Alleviation of Glucotoxicity in Pancreatic Beta Cells

总结 2型糖尿病（T2D）是由胰岛素抵抗的组合引起的，最常见的是由以下因素引起的： 肥胖，以及胰腺β细胞分泌足够胰岛素的能力的逐渐和无情的侵蚀 以满足对胰岛素的增加的代谢需求。β细胞功能障碍的主要介质是葡萄糖 毒性，由持续高血糖介导。在T2D的发病过程中， 胰岛素抵抗增加了对更多胰岛素的需求，但β细胞变得“疲惫”，无法 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 衰竭和死亡，β细胞群的侵蚀，最终需要胰岛素治疗。因此 迫切需要新的治疗方法来阻止恶性循环并保护β细胞群。我们相信我们 他们发现了一种分子机制，解释了侵蚀β细胞功能和β细胞功能的恶性循环。 T2D期间的细胞质量。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模型中保护啮齿动物和人类β细胞的治疗干预。 该建议的首要假设是ChREBPβ表达的前馈机制 在T2D中变得失调，并通过促氧化活性的表达驱动葡萄糖毒性。 Txnip，其作用可以通过Nrf2的活化来减轻。此外，演习，打破了 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细胞群并减轻糖尿病负担。本提案将通过探索 这3种因子之间的分子调节机制，并通过消耗ChREBPβ或Txnip，或 在糖尿病或葡萄糖毒性的小鼠模型中，或在葡萄糖毒性或T2D人胰岛中，升高NRF 2。具体 目的1探讨ChREBPβ、Txnip和NRF 2对β细胞凋亡的调控关系 命运具体目标2将检查ChREBPβ或Txnip的消耗或NRF 2的激活如何影响β细胞 糖尿病和葡萄糖毒性小鼠模型的功能和葡萄糖稳态。具体目标3将测试是否耗尽 ChREBPβ或TXNIP的表达或NRF2的激活影响葡萄糖毒性或T2D中的β细胞功能和存活 人类的小岛我们的研究结果将为减轻β细胞葡萄糖毒性的治疗设计提供信息， 导致靶向β细胞的非常特异性的药物，以保护β细胞的质量和功能，并减轻糖尿病 症状和并发症。

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.