BETA-CELL EXHAUSTION AND GLUCOTOXICITY IN DIABETES
糖尿病中的β细胞耗竭和糖毒性
基本信息
- 批准号:8690841
- 负责人:
- 金额:$ 33.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAnimal ModelArchitectureAutomobile DrivingBeta CellBlood GlucoseCell DeathCell physiologyCellsCessation of lifeChronicCoupledCytoprotectionDefectDepressed moodDeteriorationDiabetes MellitusDiabetic mouseDiseaseDisease ProgressionEventFailureFunctional disorderGenesGlucoseGlycolysisGoalsHumanHyperglycemiaImaging TechniquesIn VitroIndividualInsulinLeadMediatingMembraneMetabolicMetabolismMitochondriaModelingMolecularMusNon-Insulin-Dependent Diabetes MellitusOxidative StressPancreasPathogenesisPathologyPlayProductionProteinsReactive Oxygen SpeciesRoleSecretory CellTestingTimeWorld Healthdesensitizationdiabeticendoplasmic reticulum stressexhaustiongene therapyglucose metabolismin vivoinnovationinsulin secretionisletmitochondrial dysfunctionmitochondrial oxidative dysfunctionmouse modelneonatal diabetes mellitusnovelprotein phosphatase inhibitor-2public health relevanceresearch studyresponse
项目摘要
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<$-细胞对急性升高的血糖有胰岛素分泌反应,对持续升高的血糖(高血糖症)有胰岛素分泌和<$-细胞质量的代偿性增加反应。持续性高血糖也可能导致矛盾的“葡萄糖毒性”胰腺细胞功能障碍,减少细胞质量和胰岛素含量的损失,尽管潜在的机制仍然不完全确定。慢性高血糖会导致代谢过度刺激、细胞膜过度兴奋和[Ca 2 +]i升高。已经表明,过度兴奋,高[Ca 2 +]i和胰岛素分泌过多可能在细胞脱敏和葡萄糖毒性中起关键作用。然而,具有遗传上不可兴奋的<$-1细胞和持续低[Ca 2 +]I的新生儿糖尿病小鼠模型显示出胰岛素含量的显著损失、胰腺结构的破坏和<$-1细胞质量随时间的损失。因此,在本发明中,
必须了解高代谢和高兴奋性在T2 DM的细胞病理学中的独立作用。因此,该小鼠提供了一种糖尿病模型,在该模型中检查了过度刺激的代谢的葡萄糖毒性作用,其独立于正常偶联的过度兴奋性和高[Ca 2 +]i。该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。高血压诱导过度刺激的代谢和增加的活性氧(ROS)形成,这可能是有害的?-细胞。过量的ROS可诱导线粒体功能障碍以及氧化和内质网(ER)应激,这可能是胰腺细胞葡萄糖毒性的主要贡献者。因此,该提案的第二个主要目标是解决是什么驱动体内糖尿病中的细胞质量逐渐减少的问题。我将专门测试在低兴奋性驱动的糖尿病中,细胞质量的减少是否是葡萄糖毒性的结果,这种效应是否是由葡萄糖代谢和ROS产生的增加介导的,以及它是否涉及线粒体功能障碍。在寻求这些问题的答案时,本项目中提出的实验代表了理解糖尿病葡萄糖毒性机制的重要努力,并将与人类糖尿病的进展直接相关。
项目成果
期刊论文数量(0)
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Maria Sara Remedi其他文献
HMR 1098 is not an Sur Isotype Specific Inhibitor of Sarcolemmal or Heterologous K<sub>ATP</sub> Channels
- DOI:
10.1016/j.bpj.2009.12.742 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Haixia Zhang;Alejandro Akrouh;Harley T. Kurata;Maria Sara Remedi;Colin G. Nichols - 通讯作者:
Colin G. Nichols
Maria Sara Remedi的其他文献
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{{ truncateString('Maria Sara Remedi', 18)}}的其他基金
Beta-Cell Exhaustion and Glucotoxicity in Diabetes
糖尿病中的β细胞耗竭和糖毒性
- 批准号:
10618246 - 财政年份:2020
- 资助金额:
$ 33.06万 - 项目类别:
Beta-Cell Exhaustion and Glucotoxicity in Diabetes
糖尿病中的β细胞耗竭和糖毒性
- 批准号:
10399636 - 财政年份:2020
- 资助金额:
$ 33.06万 - 项目类别:
Beta-Cell Exhaustion and Glucotoxicity in Diabetes
糖尿病中的β细胞耗竭和糖毒性
- 批准号:
10200803 - 财政年份:2020
- 资助金额:
$ 33.06万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 33.06万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 33.06万 - 项目类别:
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