G(alpha)Z signaling in insulin secretion and glucose tolerance

胰岛素分泌和葡萄糖耐量中的 G(α)Z 信号传导

基本信息

批准号：
8117983
负责人：
Michelle E Kimple
金额：
$ 5.05万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117983
关键词：
Address Adenylate Cyclase Age Animals Beta Cell Binding Blood Blood Glucose Bypass Cell Culture Techniques Cell Line Cell physiology Cells Complement Coupled Development Diabetes Mellitus Diet Drug Delivery Systems Event Exhibits Fatty acid glycerol esters Functional disorder GTP-Binding Protein alpha Subunits GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Glucose Glucose tolerance test Heterotrimeric GTP-Binding Proteins Homeostasis Insulin Insulin Resistance Islet Cell Islets of Langerhans Knockout Mice Knowledge Location Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Phenotype Physiological Physiological Processes Plasma Prostaglandins Proteins Regulation Research Resistance Role Signal Pathway Signal Transduction Societies Testing Variant Wild Type Mouse Work base glucose tolerance improved in vivo insight insulin secretion insulinoma islet mutant new therapeutic target receptor receptor coupling research study secretion process tool

项目摘要

DESCRIPTION (provided by applicant): It is currently appreciated that both insulin resistance and beta-cell dysfunction are early and essential events in the development of type 2 diabetes. Our current knowledge of factors that influence beta-cell function is lacking, despite research in this field having been conducted for several decades. To this end, we have recently shown that the heterotrimeric G-protein alpha-subunit, G{alpha}z, modulates an endogenous signaling pathway that is inhibitory to glucose-stimulated insulin secretion in an insulinoma cell line [Kimple et al. (2005) J Biol Chem 280:31708]. These results led to the hypothesis that loss of G{alpha}z activity would result in increased insulin secretion and improved beta-cell function in vivo, possibly protecting against the development of type 2 diabetes. In support of this hypothesis, we have performed preliminary experiments in which G{alpha}z-null mice, when compared to wild-type littermate controls, display increased plasma insulin concentrations and correspondingly decreased blood glucose levels during glucose tolerance tests. Furthermore, the increased plasma insulin levels observed in G{alpha}z-null mice are likely a direct result of enhanced insulin secretion, as pancreatic islets isolated from G{alpha}z-null mice exhibit significantly higher glucose-stimulated insulin secretion than those from wild-type mice. To further address our hypothesis, and our understanding of the role of G{alpha}z signaling in insulin secretion and islet cell function, we propose the following Specific Aims: (1) to delineate the signaling pathways upstream and downstream of G{alpha}z that are important for its inhibition of insulin secretion, (2) to determine at which step in the stimulated secretion process G{alpha}z is acting, and (3) to determine whether loss of G{alpha}z is protective against the development of diabetes, both age-induced and high-fat diet-induced. The results of these studies are expected to yield important new insights into the regulation of insulin secretion and beta- cell function at a molecular level, and may point to G{alpha}z as a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes. Relevance: This proposal aims to delineate the specific pathways by which a protein involved in the regulation of insulin secretion functions. How much insulin is secreted into the blood is one determinant of blood glucose levels; therefore, this project has direct relevance to diabetes.

描述（由申请人提供）：目前，人们对胰岛素抵抗和β细胞功能障碍都是早期和2型糖尿病发展的基本事件。尽管在该领域进行了数十年的研究，但我们目前缺乏影响β细胞功能的因素的知识。为此，我们最近表明，异源三聚体G蛋白α-亚基g {alpha} Z调节了一种内源信号通路，该信号通路是抑制葡萄糖刺激的胰岛素分泌中胰岛素瘤细胞系中的胰岛素分泌[Kimple等人[Kimple等。（2005）J Biol Chem 280：31708]。这些结果导致了以下假设：g {alpha}活性的丧失将导致胰岛素分泌增加并改善体内β细胞功能，从而可以防止2型糖尿病的发展。为了支持这一假设，我们进行了初步实验，与野生型同胞对照相比，g {alpha} z-null小鼠在葡萄糖耐受性测试中显示出增加的血浆胰岛素浓度，并相应地降低了血糖水平。此外，在G {alpha} z-null小鼠中观察到的血浆胰岛素水平升高可能是胰岛素分泌增强的直接结果，因为从G {alpha} Z-Null小鼠中分离出的胰岛胰岛细胞表现出明显更高的葡萄糖刺激的胰岛素分泌。为了进一步解决我们的假设，以及我们对g {alpha} z信号在胰岛素分泌和胰岛细胞功能中的作用的理解，我们提出以下具体目的：（1）描述G {alpha} Z上游的信号通路，这对于抑制胰岛素的抑制（2）的刺激（2），以确定iS exte z e e e e e e e e e e iS secletion n exteriation（2），该步骤均匀{2）表演，（3）确定g {alpha} z的丧失是否具有防止年龄诱导和高脂饮食诱导的糖尿病的发展。预计这些研究的结果将对分子水平的胰岛素分泌和β细胞功能的调节产生重要的新见解，并可能指出G {alpha} Z是旨在改善2型糖尿病中β细胞功能障碍的治疗剂的潜在新靶标。相关性：该建议旨在描述参与胰岛素分泌功能调节的蛋白质的特定途径。血液中分泌多少胰岛素是血糖水平的决定因素。因此，该项目与糖尿病有直接的相关性。