Regulatory Mechanisms of Insulin Secretion

胰岛素分泌的调节机制

• 批准号: 8916674
• 负责人: MEGAN A RIZZO
• 金额: $ 36.46万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916674
• 关键词: Affect; Beta Cell; Biochemical; Biosensor; Blood Glucose; Cell model; Cells; Cellular Stress; Complex; Data; Defect; Depressed mood; Diabetes Mellitus; Diet; Endoplasmic Reticulum; Event; Failure; Fluorescence Resonance Energy Transfer; Funding; Gene Mutation; Genetic; Glucokinase; Glucose; Health; Hormonal; Hormones; Human; ITPR1 gene; Inositol; Insulin; Insulin Resistance; Lead; Life; Mediating; Molecular; Molecular Conformation; Molecular Structure; Mus; Nature; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Peripheral; Phase; Post-Translational Regulation; Proteins; Reaction; Regulation; Role; Stress; Structure of beta Cell of islet; Testing; Time; Tissues; Work; adapter protein; base; biochemical model; chemical reaction; design; diabetic; endoplasmic reticulum stress; glucose metabolism; glucose sensor; insulin secretion; islet; mouse model; novel; protein protein interaction; quantitative imaging; receptor; research study; structural biology; targeted treatment

DESCRIPTION (provided by applicant): Progression of type 2 diabetes mellitus tracks with the failure of pancreatic beta cells to compensate for peripheral insulin resistance. Loss of glucose sensitivity, particularly during the sharp rise in blood glucose that follows a meal, is strongly associated with peripheral tissue damage during diabetes. Yet the molecular mechanisms underlying defects in beta-cell glucose sensing during type 2 diabetes are not well understood. This proposal seeks critical information regarding the regulation of glucokinase, which is the glucose sensing protein in insulin-secreting beta cells. Work in the previous funding period focused on hormonal activation of glucokinase through chemical reaction with nitric oxide. These studies revealed important new connections between defects in glucokinase regulation and a genetic form of human diabetes. Even so, major questions remain concerning the mechanism of glucokinase activation and the impact of diabetes-related cell stress on glucokinase function. Three aims are proposed. Aim 1 will utilize a newly developed glucokinase biosensor to reveal the connection between cellular activation by nitric oxide and the underlying biochemical states suggested by its molecular structure. Aim 2 will focus on understanding the molecular mechanism that leads to glucokinase association with nitric oxide synthase, which is a critical interaction required for cellular activation of glucokinase. Experiments in this aim wil also reveal whether defects in glucokinase regulation may explain the association of NOS1AP gene mutations with human diabetes. Aim 3 will focus on the impact of diabetes-related cell stress on glucokinase activation. Our preliminary data show that impaired endoplasmic reticulum function disrupts glucokinase regulation. The planned studies seek to identify the mechanism behind this disruption, and test whether diet-related obesity can similarly disrupt glucokinase regulation. If so, these studies will provide a molecular explanation for inhibited glucose sensing during type 2 diabetes. In summary, these studies have the potential to unify cellular and biochemical models of glucokinase function, identify new molecular regulators of glucokinase activity, and will lead to new ideas about the molecular causes underlying the deficit in ß-cell glucose sensing observed in type 2 diabetes mellitus. Understanding the molecular events that worsen type 2 diabetes mellitus is vital for designing new therapies that target beta-cell glucose sensing.

描述（由适用提供）：2型糖尿病的进展，胰腺β细胞失败以补偿周围胰岛素抵抗。葡萄糖敏感性的丧失，尤其是在进餐后血糖急剧上升期间，与糖尿病期间的外周组织损伤密切相关。然而，在2型糖尿病期间β细胞葡萄糖敏感性中缺陷的分子机制尚不清楚。该提案寻求有关调节葡萄糖酶的关键信息，葡萄糖酶是葡萄糖酶传感蛋白在分泌胰岛素β细胞中。在上一个资金期间的工作重点是通过用一氧化氮化学反应对葡萄糖酶的激素激活。这些研究揭示了葡萄糖酶调节中缺陷与人类糖尿病的遗传形式之间的重要新联系。即便如此，主要问题仍然涉及葡萄糖酶激活的机制以及与糖尿病相关细胞应激对葡萄糖激酶功能的影响。提出了三个目标。 AIM 1将利用新开发的葡萄糖酶生物传感器来揭示一氧化氮的细胞激活与其分子结构所暗示的基本生化状态之间的联系。 AIM 2将集中于理解导致葡萄糖激酶与一氧化氮合酶的关联的分子机制，这是细胞激活葡萄糖激酶所需的关键相互作用。该目标的实验还将揭示葡萄糖酶调节中的缺陷是否可以解释NOS1AP基因突变与人糖尿病的关联。 AIM 3将集中于糖尿病相关细胞应激对葡萄糖酶激活的影响。我们的初步数据表明，内质网函数受损会破坏葡萄糖酶调节。计划的研究旨在确定这种破坏背后的机制，并测试与饮食相关的肥胖症是否可以类似地破坏葡萄糖酶调节。如果是这样，这些研究将为2型糖尿病期间抑制葡萄糖敏感性提供分子解释。总而言之，这些研究具有统一葡萄糖酶功能的细胞和生化模型，确定葡萄糖激酶活性的新分子调节剂，并将导致有关在2型2型糖尿病中观察到的ß细胞葡萄糖敏感性赤字差的分子原因的新观念。了解较差的2型糖尿病的分子事件对于设计靶向β细胞葡萄糖传感的新疗法至关重要。