title: Snapin mediates incretin action and augments glucose-dependent insulin secretion.
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.
authors.affiliation: Department of Pediatrics, Metabolism Division, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Song
authors.forename: Madhav
authors.initials: M
authors.lastname: Seshadri
authors.forename: Uzair
authors.initials: U
authors.lastname: Ashraf
authors.forename: Thembi
authors.initials: T
authors.lastname: Mdluli
authors.forename: Prosenjit
authors.initials: P
authors.lastname: Mondal
authors.forename: Meg
authors.initials: M
authors.lastname: Keil
authors.forename: Monalisa
authors.initials: M
authors.lastname: Azevedo
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Mehboob A
authors.initials: MA
authors.lastname: Hussain
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054795:Incretins; D007328:Insulin; C517834:PRKAR1A protein, human; C517835:Prkar1a protein, mouse; D034741:RNA, Small Interfering; C118519:SNAPIN protein, human; C498451:Snapin protein, mouse; D033921:Vesicular Transport Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose