G protein mediated mechanisms of beta-cell compensation and failure in type 2 diabetes

G 蛋白介导的 2 型糖尿病 β 细胞补偿和衰竭机制

• 批准号: 10485702
• 负责人: Michelle E Kimple
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485702
• 关键词: Adenylate Cyclase; Aging; Agonist; Ally; Alpha Cell; Arachidonic Acids; Beta Cell; Blood Circulation; Blood Glucose; Caring; Cell Death; Cell physiology; Cells; Chemicals; Child; Cholecystokinin; Chronic Disease; Compensation; Complex; Coupled; Critical Pathways; Cyclic AMP; Cytoplasm; Data; Diabetes Mellitus; Diabetes prevention; Dinoprostone; Etiology; Exposure to; Failure; Functional disorder; GLP-I receptor; GTP-Binding Protein alpha Subunits; GTP-Binding Proteins; Gene Expression Profile; General Population; Genes; Genetic; Glucose; Goals; Growth; Health; Hormones; Human; Hyperglycemia; Immune; Individual; Insulin; Islet Cell; Knock-out; Knockout Mice; Life Style; Link; Longevity; Mediating; Membrane; Metabolic; Methods; Molecular; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ Donor; Osmosis; Pancreas; Paracrine Communication; Pathway interactions; Pharmaceutical Preparations; Pre-Clinical Model; Prediabetes syndrome; Prevalence; Process; Production; Protein Isoforms; Public Health; Pump; RNA Splicing; Regulation; Research; Residual state; Resistance; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Structure of beta Cell of islet; Sulfonylurea Compounds; Testing; Therapeutic; Tissues; Variant; Veterans; Work; antagonist; autocrine; cell type; cellular targeting; cost; diabetes mellitus therapy; diabetes risk; diabetic; diabetic patient; diabetogenic; functional loss; glucagon-like peptide 1; improved; incretin hormone; innovation; insulin secretion; islet; lifetime risk; metabolome; military veteran; non-diabetic; novel; paracrine; patient population; pharmacologic; preservation; prevent; programs; receptor; therapeutic target

Diabetes is a costly and complex chronic illness and a serious public health problem. Currently, the prevalence of diabetes in the VA patient population is approximately 25%, with many more Veterans at risk for diabetes due to obesity, aging, and poor lifestyle, as well as exposure to known diabetogenic chemicals in the line of duty. The number of Veterans with diabetes is certain to increase over the next decades, as the children of today have an estimated overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new methods for preventing diabetes and identifying and properly treating diabetic patients is very timely and of great significance. By definition, diabetes occurs when insufficient insulin is produced from the β-cells of the pancreas to properly stimulate the body cells to take up glucose from the blood and shut off production of more glucose. While they have different etiologies, the pathophysiology of type 1 (immune-mediated) and type 2 (obesity-related) diabetes is increasingly being linked by dysfunctional cellular and molecular signaling processes that act in the insulin- secreting β-cells. One molecule that is a cornerstone of our research program, termed Gαz, has the potential to act as a hub in one or more signaling processes impacting on β-cell function, replication, growth and/or survival. Thus, targeting these dysfunctional Gαz signaling processes could potentially help to improve functional β-cell mass in both types of diabetes. Our long-term goal is to fully characterize the Gαz activation and signaling pathways in the diabetic state at the organismal, tissue, cellular, and molecular levels, guiding us in modulating this pathway for preventative and therapeutic purposes. The overall objective of this work, which is the next logical step in pursuit of our goal, is to characterize the molecular and cellular signaling pathways responsible for the impact of Gαz signaling on diabetes pathophysiology. Our central hypothesis is activated β-cell Gαz negatively modulates specific intracellular and autocrine/paracrine signaling pathways critical for β-cell compensation, ultimately leading to β-cell death and dysfunction and exacerbating the diabetic condition. We will test our central hypothesis in multiple pre-clinical models of diabetes and, thereby, accomplish the objective of this application, by pursuing the following two specific aims: 1. Determine the requirement of islet CCKAR and/or GLP1R in the T2D protection of full-body Gαz-null mice and the mechanisms behind this protection; And 2. Determine the molecular mechanisms downstream of constitutively-active and agonist-stimulated EP3 and how these are altered in the highly-compensating and T2D beta-cell. In both aims, the relationship between agonist-dependent and -independent signaling of EP3 splice variants in islet responsiveness to GLP1-RAs will be determined. With the completion of these aims, we anticipate a much more complete understanding of the role of the β-cell and its signaling molecules in the pathophysiology of diabetes. Ultimately, isolating Gαz effects to the β-cell and fully characterizing its signaling mechanisms will aid in rationally and specifically targeting this pathway in the β-cell to improve diabetic β-cell dysfunction and loss of functional β-cell mass.

糖尿病是一种昂贵且复杂的慢性病，​​也是一个严重的公共卫生问题。目前，患病率 VA患者人群中的糖尿病大约为25％，还有更多的退伍军人有糖尿病的风险 肥胖，衰老和生活方式差，以及在职责范围内暴露于已知的糖尿病性化学物质。 在接下来的几十年中，糖尿病的退伍军人人数肯定会增加，因为今天的孩子已经 估计的总体终身糖尿病风险近50％。因此，开发新方法 防止糖尿病并识别和适当治疗糖尿病患者是非常及时且具有重要意义的。 根据定义，当从胰腺的β细胞中产生胰岛素不足至正确的胰岛素时，会发生糖尿病 刺激体细胞从血液中吸收葡萄糖并关闭更多葡萄糖的产生。当他们 具有不同的病因，即1型（免疫介导）和2型（与肥胖相关的）糖尿病的病理生理学 越来越多地通过在胰岛素中作用的细胞和分子信号传导过程的联系 分泌β细胞。我们研究程序的一个基石的一个分子称为GαZ，具有潜力 在一个或多个影响β细胞功能，复制，生长和/或存活的信号传导过程中充当集线器。 靶向这些功能失调的GαZ信号传导过程可能有助于改善功能性β细胞 两种类型的糖尿病的质量。我们的长期目标是充分表征GαZ激活和信号传导 有机，组织，细胞和分子水平的糖尿病态的途径，指导我们调节 这是用于预防和治疗目的的途径。这项工作的总体目标，这是下一个 追求我们目标的逻辑步骤是表征负责的分子和细胞信号通路 GαZ信号传导对糖尿病病理生理学的影响。我们的中心假设被激活 负面调节特定的细胞内和自分泌/旁分泌信号通路对β细胞至关重要 补偿，最终导致β细胞死亡和功能障碍并加剧糖尿病状况。 将在多种糖尿病前临床前模型中检验我们的中心假设，从而实现目标 在此应用程序中，通过追求以下两个具体目的：1。确定胰岛CCKAR的要求 和/或GLP1R在全体Gαz-null小鼠的T2D保护中以及其背后的机制 保护;和2。确定组成型活性下游的分子机制和 激动剂刺激的EP3以及在高度补偿和T2Dβ细胞中如何改变它们。在这两个中 目的，胰岛中EP3剪接变体的激动剂依赖性和非依赖性信号之间的关系 将确定对GLP1-RAS的响应。随着这些目标的完成，我们预计会有更多 完全了解β细胞的作用及其信号分子在糖尿病的病理生理中。 最终，将GαZ效应分离为β细胞并充分表征其信号传导机制将有助于合理地 并专门针对β细胞中的这一途径，以改善糖尿病β细胞功能障碍和功能丧失 β细胞质量。