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，