联合应用GPR119激活剂和DPP-IV抑制剂刺激Beta细胞再生的研究

The goal of this proposal is to investigate the novel therapeutic strategy of combining G protein-coupled receptor 119 (GPR119) agonist with dipeptidyl peptidase-IV (DPP-IV) inhibitor on stimulating beta cell regeneration and improving islet graft function in mouse models of human type 1 diabetes, and to investigate the relevant mechanisms of modulating inflammation to islets and stimulating β cell regeneration. Glucagon-like peptide-1 (GLP-1) stimulate insulin secretion, promote beta cell regeneration and prevent beta cell apoptosis. Activation of GPR119 by GPR 119 agonist stimulates GLP-1. However, GLP-1 have extremely short half-lives after secretion, because of their rapid degradation by DPP-IV. Therefore, inhibition of DPP-IV activity can potentially improve the therapeutic efficacy of GPR119 agonist. Our preliminary results indicated that NVP-DPP728, a DPP-IV inhibitor, has the dual potential to restore beta cell function in the setting of type 1 diabetes. Inhibition of DPP-IV activity by NVP-DPP728 reversed new-onset diabetes, reduced insulitis, increased regulatory CD4+CD25+Fox3+ T cells in pancreatic lymph nodes and thymus, and sustained beta cell mass in diabetic NOD mice. Therefore, inhibition of DPP-IV activity can also ameliorate autoimmunity to beta cells. We hypothesize that combined stimulation of GLP-1 and GIP release by GPR119 agonist and inhibition of DPP-IV activity by DPP-IV inhibitor not only promotes beta cell regeneration, but also ameliorates autoimmunity, thereby restoring normoglycemia in diabetic NOD mice. In Specific Aim #1, we will determine the effect of combined GPR 119 agonist and DPP-IV inhibitor treatment on reversing diabetes in NOD mice through modulating inflammation and stimulating beta cell regeneration. In Specific Aim #2, we will determine whether combined GPR 119 agonist and DPP-IV inhibitor treatment can stimulate beta cell replication in islet grafts in streptozotocin (STZ)-induced diabetic C57BL/6 mice and in spontaneously diabetic NOD mice under immunosuppression. In Specific Aim #3, we will determine the molecular mechanisms of restoring beta cell function in NOD mice treated with GPR 119 agonist and DPP-IV inhibitor, by integrating the technologies of laser capture microdissection (LCM) and RNA amplification with gene microarray analysis. Success in our proposed experiments would help us to develop a new therapeutic approach to treat patients with new-onset type 1 diabetes by ameliorating autoimmunity and promoting beta cell regeneration .

胰高血糖素样肽-1（GLP-1）可以刺激胰岛素分泌、促进β细胞再生和抑制β细胞凋亡。但由于半衰期极短，GLP-1分泌后迅速被二肽酶IV（DPP-IV）降解。研究表明，DPP-IV抑制剂可以逆转与人类1型糖尿病发病机制和临床症状相当类似的非肥胖型糖尿病（NOD）小鼠新生糖尿病、减少胰岛炎、上调胰腺周围淋巴结和胸腺中T调节细胞，并且可以扩大NOD小鼠β细胞团。我们的研究结果显示，G蛋白偶联受体119（GPR119）激活剂可以激活GPR119，促进GLP-1释放，刺激β细胞再生。本研究我们拟应用NOD小鼠模型和STZ诱发的糖尿病C57BL/6小鼠胰岛移植模型探讨联合应用GPR119激活剂和DPP-IV抑制剂是否可以刺激β细胞再生、减轻胰岛炎症反应、促进胰岛移植物的功能，用激光捕获显微切割和基因芯片技术探讨刺激β细胞再生的相关机制，为临床上提供可能逆转1型糖尿病的新方法。

胰高血糖素样肽-1（GLP-1）可以刺激胰岛素分泌、促进β细胞再生和抑制β细胞凋亡。但由于半衰期极短，GLP-1分泌后迅速被二肽酶IV（DPP-IV）降解。研究表明，DPP-IV抑制剂可以逆转与人类1型糖尿病发病机制和临床症状相当类似的非肥胖型糖尿病（NOD）小鼠新生糖尿病、减少胰岛炎、上调胰腺周围淋巴结和胸腺中T调节细胞，并且可以扩大NOD小鼠β细胞团。我们的研究结果显示，G蛋白偶联受体119（GPR119）激活剂可以激活GPR119，促进GLP-1释放，刺激β细胞再生。本研究主要内容：确定联合应用GPR 119激活剂和DPP - IV抑制剂通过刺激β细胞再生和调节炎症反应两个方面对逆转NOD小鼠糖尿病的作用；观察在链脲佐菌素（STZ）诱发的糖尿病C57BL/6小鼠中，GPR119激活剂和DPP- IV抑制剂的联合治疗是否可以进一步刺激移植的胰岛β细胞再生；探讨联合应用GPR119激活剂和DPP - IV抑制剂治疗NOD小鼠和STZ诱发的糖尿病C57BL/6小鼠糖尿病时β细胞再生的分子机制。我们应用NOD小鼠模型和STZ诱发的糖尿病C57BL/6小鼠胰岛移植模型，根据目前实验数据，已初步确定联合应用GPR 119激活剂和DPP - IV抑制剂通过刺激β细胞再生和调节炎症反应两个方面逆转NOD小鼠糖尿病的发展，可刺激β细胞再生，改善局部调节性T细胞的功能，改善NOD小鼠自身免疫反应。在链脲佐菌素（STZ）诱发的糖尿病C57BL/6小鼠同种胰岛移植中，GPR119激活剂和DPP- IV抑制剂的联合治疗可以刺激移植的胰岛β细胞再生。这为临床上通过胰岛移植技术，提供了可能逆转1型糖尿病的新方法。

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