近年来发现，胰岛局部存在DPP-4及其底物激素GLP-1、PYY等相组成的完整系统，这一系统对胰岛功能和胰岛的适应性变化发挥了重要作用。申请人在前期研究中发现，胰岛内DPP-4在糖尿病模型中不适当升高，且它可能是短程强化治疗胰岛保护作用的靶点，然而，这一微观系统的其变化规律和具体机制尚不明确。本研究将以高脂喂养诱导的糖尿病小鼠作为研究模型，首先通过纵向观察不同病程小鼠胰岛内DPP-4系统相关分子的的分布、活性及表达，明确其在糖尿病发生发展中的规律；随后拟对糖尿病小鼠进行早期强化治疗，探讨治疗对胰岛形态、胰岛素分泌功能、胰岛局部DPP-4和GLP-1、PYY的影响，分析胰岛内DPP-4系统的变化短程强化治疗胰岛功能保护机制等方面的作用。最后，项目将构建稳定高表达/低表达DPP-4的INS-1细胞株以验证上述发现，并研究其分子机制。预计结果将加深对2型糖尿病进展和短程强化治疗的胰岛内机制的了解，有助于为糖尿病的干预探索新的靶点。

In recent years, DPP-4 and its substrate peptides GLP-1 and PYY are discovered to localize within the islets, this system plays a important role in islet function and its adaptive response. We previously found that intra-islet DPP-4 elevated inappropriately in diabetes model, and its change may mediate the islet-protective effects of short-term intensive therapy, but the detailed mechanism remained unknown. This study will apply high-fat diet induced diabetes mouse as the study model. Firstly change of distribution, activity and expression of intra-islet DPP-4 system will be longitudinally observed during development of type 2 diabetes . Then early short-term intensive therapy will be performed. Changes in islet morphology, insulin secretion capacity and local DPP-4, GLP-1, PYY action will be analyzed to illustrate the role of intra-islet DPP-4 system in diabetes development and the mechanism of short-term intensive therapy. DPP-4 over-expression and DPP-4 knock-down INS-1 cells will be applied to confirm the findings and investigate the detailed pathways. Results of this study will enhance understanding of the intra-islet mechanism of type 2 diabetes as well as short-term intensive therapy, thereby providing new treatment targets for type 2 diabetes.