Snapin mediates incretin action and augments glucose-dependent insulin secretion

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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucose / metabolism*
  • Humans
  • Incretins / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*


  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Incretins
  • Insulin
  • PRKAR1A protein, human
  • Prkar1a protein, mouse
  • RNA, Small Interfering
  • SNAPIN protein, human
  • Snapin protein, mouse
  • Vesicular Transport Proteins
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose