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

糖尿病的流行在世界范围内已经达到了流行的程度。根据美国疾病控制与预防中心 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8410万人患有糖尿病前期。高血糖是糖尿病的标志，胰岛素分泌 从胰岛的β细胞中释放对于维持适当的血糖水平至关重要。目前已被接受 β细胞功能障碍是糖尿病发展的早期和基本事件，包括与肥胖有关的 2型糖尿病(T2D)。环磷酸腺苷(CAMP)和离子钙(Ca~(2+))是关键的细胞信号分子 刺激β细胞的胰岛素分泌。钙离子是胰岛素分泌的触发物，而cAMP是胰岛素分泌的最大值 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(BAI3：AKA 补体1q样蛋白-3分泌蛋白(C1q13)的G蛋白偶联受体(ADGRB3)可能是一个关键角色 在T2D的β细胞功能障碍中的作用。BAI3、C1qL3的表达和分泌均较高 来自T2D小鼠和人类的胰岛。BAI3和C1qL3在胰岛β细胞中特异表达，而不是 在其他胰岛细胞类型中。最后，C1ql3治疗减少了葡萄糖刺激的胰岛胰岛素分泌和 提高β细胞内钙离子或cAMP水平的药物。然而，β-细胞C1q13/BAI3的确切分子机制 信号，特别是在肥胖和T2D的病理生理状态下，仍然没有特征。一个完整的 为了实现我们发现调制方式的长期目标，需要对这些过程进行理解 BAI3活性改善或逆转T2D的β细胞功能障碍。这个项目的首要目标是 迈向这一目标的下一个合乎逻辑的步骤是定义BAI3和C1ql3水平、信号机制和对 葡萄糖刺激和cAMP增强的胰岛素分泌及其在β细胞代偿过程中的变化 肥胖症和T2Dβ细胞衰竭。凭借我们独特的科学专长和技术创新的结合 通过各种方式，我们非常适合完成这一意义重大的项目。可持续发展的切实成果 建议的工作是：i)揭示BAI3的表达和C1qL3的表达和分泌是如何变化的 2)量化BAI3激活对β细胞钙内流和cAMP水平的影响； 以及iii)确定C1ql3介导的BAI3信号如何抑制葡萄糖刺激和cAMP增强 瘦身、肥胖和T2D状态下的胰岛素分泌及其影响的大小。如果成功，我们的工作将 两者都定义了BAI3下游的信号机制，BAI3是一种特性不佳的G蛋白偶联受体， 并为未来的T2D药物开发研究提供了强有力的初步数据，留下了高而持久的 对赛场的影响。

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.