Molecular Basis of Antidiabetogenic Hormone Action

实验治疗学中的一个新主题涉及到胰升糖素样肽-1-(7-36)的使用。 降低血糖水平的酰胺(GLP-1)及其合成肽类似物(“胰岛素模拟物”) 在2型糖尿病患者中。GLP-1的这种作用至少部分是由于它能够刺激 位于朗格汉斯胰岛的胰岛β细胞分泌胰岛素。鉴于已建立的 GLP-1在糖尿病治疗中的重要性，我们的实验室有兴趣定义信号 β细胞GLP-1受体(GLP-1-R)的转导特性为此，我们将重点放在 新发现的信号机制，利用第二信使cAMP激活cAMP- 被指定为EPAD和Epac2(交换蛋白)的受调控的鸟核苷酸交换因子 由环状AMP直接激活)。我们的研究让我们假设GLP-1，一种提升营地的 激素，刺激钙依赖的胰岛素分泌，并且这种胰岛素调节作用不是通过中介实现的 简单地通过蛋白激酶A(PKA)，也可以通过EPAC。来检验我们关于推定角色的假设 EPAC在GLP-1-R介导的信号转导中的作用，本项目的具体目的是：1)确定 GLP-1使用Epad和/或Epac2通过钙离子诱导的钙离子过程来动员细胞内的钙离子 释放(CICR)，起源于内质网(ER)，可能涉及IP3受体或 Ryanodine受体，2)评估Rap家族GTP酶在内质网钙“1”过程中的作用 动员，特别强调RAP1作为连接激活的中介的潜在作用 EPAC对磷脂酶C-epsilon的刺激，以及3)确定一种新信号的性质 β细胞生长因子和受体酪氨酸激酶利用RAS GTP酶的机制 将Epac2重新招募到质膜，在那里Epac2与其可能的效应分子相互作用 磺脲类药物受体-1(SUR1)的存在。这条调查路线的相关性是完全显而易见的。 我们希望建立一种新型血液“抗糖尿病”特性的分子基础。 能激活GLP-1-R并刺激胰腺胰岛素分泌的降糖剂。

An emerging theme in experimental therapeutics concerns the use of glucagon-like peptide-1-(7-36)- amide (GLP-1) and its synthetic peptide analogs (the "incretin mimetics") to lower levels of blood glucose in Type 2 diabetic subjects. This action of GLP-1 results, at least in part, from its ability to stimulate the secretion of insulin from pancreatic beta cells located in the islets of Langerhans. Given the established importance of GLP-1 for the treatment of diabetes, our laboratory is interested in defining the signal transduction properties of the beta cell GLP-1 receptor (GLP-1-R). To this end, we have focused on a newly-discovered signaling mechanism that uses the second messenger cAMP to activate cAMP- regulated guanine nucleotide exchange factors designated as Epad and Epac2 (the Exchange Proteins directly Activated by Cyclic AMP). Our studies lead us to Hypothesize that GLP-1, a cAMP-elevating hormone, stimulates Ca2+-dependent insulin secretion, and that this insulinotropic action is mediated not simply by protein kinase A (PKA), but also by Epac. To test our Hypothesis concerning the putative role of Epac in GLP-1-R-mediated signal transduction, the Specific Aims of this project are to: 1) determine if GLP-1 uses Epad and/or Epac2 to mobilize intracellular Ca2+ via a process of Ca2+-induced Ca2+ release (CICR) that originates at the endoplasmic reticulum (ER) and which may involve IP3 receptors or ryanodine receptors, 2) assess what role Rap family GTPases play in the process of ER Ca2"1" mobilization, with special emphasis on the potential role of Rap1 as an intermediary linking activation of Epac to the stimulation of phospholipase C-epsilon, and 3) determine the nature of a novel signaling mechanism by which beta cell growth factors and receptor tyrosine kinases utilize the Ras GTPases to recruit Epac2 to the plasma membrane where an interaction of Epac2 with its putative effector molecule the sulfonylurea receptor-1 (SUR1) occurs. The Relevance of this line of investigation is fully apparent. We wish to establish the molecular basis for "antidiabetogenic" properties of a new class of blood glucose-lowering agents that activate the GLP-1-R and which stimulate pancreatic insulin secretion.