biostudies-literatureSong WJNIDDK NIH HHSNCI NIH HHS308-19https://www.ebi.ac.uk/biostudies/studies/S-EPMC3053597biostudies-literatureUnknown13(3)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 ? cell function in T2DM.Cell metabolismSnapin mediates incretin action and augments glucose-dependent insulin secretion.PMC3053597R24 DK084949R01 CA112268-05R01 DK081472-01A1P60 DK079637-05P30 DK079637P60 DK079637R01 DK081472R01 DK081472-02R01 DK081472-03RC4 DK090816R24 DK084949-01R01 CA112268Kirschner LSMondal PSong WJAshraf USeshadri MStratakis CAKeil MMdluli THussain MAAzevedo MfalseSnapin mediates incretin action and augments glucose-dependent insulin secretion.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 ? cell function in T2DM.2011-01-01T00:00:00Z2011 Mar2020-10-29T10:41:53Z2019-03-27T00:39:32ZS-EPMC30535972135652010.1016/j.cmet.2011.02.002