found that activation of G protein-coupled receptor 120 (GPR120) can increase the expression level of PDX1 that is down-regulated by lipotoxicity, promote insulin transcription and secretion, and improve pancreatic β-cell dysfunction induced by high fat diet, but the molecular regulation mechanism is still unclear. This project will start with the transcription factors PPARγ and FoxO1 of the Pdx1 gene, using mouse pancreatic islet cell line, human pancreatic islet cell line, to demonstrate the participation mechanism of PPARγ and FoxO1 in the process of how GPR120 regulates the expression of PDX1 in pancreatic β cells at the cellular levels, and using GPR120 knockout mice and db/db type 2 diabetic mice to clarify the effect and mechanism of the combined administration of GPR120 agonist and PPARγ agonist or FoxO1 antagonist on pancreatic β-cell dysfunction in type 2 diabetes, and provide a theoretical basis for improving β-cell function.