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.

糖尿病是一种昂贵而复杂的慢性疾病，也是一个严重的公共卫生问题。目前， VA患者人群中糖尿病的比例约为25%，由于糖尿病的风险， 肥胖、衰老和不良的生活方式，以及在工作中暴露于已知的致糖尿病化学物质。 在未来的几十年里，患糖尿病的退伍军人的数量肯定会增加，就像今天的孩子一样。 估计一生中患糖尿病的风险接近50%。因此，开发新的方法 预防糖尿病，识别和正确治疗糖尿病患者，非常及时，意义重大。 根据定义，当胰腺β细胞产生的胰岛素不足时，糖尿病就会发生， 刺激身体细胞从血液中吸收葡萄糖，并停止产生更多的葡萄糖。虽然他们 有不同的病因，1型（免疫介导）和2型（肥胖相关）糖尿病的病理生理学 越来越多地与功能失调的细胞和分子信号传导过程联系在一起，这些信号传导过程作用于胰岛素， 分泌β细胞一种分子是我们研究计划的基石，称为Gαz，有可能 在影响β细胞功能、复制、生长和/或存活的一个或多个信号传导过程中充当枢纽。 因此，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 两种类型的糖尿病都有。我们的长期目标是充分表征Gαz的激活和信号传导 糖尿病状态下的生物体，组织，细胞和分子水平的途径，指导我们调节 用于预防和治疗目的。这项工作的总体目标是， 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信号对糖尿病病理生理学的影响。我们的中心假设是激活的β细胞Gαz 负性调节对β细胞关键的特定细胞内和自分泌/旁分泌信号传导途径 这可能会导致β细胞死亡和功能障碍，并使糖尿病病情恶化。我们 将在糖尿病的多个临床前模型中测试我们的中心假设，从而实现目标 通过追求以下两个具体目的，本申请的目的是：1.确定胰岛CCKAR的要求 和/或GLP 1 R在全身Gα z缺失小鼠的T2 D保护中的作用及其背后的机制 保护; 2。确定组成型活性和 激动剂刺激的EP 3以及这些在高度补偿和T2 D β细胞中如何改变。无论是 目的，研究胰岛细胞中EP 3剪接变异体激动剂依赖性和非依赖性信号传导之间的关系， 将测定对GLP 1-RA的反应性。随着这些目标的实现，我们预计 完全理解β细胞及其信号分子在糖尿病病理生理学中的作用。 最终，分离Gαz对β细胞的影响并充分表征其信号传导机制将有助于合理地 并特异性靶向β细胞中的该途径以改善糖尿病β细胞功能障碍和功能丧失， β细胞团。