GLP-1水平降低导致的胰岛功能缺陷是2型糖尿病(T2DM)发生和进展的重要原因。GLP-1产生包括合成、剪切和分泌,过程复杂,调节机制不清楚。迄今对TRPM5的功能及其与GLP-1产生的关系知之甚少。我们前期观察表明T2DM患者L 细胞内钙信号异常与TRPM5表达及GLP-1的产生减少相关联。因此，我们提出T2DM时TRPM5介导的细胞内钙信号改变可减少肠道L细胞的GLP-1产生。为证实上述假说，我们拟采用钙信号分析、膜片钳、组织病理学、药理学及多种分子生物学手段如定量RT-PCR,RNAi,基因过表达、免疫印迹等技术从T2DM大鼠体内和体外培养L细胞的水平上，探讨T2DM肠道L细胞的TRPM5通道在GLP-1合成、剪切、分泌调节中的作用，明确TRPM5在调控GLP-1产生中的作用机制。本研究有助于丰富对T2DM的L细胞功能缺陷的病理生理的认识，为建立T2DM新的治疗靶点提供理论依据。

Impaired pancreatic beta-cell function, due to decreased levels of glucagon-like peptide-1 (GLP-1) in circulation, is an important cause of the onset and progress of type 2 diabetes mellitus (T2DM). The production of GLP-1 is a complex process, including synthesis, cleavage and exocytosis, and their regulatory mechanisms remain unclear. To date, little is known about the function of transient receptor potential cation channel subfamily M member 5(TRPM5))and their relationship with GLP-1 production. Previous studies from our groups indicate that cytosolic calcium signaling abnormalities are associated with impaired TRPM5 channels expressions and GLP-1 production in intestinal L cells in T2DM patients. Therefore, we assume that alteration of TRPM5-mediated cytosolic calcium signals may impair GLP-1 production in intestinal L cells in T2DM. To verify the above hypothesis, in this study we plan to investigate the role of TRPM5 in regulation of GLP-1 synthesis, cleavage and exocytosis in L cell in high-fat diet-fed and low dose of streptozotocin-induced T2DM rats and murine GLUTag L cells cultured in vitro, using various methods and technologies, which include calcium signals analysis, patch clamp, histopathology, pharmacology and several molecular biology, such as quantitative real-time RT-PCR, RNA interference, gene overexpession, western blotting, et al. This study contributes to deepening our knowledge and understanding on the physiopathologic defects of intestinal L cells in T2DM. It will be provide theoretical basis for establishing a novel therapeutic target for T2DM.