京尼平苷促胰岛素分泌的葡萄糖依赖性特征及其离子通道调控机制研究

低血糖是2型糖尿病治疗中常见的不良反应。GLP-1受体激动剂是一类具有葡萄糖浓度依赖性的新型胰岛素促泌剂，不易引发低血糖，因而受到广泛重视。研究发现传统中药栀子的主要活性成分京尼平苷是一种新型GLP-1受体激动剂，具有较好的降糖作用。我们的研究也表明京尼平苷具有葡萄糖依赖性的促胰岛素分泌作用，显示了其在糖尿病治疗方面的良好前景，然而其作用机制仍待阐明。现已明确Kv通道在葡萄糖依赖性促胰岛素分泌中发挥着重要作用，我们的初步研究也显示京尼平苷具有阻断Kv通道的作用。结合当前对京尼平苷已有的研究结果，我们分析Kv通道以及cAMP/PKA信号通路在介导京尼平苷的促胰岛素分泌中发挥着重要作用。本项目拟采用膜片钳、钙成像、胰岛灌流以及动物在体实验等方法，深入研究京尼平苷的葡萄糖依赖性促胰岛素分泌机制，明确Kv通道在其中的关键作用，为开发以京尼平苷为基础的新型GLP-1类抗糖尿病药物提供理论依据。

Hypoglycemia is a common adverse reaction in the treatment of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of novel glucose-dependent insulin secretagogues, which have low risk leading to hypoglycemia. Thus,the development of new highly effective GLP-1 receptor agonists is the focus of the current antidiabetic research. Recent studies show that geniposide,an iridoid glycoside from the fruit of Gardenia jasminoides Ellis,is a novel agonist for GLP-1 receptor, and exertes hypoglycemic effect.Our data also demonstrate that geniposide glucose-dependently stimulate insulin secretion, indicating its good prospects in the treatment of diabetes.However, the mechanism underlying geniposide's insulinotropic effect remains to be elucidated.It is well established that voltage-dependent potassium (Kv) channels play an important role in glucose-dependent insulinotropic effect. And our preliminary study also showed that geniposide has inhibitory effect on pancreatic beta cell Kv channels. In combination with the findings that have been reported,we hypothesize that the Kv channel as well as cAMP / PKA signaling pathway play an important role in geniposide-mediated insulin secretion. Using patch clamp, calcium imaging, islet perfusion as well as animal in vivo experiments, present project intends to investigat the mechanism underlying geniposide's insulinotropic effect, and to elucidate the key role of Kv channel in the regulation of geniposide-mediaed glucose-dependent insulin secretion. The aim is to obtain a more comprehensive understanding of the hypoglycemic mechanism of geniposide, and provide new insight into the development of geniposide-based new GLP-1 receptor agonists for treatment of type 2 diabetes.