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疾病，也是目前流行的一个严重的公共卫生问题。 退伍军人管理局患者群体中糖尿病的比例约为 25%，由于更多退伍军人面临糖尿病风险 肥胖、衰老和不良生活方式，以及在工作中接触已知的糖尿病化学物质。 未来几十年，患有糖尿病的退伍军人人数肯定会增加，就像今天的孩子们一样 据估计，一生中罹患糖尿病的风险接近 50%，因此，需要开发新的方法来治疗糖尿病。 预防糖尿病，识别并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以正常发挥作用时，就会发生糖尿病。 刺激身体细胞从血液中吸收葡萄糖并停止产生更多葡萄糖。 1 型（免疫介导）和 2 型（肥胖相关）糖尿病具有不同的病因、病理生理学 越来越多地与作用于胰岛素的功能失调的细胞和分子信号传导过程联系在一起。 一种名为 Gαz 的分子是我们研究计划的基石，它有潜力 作为影响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的枢纽。 因此，针对这些功能失调的 Gαz 信号传导过程可能有助于改善功能性 β 细胞 我们的长期目标是充分表征 Gαz 激活和信号传导。 糖尿病状态下生物、组织、细胞和分子水平的通路，指导我们调节 该途径用于预防和治疗目的，这是下一步工作的总体目标。 追求我们的目标的合乎逻辑的步骤是表征负责的分子和细胞信号传导途径 我们的中心假设是激活的 β 细胞 Gαz。 负向调节对 β 细胞至关重要的特定细胞内和自分泌/旁分泌信号通路 代偿，最终导致 β 细胞死亡和功能障碍，并加剧糖尿病病情。 将在多个糖尿病临床前模型中测试我们的中心假设，从而实现目标 本申请通过追求以下两个具体目标： 1. 确定 islet CCKAR 的要求 和/或 GLP1R 对全身 Gαz 缺失小鼠的 T2D 保护及其背后的机制 2. 确定组成型活性和下游的分子机制 激动剂刺激的 EP3 以及这些在高补偿性和 T2D β 细胞中如何改变。 目的，胰岛中 EP3 剪接变体的激动剂依赖性和非依赖性信号传导之间的关系 随着这些目标的完成，我们预计会有更多的结果。 完全了解 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 并专门针对 β 细胞中的这一通路来改善糖尿病 β 细胞功能障碍和功能丧失 β细胞团。