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已达到流行病的程度。根据该中心疾病 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，与胰岛素分泌有关 从胰岛β细胞中提取的胰岛素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发展的早期和重要事件，包括肥胖相关的糖尿病。 2型糖尿病（T2 D）。环磷酸腺苷（cAMP）和钙离子（Ca 2+）是关键的细胞信号分子， 刺激β细胞胰岛素分泌。Ca 2+是胰岛素分泌的触发因子，而cAMP是胰岛素分泌最大化所必需的。 胰岛素分泌反应。我们小组的初步数据表明，脑血管生成抑制因子3（BAI 3：aka ADGRB 3），一种补体1 q样3分泌蛋白（C1 ql 3）的G蛋白偶联受体，可能是一个关键因素 2型糖尿病的β细胞功能障碍BAI 3表达、C1 ql 3表达和分泌均高于对照组。 来自T2 D小鼠和人类的胰岛。BAI 3和C1 ql 3在胰岛β细胞中特异性表达， 其他类型的胰岛细胞。最后，C1 q13处理减少了葡萄糖刺激的胰岛的胰岛素分泌， 提高β细胞Ca 2+或cAMP水平的药物。然而，β细胞C1 ql 3/BAI 3的精确分子机制 信号传导，特别是在肥胖和T2 D的病理生理状态中，仍然没有被表征。全 了解这些过程是实现我们的长期目标所必需的， BAI 3活性改善或逆转T2 D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合乎逻辑的步骤是定义BAI 3和C1 q13水平、信号传导机制和对 葡萄糖刺激和cAMP增强的胰岛素分泌及其在β细胞代偿期间的变化 肥胖症和2型糖尿病β细胞衰竭凭借我们独特的科学专业知识和技术创新 因此，我们非常适合完成这个非常重要的项目。会议的实质性成果 提出的工作是：i）揭示BAI 3表达和C1 ql 3表达和分泌如何响应 ii）定量BAI 3活化对β-细胞Ca 2+内流和cAMP水平的影响; 和iii）确定C1 q13介导的BAI 3信号传导如何抑制葡萄糖刺激的和cAMP增强的 胰岛素分泌及其在瘦、肥胖和2型糖尿病状态下的影响程度。如果成功，我们的工作将 两者都定义了BAI 3下游的信号传导机制，BAI 3是一种特征不佳的G蛋白偶联受体， 并为未来的T2 D药物开发研究提供强有力的初步数据， 对现场的影响。