Alleviation of Glucotoxicity in Pancreatic Beta Cells

减轻胰腺β细胞的糖毒性

基本信息

批准号：
10454391
负责人：
DONALD K. SCOTT
金额：
$ 50.21万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454391
关键词：
Affect Alternative Splicing Antioxidants Apoptosis Apoptotic Beta Cell Binding Binding Proteins Carbohydrates Cell Death Cell Proliferation Cell Survival Cell physiology Cessation of life Diabetes Mellitus Diabetic mouse Drug Targeting Functional disorder Genes Genetic Transcription Glucose Human Hyperglycemia Insulin Insulin Resistance Lead Mediating Mediator of activation protein Metabolic Modeling Molecular Names Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Export Obesity Pathogenesis Pathway interactions Pharmacology Production Protein Isoforms Response Elements Rodent Rodent Model Series Signal Transduction Site Structure of beta Cell of islet Symptoms TXNIP gene Testing Therapeutic Intervention Toxic effect Type 2 diabetic blood glucose regulation diabetic exhaust exhaustion experience experimental study feasibility testing gain of function genetic approach glucose metabolism islet mouse model novel therapeutics overexpression preservation promoter targeted treatment therapeutic development therapeutic evaluation therapy design transcription factor

项目摘要

Summary Type 2 Diabetes (T2D) results from a combination of insulin resistance, most often brought about by obesity, and a gradual and unrelenting erosion of the ability of pancreatic beta cells to secrete sufficient insulin to meet the increased metabolic demand for insulin. A major mediator of beta cell dysfunction is glucose toxicity, mediated by sustained hyperglycemia. During the pathogenesis of T2D a vicious cycle ensues, where insulin resistance increases the demand for more insulin, but beta cells become “exhausted” and unable to secret enough insulin to maintain glucose homeostasis, leading to increased hyperglycemia, more beta cell exhaustion and death, erosion of beta cell mass, and eventually the need for insulin therapy. Therefore, there is an urgent need for new therapies that block the vicious cycle and preserve beta cell mass. We believe we have uncovered a molecular mechanism that explains the vicious cycle that erodes beta cell function and beta cell mass during T2D. This proposal will explore the molecular details of this mechanism and test the feasibility of therapeutic interventions that preserve rodent and human beta cells in models of glucose toxicity and T2D. The overarching hypothesis of this proposal is that the feed-forward mechanism of ChREBPβ expression becomes dysregulated in T2D and drives glucose toxicity through expression of the pro-oxidative activity of Txnip, the effects of which can be mitigated by the activation of Nrf2. Furthermore, maneuvers that break the vicious cycle of ChREBPβ production, or mitigate its actions through Txnip inhibition, or Nrf2 activation, protects beta cell mass and alleviates diabetic burden. This proposal will test this hypothesis by exploring the molecular regulatory mechanisms between these 3 factors, and by depleting either ChREBPβ or Txnip, or elevating NRF2, in mouse models of diabetes or glucotoxicity, or in glucotoxic or T2D human islets. Specific Aim 1 will explore the regulatory relationships between ChREBPβ, Txnip, and NRF2 that determine beta cell fate. Specific Aim 2 will examine how depletion of ChREBPβ, or Txnip, or activation of NRF2 affects beta cell function and glucose homeostasis in diabetic and glucotoxic mouse models. Specific Aim 3 will test if depletion of ChREBPβ, or TXNIP, or activation of NRF2 affects beta cell function and survival in glucotoxic or T2D human islets. Our results will inform the design of therapies that will mitigate beta cell glucose toxicity and may result in very specific drugs that target beta cells to preserve beta cell mass and function and alleviate diabetic symptoms and complications.

概括 2型糖尿病（T2D）是由胰岛素抵抗的组合引起的，最常见于肥胖，以及胰腺β细胞秘密胰岛素足够胰岛素的能力的等级和不变的侵蚀满足胰岛素代谢需求的增加。 β细胞功能障碍的主要介质是葡萄糖毒性，由持续的高血糖介导。在T2D的发病机理中，随后发生了恶性循环，其中胰岛素抵抗会增加对更多胰岛素的需求，但β细胞变得“筋疲力尽”，无法秘密足够的胰岛素可维持葡萄糖稳态，导致高血糖症增加，更多的β细胞精疲力尽和死亡，β细胞肿块的侵蚀，有时需要胰岛素治疗。因此，那里迫切需要阻止恶性循环并保留β细胞量的新疗法。我们相信我们已经发现了一种分子机制，该机制解释了侵蚀β细胞功能和β的恶性循环 T2D期间的细胞质量。该建议将探讨该机制的分子细节并测试可行性在葡萄糖毒性和T2D模型中保留啮齿动物和人β细胞的热干预措施。该提议的总体假设是Chrebpβ表达的前进机制通过表达促氧化活性，在T2D中失调，并驱动葡萄糖毒性 txnip，可以通过NRF2的激活来减轻其作用。此外，动作打破了 Chrebpβ的恶性循环，或通过TXNIP抑制或NRF2激活来减轻其作用保护β细胞肿块并减轻糖尿病性伯恩。该建议将通过探索这三个因素之间的分子调节机制，以及通过耗尽chrebpβ或txnip或在糖尿病或糖毒性的小鼠模型中或葡萄毒性或T2D人类胰岛中升高NRF2。具体的 AIM 1将探索确定β细胞的Chrebpβ，TXNIP和NRF2之间的调节关系命运。具体目标2将检查Chrebpβ或TxNIP的耗竭或NRF2的激活如何影响β细胞糖尿病和葡萄毒小鼠模型中的功能和葡萄糖稳态。特定目标3将测试是否部署 chrebpβ或txnip或NRF2的激活影响β细胞功能和葡萄毒性或T2D的存活率人类胰岛。我们的结果将为您的疗法设计提供降低β细胞葡萄糖毒性的设计，并且可能导致非常具体的药物靶向β细胞以保留β细胞质量和功能并减轻糖尿病症状和并发症。