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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：
7448114
负责人：
Michelle E Kimple
金额：
$ 9.02万
依托单位：
DUKE UNIVERSITY
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 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7448114
关键词：
Address Adenylate Cyclase Age Aging Animals Beta Cell Binding Blood Blood Glucose Bypass Cell Line Cell physiology Cells Complement Coupled Cultured Cells 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 Process 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 receptor receptor coupling research study secretion process therapeutic target 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.