BETA-CELL EXHAUSTION AND GLUCOTOXICITY IN DIABETES

糖尿病中的β细胞耗竭和糖毒性

• 批准号: 8856559
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856559
• 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; Health; 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; 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的关键事件。在正常情况下，胰腺细胞对急性血糖升高的反应是胰岛素分泌，对持续升高的血糖（高血糖）的反应是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减少，尽管潜在的机制尚未完全确定。慢性高血糖会导致代谢过度刺激、膜过度兴奋和[Ca2+]i升高。高兴奋性、高[Ca2+]i和胰岛素分泌可能在细胞脱敏和糖毒性中起关键作用。然而，新生儿糖尿病小鼠模型的遗传不可兴奋的-细胞和持续低[Ca2+]I显示胰岛素含量的显著损失，胰腺结构的破坏和-细胞质量的损失随着时间的推移。因此,