Regulatory Mechanisms of Insulin Secretion

胰岛素分泌的调节机制

• 批准号: 8288794
• 负责人: MEGAN A RIZZO
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288794
• 关键词: Acute; Alleles; Amputation; Binding; Biochemical; Blindness; Blood Glucose; Cells; Complex; Cytoplasm; Data; Defect; Diabetes Mellitus; Disease; Dissociation; Endoplasmic Reticulum; Functional disorder; Genetic; Glucokinase; Glucose; Goals; Health; Heart Diseases; Homeostasis; Hormones; Hyperglycemia; Imaging Techniques; In Vitro; Indium; Insulin; Islet Cell; Kidney Failure; Kinetics; Limb structure; Measures; Methods; Modeling; Molecular; Mutation; Nerve; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; Pancreas; Pathogenesis; Pathology; Physiological; Post-Translational Regulation; Property; Proteins; Reaction; Regulation; Research; Role; Secretory Vesicles; Signal Pathway; Signal Transduction; Stroke; Testing; Tissues; Translations; blood glucose regulation; fasting glucose; fluorescence imaging; glucagon-like peptide; glucose metabolism; incretin hormone; information gathering; insulin secretion; molecular dynamics; mutant; receptor; response

DESCRIPTION (provided by applicant): Sustained hyperglycemia from diabetes causes catastrophic damage to many organs and tissues. An emerging point of view is focused on the rise in blood glucose following a meal. These blood glucose levels can be very high, and the peak concentration is more predictive of end organ damage in diabetes than the more commonly measured fasting glucose levels. Complex physiological mechanisms exist to specifically handle the post-meal glucose load, and a breakdown in these mechanisms causes diabetes. The long term goal of this study is to understand the post-meal regulation of glucose stimulated insulin secretion from pancreatic beta-islet cells. Glucokinase (GK) sets the rate of insulin secretion, and acute post-translational regulation of GK through interaction with nitric oxide synthase (NOS) and reaction with nitric oxide have recently been proposed. However, the mechanisms that control GK interaction with NOS and the physiological role of GK regulation by nitric oxide are not understood. Specific Aim 1 will quantify the effect of nitrosylation on GK kinetics. Specific Aim 2 will use a domain swapping strategy to identify the sequence elements in GK essential to complex formation with NOS. Specific Aim 3 will identify cellular mechanisms used to control GK activation on secretory granules and Specific Aim 4 will test the hypothesis that regulation of GK by NOS is utilized for positive regulation of glucose-stimulated insulin secretion by a known post-meal incretin hormone, glucagon-like peptide 1. These studies will be accomplished using biochemical methods and fluorescence imaging techniques. This research will further understanding of the mechanisms that regulate nutrient-stimulated insulin secretion and are particularly relevant to understanding the pathogenesis of diabetes, since dysfunctional insulin secretion is one of the central abnormalities associated with type 2 diabetes. PUBLIC HEALTH RELEVANCE: Insulin is secreted from the pancreas in response to rising blood glucose levels, and the strength of the secretory response is controlled by hormones. This study will gather information relating to the mechanisms that hormones use to control the rate of insulin secretion, and determine the extent that dysfunction of a particular mechanism contributes to a specific genetic type of diabetes.

描述（由申请人提供）：糖尿病的持续高血糖症会对许多器官和组织造成灾难性损害。进餐后，新兴的观点集中在血糖的上升上。这些血糖水平可能非常高，并且峰值浓度比更常见的空腹葡萄糖水平更可预测糖尿病的终端器官损伤。存在复杂的生理机制，可以专门处理圆环后葡萄糖负荷，而这些机制的分解会导致糖尿病。这项研究的长期目标是了解胰腺β-伊斯兰细胞中葡萄糖刺激的胰岛素分泌的光后调节。葡萄糖激酶（GK）通过与一氧化氮合酶（NOS）（NOS）相互作用以及与一氧化氮的反应来设置胰岛素分泌的速率和GK的急性翻译后调节。然而，尚不清楚控制GK与NOS的相互作用以及一氧化氮调节的生理作用的机制。具体目标1将量化亚硝基化对GK动力学的影响。特定的目标2将使用域交换策略来识别GK中与NOS复杂形成必不可少的序列元素。具体目标3将确定用于控制分泌颗粒上GK激活的细胞机制，具体目标4将检验以下假设：NOS对GK的调节可用于对葡萄糖刺激的胰岛素分泌的阳性调节，这些胰岛素激素激素，胰糖蛋白激素，胰糖类样肽1。使用这些研究来实现这些研究。这项研究将进一步理解调节营养刺激的胰岛素分泌的机制，并且与了解糖尿病的发病机理特别相关，因为功能失调的胰岛素分泌是与2型糖尿病相关的核心异常之一。公共卫生相关性：胰岛素是从胰腺中分泌的，以响应血糖水平上升，而分泌反应的强度由激素控制。这项研究将收集与激素用于控制胰岛素分泌速率的机制有关的信息，并确定特定机制功能障碍有助于特定遗传类型的糖尿病的功能障碍。