The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function

2型糖尿病（T2D）是影响人类健康的最常见慢性疾病。最近的纵向和全基因组关联研究提供了强有力的证据，表明胰腺β细胞通过发育、生长、生存和功能来满足胰岛素需求的能力是个体是否会发展为T2D的关键决定因素！在各种营养条件下。然而，目前还没有针对β细胞生长和维持其作为胰岛素产生细胞的分化身份的有效临床治疗方法。我们认为OGT （O-GlcNAc Transferase）是一种在β细胞中表达水平非常高的营养传感器，具有关键的发育调节特性和整合信号网络的能力，以调节β细胞对胰岛素需求和营养胁迫的可塑性。OGT是唯一一种在蛋白质上添加单个o - glcnnac翻译后修饰（o - glcnac酰化）的酶，以协调和微调葡萄糖代谢，并在营养变化和激素提示的应激反应下促进β细胞生长和维持身份。我们假设OGT严格控制下游靶标（包括Pdx1）的o - glcn酰化状态，以促进β细胞的发育和功能。因此，我们的长期目标是确定OGT如何整合影响β细胞可塑性（发育和身份）的信号网络以促进β细胞功能的机制。我们将用以下目标来检验我们的假设：1。建立OGT调控β细胞发育和质量的分子机制。2. 探讨代谢应激下OGT调节β细胞质量和特性的机制。这项拨款的影响将显示OGT在β细胞发育和大量维持中的核心作用，并说明在对代谢健康至关重要的时间窗期间，OGT的翻译相关性。最后，这些结果将推动β细胞生物学领域的发展，并为糖尿病患者的治疗开辟新的视野。

Type 2 diabetes (T2D) is the most common chronic disease affecting human health. Recent longitudinal and genome-wide association studies provide strong evidence that the ability of pancreatic β-cells to fulfill insulin demand through development, growth, survival, and function is a key determinant of whether an individual will develop T2D ! under various nutrient conditions. However, there are no effective clinical treatments that target β-cell growth and maintenance of their differentiated identity as insulin producing-cells. We propose that OGT (O-GlcNAc Transferase), a nutrient-sensor expressed at a very high level in β-cells, has key developmental regulatory properties and the ability to integrate signaling networks to regulate β-cell plasticity in response to insulin demand and nutrient stress. OGT is the sole enzyme adding a single O-GlcNAc post-translational modification (O-GlcNAcylation) onto proteins to orchestrate and fine-tune glucose metabolism, and β-cell growth and maintenance of identity under stress responses to nutrient changes and hormonal cues. We hypothesize that OGT tightly controls the O-GlcNAcylation state of downstream targets, including Pdx1, to promote β-cell development and function. Thus, our long-term goal is to define the mechanisms of how OGT integrates signaling networks impinging on β-cell plasticity (development and identity) to promote functional β-cells. We will test our hypothesis with the following Aims: 1. To establish the molecular mechanisms of how OGT regulates β-cell development and mass. 2. To delineate the mechanisms of how OGT regulates β-cell mass and identity under metabolic stress. The impact of this grant will show the central role of OGT in β-cell development and mass maintenance, and illustrate the translational relevance of OGT during time windows critical to metabolic health . Finally, these results will advance the field of β-cell biology and will open new horizons for therapies for patients with diabetes.