Alleviation of Glucotoxicity in Pancreatic Beta Cells

减轻胰腺β细胞的糖毒性

• 批准号: 10643853
• 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
• 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/10643853
• 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; Mediating; Mediator; Metabolic; Modeling; Molecular; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Export; Obesity; Pathogenesis; Pathway interactions; 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; loss of function; mouse model; novel therapeutics; overexpression; pharmacologic; preservation; promoter; targeted treatment; therapeutic development; therapeutic evaluation; therapy design; transcription factor

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.

摘要 2型糖尿病(T2D)是胰岛素抵抗的结果，最常见的原因是 肥胖，以及胰岛β细胞分泌足够胰岛素的能力逐渐和无情的侵蚀 以满足不断增加的胰岛素代谢需求。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的发病过程中，会出现恶性循环，其中 胰岛素抵抗增加了对更多胰岛素的需求，但贝塔细胞变得“筋疲力尽”，无法 秘密足够的胰岛素来维持血糖平衡，导致高血糖升高，更多的β细胞 精疲力竭和死亡，β细胞团的侵蚀，最终需要胰岛素治疗。因此，在那里 迫切需要新的疗法来阻止恶性循环并保护β细胞团。我们相信我们 揭示了一种分子机制，可以解释侵蚀贝塔细胞功能和贝塔的恶性循环 T2D过程中的细胞团。这项提案将探索这一机制的分子细节，并测试其可行性 在葡萄糖毒性和T2D模型中保存啮齿动物和人类β细胞的治疗干预。 这一建议的首要假设是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，其作用可通过激活Nrf2而减轻。此外，打破这一局面的策略 ChREBPβ产生的恶性循环，或通过抑制TXNIP或激活NRF2来减轻其作用， 保护胰岛β细胞群，减轻糖尿病负担。本提案将通过探索 这3个因子之间的分子调控机制，并通过耗尽ChREBPβ或TXNIP，或 在糖尿病或糖毒性的小鼠模型中，或者在糖毒性或T2D人类胰岛中，上调NRF2。特定的 目标1将探索ChREBPβ、TXNIP和NRF2之间的调控关系，这些调控关系决定了β细胞 命运。特定目标2将研究ChREBPβ或TXNIP的耗尽或NRF2的激活对β细胞的影响 糖尿病和糖毒性小鼠模型的功能和血糖稳态。特定目标3将测试是否耗尽 ChREBPβ或TXNIP或NRF2的激活影响β细胞的功能和在糖毒性或T2D中的存活 人类的小岛。我们的结果将为减轻β细胞葡萄糖毒性的治疗设计提供参考，并可能 导致针对β细胞的非常特定的药物的产生，以保护β细胞的质量和功能并缓解糖尿病 症状和并发症。