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Snapin Mediates Incretin Action and Augments Glucose-Dependent Insulin Secretion

2011; Cell Press; Volume: 13; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2011.02.002

1932-7420

Woo‐Jin Song, Madhav Seshadri, Uzair Ashraf, Thembi Mdluli, Prosenjit Mondal, Meg Keil, Monalisa Ferreira Azevedo, Lawrence S. Kirschner, Constantine A. Stratakis, Mehboob A. Hussain,

Metabolism, Diabetes, and Cancer

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.