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

• 批准号: 7582333
• 负责人: Michelle E Kimple
• 金额: $ 10.34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/7582333
• 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

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）： 目前人们认识到胰岛素抵抗和β细胞功能障碍是2型糖尿病发展中的早期和重要事件。尽管该领域的研究已经进行了几十年，但我们目前对影响 β 细胞功能的因素仍缺乏了解。为此，我们最近证明异三聚体 G 蛋白 α 亚基 G{alpha}z 调节内源性信号通路，抑制胰岛素瘤细胞系中葡萄糖刺激的胰岛素分泌 [Kimple 等人，2017]。 (2005) J Biol Chem 280:31708]。这些结果导致了这样的假设：G{alpha}z 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，可能预防 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，其中与野生型同窝对照小鼠相比，G{alpha}z 缺失小鼠在葡萄糖耐量测试期间表现出血浆胰岛素浓度升高和血糖水平相应降低。此外，在 G{α}z 缺失小鼠中观察到的血浆胰岛素水平增加可能是胰岛素分泌增强的直接结果，因为从 G{α}z 缺失小鼠中分离的胰岛表现出比野生型小鼠显着更高的葡萄糖刺激胰岛素分泌。为了进一步阐明我们的假设，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标：(1) 描绘 G{alpha}z 上游和下游对其抑制胰岛素分泌很重要的信号通路，(2) 确定 G{alpha}z 在刺激分泌过程中的哪一步发生 (3) 确定 G{alpha}z 的损失是否可以预防糖尿病的发展，无论是年龄引起的还是高脂肪饮食引起的。这些研究的结果预计将在分子水平上对胰岛素分泌和β细胞功能的调节产生重要的新见解，并可能指出G{alpha}z作为旨在改善2型糖尿病β细胞功能障碍的治疗的潜在新靶点。相关性：该提案旨在描述参与调节胰岛素分泌功能的蛋白质的具体途径。血液中分泌的胰岛素量是血糖水平的决定因素之一。因此，该项目与糖尿病有直接关系。