The role of the mitochondrial GTP cycle in insulin secretion

线粒体 GTP 循环在胰岛素分泌中的作用

基本信息

批准号：
8913149
负责人：
Richard G Kibbey
金额：
$ 36.21万
依托单位：
YALE 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：
2011-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913149
关键词：
Address Cells Citric Acid Cycle Co-Immunoprecipitations Complex Cytosol Data Development Diabetes Mellitus Ensure Environment Enzymes Failure Gel Chromatography Gene Silencing Glucose Grant Guanosine Triphosphate Homeostasis Hydrolysis Hyperglycemia In Vitro Insulin Insulin Resistance Lead Liver Metabolic Metabolism Mitochondria Mitochondrial Matrix Modeling Molecular Molecular Target Mouse Strains Mus Oxaloacetates Pancreas Pathway interactions Phenotype Phosphoenolpyruvate Phosphoenolpyruvate Carboxylase Physiological Physiology Protein Isoforms Proteins Publishing Pyruvate Pyruvate Carboxylase Pyruvate Kinase Rattus Regulation Role Second Messenger Systems Series Signal Transduction Succinate-CoA Ligases Techniques Testing Tetanus Helper Peptide Transgenic Mice Work base blood glucose regulation design glucose metabolism in vivo innovation insight insulin secretion insulin signaling islet mouse model new therapeutic target prevent protein complex second messenger sensor

项目摘要

DESCRIPTION (provided by applicant): Failure of �-cells to secrete adequate insulin is essential for the development of diabetes mellitus. The long- term objectives of this grant are to elucidate the cellular mechanisms of �-cell glucose sensing by the mitochondrial GTP (mtGTP) cycle. This grant builds on our recent studies demonstrating a key role for mtGTP directly synthesized by the TCA cycle by the GTP-specific isoform of the enzyme succinyl CoA synthetase (SCS-GTP) as a sensor of glucose metabolism. The mtGTP is trapped within the mitochondria and must convert anaplerotic metabolites into PEP by the GTP-dependent mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) that then transmits the signal to the cytosol. Therefore, understanding the mechanism of this important signal and its role in the normal physiology of insulin secretion in vivo is the focus of this grant. Specifically it will assess the role of the mtGTP cycle by: 1) using two newly generated strains of mice with the inducible �-cell specific expression of SCS-GTP or SCS-ATP to study the impact of mtGTP synthesis on insulin secretion in vivo, 2) characterize the functional interaction of a complex formed by PEPCK-M and SCS-GTP, and 3) using a series of molecular short-circuits and leaks to assess the role of each of the components of the mtGTP cycle in insulin secretion. Based on strong preliminary data for all three aims that support an essential role for the mtGTP cycle in the regulation of glucose-stimulated insulin secretion, it is anticipated that the results of these studies will lead to important new paradigm shifting insights into the function of pancreatic �-cells that will lead to the rational development of novel therapeutic targets for either augmenting insulin secretion or preventing �-cell failure.

描述（由适用提供）：``细胞失败秘密胰岛素都对糖尿病的发展至关重要。该赠款的长期目标是通过线粒体GTP（MTGTP）循环阐明 - 细胞葡萄糖传感的细胞机制。这项赠款基于我们最近的研究，表明MTGTP由TCA循环直接通过GTP特异性同工型直接合成的MTGTP作为葡萄糖代谢的传感器。 MTGTP被困在线粒体内，必须通过磷酸烯醇丙酮酸羧化酶（PEPCK-M）的GTP依赖性线粒体同工型（PEPCK-M）转化为PEP，然后将信号传输到细胞质。因此，了解这种重要信号的机制及其在体内胰岛素分泌正常生理中的作用是该赠款的重点。具体而言，它将通过以下方式评估MTGTP周期的作用：1）使用两种新生成的小鼠菌株具有可诱导的scs-GTP或SCS-ATP的诱导型特异性表达来研究MTGTP合成对体内胰岛素分泌的影响，2）使用PEPC-GT和SCS-gt的功能相互作用，并表征pepc-gt和Scs-gt的功能相互作用，短路和泄漏以评估MTGTP周期在胰岛素分泌中的每个成分的作用。基于所有三个目标的强大初步数据，这些目标支持MTGTP周期在调节葡萄糖刺激的胰岛素分泌中的重要作用，预计这些研究的结果将导致重要的新范式转移范围的洞察力，以使胰腺的功能能够导致panceReatic-cell的功能。