BETA-CELL EXHAUSTION AND GLUCOTOXICITY IN DIABETES

糖尿病中的β细胞耗竭和糖毒性

• 批准号: 8596231
• 负责人: Maria Sara Remedi
• 金额: $ 33.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596231
• 关键词: Address; Animal Model; Architecture; Automobile Driving; Beta Cell; Blood Glucose; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; Coupled; Cytoprotection; Defect; Depressed mood; Deterioration; Diabetes Mellitus; Diabetic mouse; Disease; Disease Progression; Event; Failure; Functional disorder; Genes; Glucose; Glycolysis; Goals; Human; Hyperglycemia; Imaging Techniques; In Vitro; Individual; Insulin; Lead; Mediating; Membrane; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pancreas; Pathogenesis; Pathology; Play; Production; Proteins; Reactive Oxygen Species; Role; Secretory Cell; Testing; Time; World Health; desensitization; diabetic; endoplasmic reticulum stress; exhaustion; gene therapy; glucose metabolism; in vivo; innovation; insulin secretion; islet; mitochondrial dysfunction; mitochondrial oxidative dysfunction; mouse model; neonatal diabetes mellitus; novel; protein phosphatase inhibitor-2; public health relevance; research study; response

DESCRIPTION (provided by applicant): Reduced pancreatic ¿-cell function and enhanced ¿-cell death are key events in the pathogenesis of diabetes mellitus. In normal conditions, the pancreatic ¿-cell responds to acutely elevated blood glucose with insulin secretion, and to persistently elevated blood glucose (hyperglycemia) with compensatory increase in insulin secretion and ¿-cell mass. Persistent hyperglycemia may also lead to paradoxical 'glucotoxic' pancreatic ¿-cell dysfunction, reduced ¿-cell mass and loss of insulin content, although underlying mechanisms remain incompletely defined. Chronic hyperglycemia will lead to hyperstimulated metabolism, membrane hyperexcitability and increased [Ca2+]i. It has been suggested that hyperexcitability, high [Ca2+]i and insulin hypersecretion may play a key role in ¿-cell desensitization and glucotoxicity. However, a mouse model of neonatal diabetes with genetically inexcitable ¿-cells and persistently low [Ca2+]I demonstrates a marked loss of insulin content, disruption of the pancreatic architecture and loss of ¿-cell mass over time. Thus, it is imperative to understand the independent contributions of hypermetabolism and hyperexcitability in ¿-cell pathology of T2DM. This mouse therefore provides a diabetic model in which to examine glucotoxic effects of hyperstimulated metabolism, independent of the normally coupled hyperexcitability and high [Ca2+]i. One major goal of this proposal to address this question using in vivo and in vitro approaches in these unique animal models. Hyperglycemia induces hyperstimulated metabolism and increased reactive oxygen species (ROS) formation, which can be detrimental for ¿-cells. Excessive ROS can induce mitochondrial dysfunction, and oxidative and endoplasmic reticulum (ER) stress, which are likely to be major contributors in pancreatic ¿-cell glucotoxicity. A second major goal of this proposal is therefore to address the question of what is driving the gradual reduction of ¿-cell mass in diabetes in vivo. I will specifically test whether the decrease in ¿-cell mass in underexcitability-driven diabetes is a consequence of glucotoxicity, wheher this effect is mediated by an increase in glucose metabolism and ROS production, and whether it involves mitochondrial dysfunction. In seeking answers to these questions, the experiments proposed in this project represent a significant effort to understand mechanisms underlying diabetic glucotoxicity and will be of direct relevance to the progression of human diabetes.

描述(由申请人提供)：胰腺细胞功能降低和细胞死亡增加是糖尿病发病机制中的关键事件。在正常情况下，胰腺细胞对急剧升高的血糖和胰岛素分泌的反应，以及对持续升高的血糖(高血糖)的反应，胰岛素分泌和细胞质量的代偿性增加。持续的高血糖也可能导致自相矛盾的“糖毒性”胰腺细胞功能障碍、细胞质量减少和胰岛素含量丧失，尽管潜在的机制仍不完全清楚。慢性高血糖可导致细胞代谢亢进、膜高兴奋性和[Ca~(2+)]i升高，提示高兴奋性、高[Ca~(2+)]i和胰岛素高分泌可能在细胞脱敏和糖毒性中起关键作用。然而，具有遗传不兴奋细胞和持续低[Ca~(2+)]i的新生儿糖尿病小鼠模型显示，随着时间的推移，胰岛素含量显著减少，胰腺结构中断，细胞质量丢失。因此， 了解高代谢和高兴奋性在T2 DM细胞病理中的独立作用是十分必要的。因此，该小鼠提供了一种糖尿病模型，在该模型中，可以独立于正常耦合的高兴奋性和高[Ca~(2+)]i来检查过度刺激的代谢的糖毒性效应。本提案的一个主要目标是在这些独特的动物模型中使用体内和体外方法来解决这个问题。高血糖导致过度刺激的代谢和增加的活性氧(ROS)的形成，这可能是有害的细胞。过量的ROS可导致线粒体功能障碍以及氧化和内质网(ER)应激，这可能是胰腺细胞糖毒性的主要贡献因素。因此，这项提案的第二个主要目标是解决体内糖尿病细胞质量逐渐减少的驱动因素。我将专门测试兴奋性不足的糖尿病患者细胞质量的减少是否是糖毒性的结果，这种影响是否由葡萄糖代谢和ROS产生的增加所介导，以及是否涉及线粒体功能障碍。为了寻求这些问题的答案，本项目中提出的实验代表了理解糖尿病糖毒性的潜在机制的重大努力，并将与人类糖尿病的进展直接相关。