Snapin mediates incretin action and augments glucose-dependent insulin secretion

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)308-319
Number of pages12
JournalCell Metabolism
Volume13
Issue number3
DOIs
StatePublished - Mar 2 2011

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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