Regulation of Insulin Secretion by G6PC2

G6PC2 对胰岛素分泌的调节

基本信息

批准号：
8663897
负责人：
Richard M O'Brien
金额：
$ 34.52万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-23 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663897
关键词：
Address Affect Amino Acids Beta Cell Biological Assay Blood Glucose Calcium Oscillations Cardiovascular system Cells Clinical Data Development Diabetes Mellitus Enzymes Excision Exercise Fasting Futile Cycling Generations Genes Glucokinase Glucose Glucose-6-Phosphate Goals Hemoglobin Hemoglobin A Human Hydrolysis Hypoglycemia In Situ In Vitro Individual Islets of Langerhans Kinetics Knockout Mice Link Metabolic Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Physiological Play Prevention Proteins Regulation Rest Risk Role Structure Testing Tracer Variant attenuation base biophysical techniques blood glucose regulation cardiovascular risk factor diabetes risk fasting blood glucose level genome wide association study glucose production glucose sensor glucose-6-phosphatase in vitro Assay in vivo innovation insight insulin secretion islet mortality novel novel strategies relating to nervous system research study response selective expression sensor tool

项目摘要

DESCRIPTION (provided by applicant): Genome wide association (GWA) studies have linked the G6PC2 gene to variations in fasting blood glucose (FBG) and hemoglobin A1C levels in humans, parameters that are associated with both the risk of type 2 diabetes and cardiovascular-associated mortality. The overall objective of this application is to build on the results of these GWA studies by determining the function of G6PC2. Our preliminary data show that the human G6PC2 gene is selectively expressed in pancreatic islet beta cells and that G6PC2 hydrolyzes glucose-6-phosphate (G6P). Based on these data our first hypothesis is that the glucose-6-phosphatase activity of G6PC2 opposes the action of glucokinase (GCK), which catalyses the conversion of glucose to G6P. Glycolytic flux has been shown to determine the S {0.5} of glucose-stimulated insulin secretion (GSIS) and the existing paradigm in the islet field proposes that GCK alone is the beta cell glucose sensor. The significance of our observations is that they challenge this paradigm and suggest that G6PC2 is a fundamental inhibitory component of that sensor. Instead we propose that a GCK/G6PC2 futile cycle acts as the beta cell glucose sensor determining glycolytic flux and the S{0.5} of GSIS. Additional preliminary data show that the mouse G6pc2 gene is also selectively expressed in pancreatic islet beta cells and that G6pc2 also hydrolyzes G6P. This suggests that the use of G6pc2 knockout (KO) mice represents an innovative and appropriate tool to study the function of G6PC2. Deletion of the mouse G6pc2 gene results in reduced FBG levels, consistent with the human GW A study data. But in addition we have found that deletion of the G6pc2 gene also results in exercise intolerance, characterized by hypoglycemia and inappropriately high GSIS. Based on these data our second hypothesis is that the GCK/G6PC2 futile cycle is physiologically important for the attenuation of insulin secretion during exercise. Neural inputs to the islet are activated during exercise and the existing paradigm in the islet field proposes that these inputs inhibit insulin secretion by hyperpolarizing the beta cell and also directly inhibiting the exocytotic machinery. The significance of our observations is that they challenge this paradigm and suggest that G6PC2 is a fundamental component of the machinery through which GSIS is inhibited during exercise. As with the control of FBG and hemoglobin AIC, this topic is also clinically important because exercise induced hypoglycemia is a major problem in individuals with diabetes that limits the duration and hence the beneficial effects of exercise. The goal of this proposal is to test our two hypotheses. The application is divided into two matching Specific Aims. Aim I explores the function of G6pc2 at a molecular level whereas Aim 2 explores the physiological importance of the Gck/G6pc2 futile cycle for the attenuation of insulin secretion during exercise.

描述（由申请人提供）：基因组广泛的关联（GWA）研究将G6PC2基因与人类的空腹血糖（FBG）和血红蛋白A1C水平的变化联系起来，与2型糖尿病的风险和心血管 - 心血管疾病的风险相关的参数。该应用程序的总体目的是通过确定G6PC2的功能来基于这些GWA研究的结果。我们的初步数据表明，人G6PC2基因在胰岛β细胞中有选择地表达，而G6PC2水解了葡萄糖-6-磷酸（G6P）。基于这些数据，我们的第一个假设是G6PC2的葡萄糖-6-磷酸酶活性反对葡萄糖酶（GCK）的作用，葡萄糖酶（GCK）催化葡萄糖转化为G6P。糖酵解通量已被证明可以确定葡萄糖刺激的胰岛素分泌（GSIS）的S {0.5}，并且胰岛场中的现有范式表明，单独的GCK是β细胞葡萄糖传感器。我们观察的意义在于它们挑战了这一范式，并表明G6PC2是该传感器的基本抑制成分。取而代之的是，我们建议GCK/G6PC2徒劳的循环充当β细胞葡萄糖传感器确定GSIS的糖酵解通量和S {0.5}。其他初步数据表明，小鼠G6PC2基因在胰岛β细胞中也有选择地表达，并且G6PC2还水解G6P。这表明使用G6PC2敲除（KO）小鼠代表了研究G6PC2功能的创新且适当的工具。小鼠G6PC2基因的缺失导致FBG水平降低，与人类GW A研究数据一致。但是此外，我们发现G6PC2基因的缺失也导致运动不耐受，其特征是低血糖和不当GSIS。基于这些数据，我们的第二个假设是GCK/G6PC2徒劳的周期在运动过程中对胰岛素分泌的衰减在生理上很重要。胰岛的神经输入在运动过程中被激活，胰岛场中的现有范式提出，这些输入通过超极化β细胞抑制胰岛素分泌，也直接抑制胞胞胞菌机械。我们观察的意义在于它们挑战了这一范式，并表明G6PC2是运动过程中GSIS抑制GSIS的基本组成部分。与FBG和血红蛋白AIC的控制一样，该主题在临床上也很重要，因为运动诱发的低血糖是糖尿病患者的主要问题，它限制了持续时间，从而对运动的有益作用。该提案的目的是检验我们的两个假设。该应用程序分为两个匹配的特定目标。 AIM I探讨了G6PC2在分子水平上的功能，而AIM 2探讨了GCK/G6PC2在运动过程中胰岛素分泌的衰减的生理重要性。