Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany; Leipzig University Medical Center, IFB AdiposityDiseases, 04103 Leipzig, Germany.
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany.
Cell Rep. 2019 Feb 5;26(6):1573-1584.e5. doi: 10.1016/j.celrep.2019.01.040.
Insulin secretion from pancreatic β cells is a highly complex and tightly regulated process. Its dysregulation is one characteristic of type 2 diabetes, and thus, an in-depth understanding of the mechanisms controlling insulin secretion is essential for rational therapeutic intervention. G-protein-coupled receptors (GPCRs) have been established as major regulators of insulin exocytosis. Recent studies also suggest the involvement of adhesion GPCRs, a non-prototypical class of GPCRs. Here, we identify latrophilins, which belong to the class of adhesion GPCRs, to be highly expressed in different cell types of pancreatic islets. In vitro and ex vivo analyses show that distinct splice variants of the latrophilin LPHN3/ADGRL3 decrease insulin secretion from pancreatic β cells by reducing intracellular cyclic AMP levels via the G-mediated pathway. Our data highlight the key role of LPHN3 in modulating insulin secretion and its potential as therapeutic target for type 2 diabetes.
胰岛β细胞的胰岛素分泌是一个高度复杂和严格调控的过程。其失调是 2 型糖尿病的一个特征，因此，深入了解控制胰岛素分泌的机制对于合理的治疗干预至关重要。G 蛋白偶联受体（GPCRs）已被确立为胰岛素胞吐作用的主要调节剂。最近的研究还表明，粘附 GPCRs（非典型 GPCR 类）也参与其中。在这里，我们鉴定出属于粘附 GPCR 类的拉普罗林（latrophilin）在胰岛的不同细胞类型中高度表达。体外和离体分析表明，拉普罗林 LPHN3/ADGRL3 的不同剪接变体通过 G 介导的途径降低细胞内环腺苷酸（cAMP）水平，从而减少胰腺β细胞的胰岛素分泌。我们的数据强调了 LPHN3 在调节胰岛素分泌中的关键作用及其作为 2 型糖尿病治疗靶点的潜力。
