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：
10316752
负责人：
DONALD K. SCOTT
金额：
$ 50.29万
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/10316752
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) 是胰岛素抵抗综合作用的结果，最常见的原因是肥胖，以及胰腺β细胞分泌足够胰岛素的能力逐渐且无情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。由持续高血糖介导的毒性在 T2D 发病过程中会发生恶性循环。胰岛素抵抗会增加对更多胰岛素的需求，但β细胞会变得“精疲力竭”，无法再补充胰岛素。分泌足够的胰岛素来维持葡萄糖稳态，导致高血糖增加，更多的β细胞疲惫和死亡，β细胞团的侵蚀，最终需要胰岛素治疗。我们相信我们迫切需要新的疗法来阻止恶性循环并保留β细胞质量。发现了一种分子机制，可以解释侵蚀β细胞功能和β细胞的恶性循环该提案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类 β 细胞的治疗干预措施。该提案的总体假设是 ChREBPβ 表达的前馈机制在 T2D 中变得失调，并通过表达促氧化活性来驱动葡萄糖毒性 Txnip，其影响可以通过激活 Nrf2 来减轻。 ChREBPβ 产生的恶性循环，或通过 Txnip 抑制或 Nrf2 激活减轻其作用，保护β细胞质量并减轻糖尿病负担该提案将通过探索来检验这一假设。这 3 个因素之间的分子调节机制，以及通过消耗 ChREBPβ 或 Txnip，或在糖尿病或糖毒性小鼠模型中，或在糖毒性或 T2D 人类胰岛中，NRF2 升高。目标 1 将探索 ChREBPβ、Txnip 和 NRF2 之间决定 β 细胞的调节关系具体目标 2 将检查 ChREBPβ 或 Txnip 的消耗或 NRF2 的激活如何影响 β 细胞。具体目标 3 将测试糖尿病和糖中毒小鼠模型中的功能和葡萄糖稳态。 ChREBPβ 或 TXNIP 的激活或 NRF2 的激活影响糖中毒或 T2D 中的 β 细胞功能和存活我们的结果将为减轻β细胞葡萄糖毒性的疗法的设计提供信息，并可能产生针对 β 细胞的非常特殊的药物，以保护 β 细胞质量和功能并缓解糖尿病症状和并发症。