Department of Pediatrics, Metabolism Division, Johns Hopkins University, Baltimore, MD 21287, USA.
Cell Metab. 2011 Mar 2;13(3):308-19. doi: 10.1016/j.cmet.2011.02.002.
Impaired insulin secretion contributes to the pathogenesis of type 2 diabetes mellitus (T2DM). Treatment with the incretin hormone glucagon-like peptide-1 (GLP-1) potentiates insulin secretion and improves metabolic control in humans with T2DM. GLP-1 receptor-mediated signaling leading to insulin secretion occurs via cyclic AMP stimulated protein kinase A (PKA)- as well as guanine nucleotide exchange factor-mediated pathways. However, how these two pathways integrate and coordinate insulin secretion remains poorly understood. Here we show that these incretin-stimulated pathways converge at the level of snapin, and that PKA-dependent phosphorylation of snapin increases interaction among insulin secretory vesicle-associated proteins, thereby potentiating glucose-stimulated insulin secretion (GSIS). In diabetic islets with impaired GSIS, snapin phosphorylation is reduced, and expression of a snapin mutant, which mimics site-specific phosphorylation, restores GSIS. Thus, snapin is a critical node in GSIS regulation and provides a potential therapeutic target to improve β cell function in T2DM.
胰岛素分泌受损是 2 型糖尿病（T2DM）发病机制的一个重要因素。肠促胰岛素激素胰高血糖素样肽-1（GLP-1）的治疗作用可以增强 T2DM 患者的胰岛素分泌，并改善代谢控制。GLP-1 受体介导的信号通路通过环腺苷酸（cAMP）刺激蛋白激酶 A（PKA）以及鸟苷酸交换因子（GEF）介导的途径来促进胰岛素分泌。然而，这两种途径如何整合和协调胰岛素分泌仍然知之甚少。在这里，我们发现这些肠促胰岛素刺激的途径在衔接蛋白（snapin）水平上汇聚，并且 PKA 依赖性的 snapin 磷酸化增加了与胰岛素分泌囊泡相关的蛋白之间的相互作用，从而增强了葡萄糖刺激的胰岛素分泌（GSIS）。在 GSIS 受损的糖尿病胰岛中，snapin 的磷酸化减少，而模拟特定位点磷酸化的 snapin 突变体的表达则恢复了 GSIS。因此，snapin 是 GSIS 调节的关键节点，并为改善 T2DM 中β细胞功能提供了一个潜在的治疗靶点。
