Investigating the Effects of ADGRB3 Signaling on Incretin-Mediated Insulin Secretion from Pancreatic Beta-Cells

研究 ADGRB3 信号传导对肠促胰素介导的胰腺 β 细胞胰岛素分泌的影响

• 批准号: 10666206
• 负责人: Sushant Bhatnagar
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10666206
• 关键词: Adenosine Triphosphate; Adhesions; Adult; Affect; Agonist; Angiogenesis Inhibitors; Beta Cell; Binding; Biological Assay; Blood Glucose; Brain; Calcium; Calcium Channel; Calcium Oscillations; Cell membrane; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Compensation; Complement 1q; Coupled; Cyclic AMP; Data; Development; Diabetes Mellitus; Disease; Docking; Endocrine; Epidemic; Event; Exocytosis; Failure; Functional disorder; Future; G-Protein-Coupled Receptors; GLP-I receptor; Genes; Genetic study; Glucose; Goals; Human; Image; Individual; Insulin; Insulin Resistance; Islet Cell; Islets of Langerhans; Knowledge; Ligands; Link; Mediating; Metabolic Diseases; Mission; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Output; Persons; Pharmaceutical Preparations; Pharmacology Study; Phenotype; Physiological; Population; Prediabetes syndrome; Prevalence; Process; Production; Protein Secretion; Proteins; Public Health; Publishing; Role; Second Messenger Systems; Signal Transduction; Signaling Molecule; Structure of beta Cell of islet; Study models; Testing; Therapeutic; Thinness; Time; United States; United States National Institutes of Health; Work; antagonist; autocrine; brain cell; cell type; complement 1q receptor; disorder risk; drug development; exenatide; expectation; fluorescence imaging; glucagon-like peptide 1; glucose metabolism; imaging platform; improved; incretin hormone; inhibitor; innovation; insulin granule; insulin secretion; islet; new therapeutic target; non-diabetic; paracrine; protein expression; response; therapeutic target; voltage

The prevalence of diabetes has reached epidemic proportions worldwide. According to the Centers for Disease Control and Prevention, more than 37 million individuals in the US have diabetes (~10% of the adult population), and another 84.1 million are prediabetic. Elevated blood sugar is the hallmark of diabetes, and insulin secreted from the β-cells of the pancreatic islets is critical for maintaining proper blood sugar levels. It is currently accepted that β-cell dysfunction is an early and essential event in the development of diabetes, including obesity-linked type 2 diabetes (T2D). Cyclic AMP (cAMP) and ionic calcium (Ca2+) are key cellular signaling molecules that stimulate β-cell insulin secretion. Ca2+ is the trigger for insulin secretion, while cAMP is required for the maximal insulin secretion response. Preliminary data from our group suggests brain angiogenesis inhibitor-3 (BAI3: aka ADGRB3), a G protein-coupled receptor for complement 1q like-3 secreted protein (C1ql3), may be a key player in the β-cell dysfunction of T2D. BAI3 expression, and C1ql3 expression and secretion are both higher in pancreatic islets from T2D mice and humans. BAI3 and C1ql3 are specifically expressed in islet β-cells and not in other islet cell types. Finally, C1ql3 treatment reduces insulin secretion from islets stimulated by glucose and drugs that raise β-cell Ca2+ or cAMP levels. Yet, the precise molecular mechanisms underlying β-cell C1ql3/BAI3 signaling, particularly in the pathophysiological states of obesity and T2D, remain uncharacterized. A full understanding of these processes is required to achieve our long-term goal of discovering ways to modulate BAI3 activity to improve or reverse the β-cell dysfunction of T2D. The overarching goal of this project, which is the next logical step towards this goal, is to define BAI3 and C1ql3 levels, signaling mechanisms, and effects on glucose-stimulated and cAMP-potentiated insulin secretion and how these change during β-cell compensation for obesity and T2D β-cell failure. With our unique combination of scientific expertise and technically innovative approaches, we are uniquely suited to complete this highly significant project. Tangible outcomes of the proposed work are: i) revealing how BAI3 expression and C1ql3 expression and secretion change in response to obesity and, ultimately, T2D; ii) quantifying the effects of BAI3 activation on β-cell Ca2+ influx and cAMP levels; and iii) establishing how C1ql3-mediated BAI3 signaling inhibits glucose-stimulated and cAMP-potentiated insulin secretion and the magnitude of its effects in the lean, obese, and T2D states. If successful, our work will both define the signaling mechanisms downstream of BAI3, a poorly-characterized G protein-coupled receptor, and provide strong preliminary data for future T2D drug development studies, leaving a high and long-lasting impact on the field.

糖尿病的患病率在全世界范围内已达到流行病的程度。据疾病中心称 控制和预防，美国有超过 3700 万人患有糖尿病（约占成年人口的 10%）， 另有 8410 万人处于糖尿病前期。血糖升高是糖尿病的标志，胰岛素分泌 来自胰岛 β 细胞的葡萄糖对于维持适当的血糖水平至关重要。目前已接受 β细胞功能障碍是糖尿病（包括与肥胖相关的）发展的早期和重要事件 2 型糖尿病 (T2D)。环磷酸腺苷 (cAMP) 和离子钙 (Ca2+) 是关键的细胞信号分子， 刺激β细胞胰岛素分泌。 Ca2+ 是胰岛素分泌的触发因素，而 cAMP 是最大胰岛素分泌所必需的。 胰岛素分泌反应。我们小组的初步数据表明脑血管生成抑制剂-3（BAI3：又名 ADGRB3) 是补体 1q like-3 分泌蛋白 (C1ql3) 的 G 蛋白偶联受体，可能是关键角色 T2D 的 β 细胞功能障碍。 BAI3 表达、C1ql3 表达和分泌均较高 来自 T2D 小鼠和人类的胰岛。 BAI3 和 C1ql3 在胰岛 β 细胞中特异性表达，而不是 在其他胰岛细胞类型中。最后，C1ql3 治疗减少了受葡萄糖刺激的胰岛的胰岛素分泌， 提高 β 细胞 Ca2+ 或 cAMP 水平的药物。然而，β 细胞 C1ql3/BAI3 的精确分子机制 信号传导，特别是在肥胖和 T2D 的病理生理状态中，仍然未知。一个完整的 为了实现我们发现调节方法的长期目标，需要了解这些过程 BAI3 活性可改善或逆转 T2D 的 β 细胞功能障碍。该项目的总体目标是 实现这一目标的下一个逻辑步骤是定义 BAI3 和 C1ql3 水平、信号传导机制以及对 葡萄糖刺激和 cAMP 增强的胰岛素分泌以及这些在 β 细胞补偿过程中如何变化 用于肥胖和 T2D β 细胞衰竭。凭借我们独特的科学专业知识和技术创新的结合 方法，我们非常适合完成这个非常重要的项目。的切实成果 拟议的工作是：i) 揭示 BAI3 表达和 C1ql3 表达和分泌如何响应变化 导致肥胖，最终导致 T2D； ii) 量化 BAI3 激活对 β 细胞 Ca2+ 流入和 cAMP 水平的影响； iii)确定C1ql3介导的BAI3信号传导如何抑制葡萄糖刺激和cAMP增强 胰岛素分泌及其在瘦、肥胖和 T2D 状态下的影响程度。如果成功的话，我们的工作将 两者都定义了 BAI3 下游的信号传导机制，BAI3 是一种特性较差的 G 蛋白偶联受体， 并为未来T2D药物开发研究提供有力的初步数据，留下高而持久的成果 对场上的影响。