title: Glucose-dependent changes in SNARE protein levels in pancreatic β-cells.
abstract: Prolonged exposure to high glucose concentration alters the expression of a set of proteins in pancreatic β-cells and impairs their capacity to secrete insulin. The cellular and molecular mechanisms that lie behind this effect are poorly understood. In this study, three either in vitro or in vivo models (cultured rat pancreatic islets incubated in high glucose media, partially pancreatectomized rats, and islets transplanted to streptozotozin-induced diabetic mice) were used to evaluate the dependence of the biological model and the treatment, together with the cell location (insulin granule or plasma membrane) of the affected proteins and the possible effect of sustained insulin secretion, on the glucose-induced changes in protein expression. In all three models, islets exposed to high glucose concentrations showed a reduced expression of secretory granule-associated vesicle-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins synaptobrevin/vesicle-associated membrane protein 2 and cellubrevin but minor or no significant changes in the expression of the membrane-associated target-SNARE proteins syntaxin1 and synaptosomal-associated protein-25 and a marked increase in the expression of synaptosomal-associated protein-23 protein. The inhibition of insulin secretion by the L-type voltage-dependent calcium channel nifedipine or the potassium channel activator diazoxide prevented the glucose-induced reduction in islet insulin content but not in vesicle-SNARE proteins, indicating that the granule depletion due to sustained exocytosis was not involved in the changes of protein expression induced by high glucose concentration. Altogether, the results suggest that high glucose has a direct toxic effect on the secretory pathway by decreasing the expression of insulin granule SNARE-associated proteins.
authors.affiliation: Departamento de Patologia i Terapèutica Experimental, Institut d'Investigació Biomèdica de Bellvitge-Universitat de Barcelona, Laboratori 4145, Campus de Bellvitge, Edifici del Pavelló de Govern, C/Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Torrejón-Escribano
authors.forename: Jessica
authors.initials: J
authors.lastname: Escoriza
authors.forename: Eduard
authors.initials: E
authors.lastname: Montanya
authors.forename: Juan
authors.initials: J
authors.lastname: Blasi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003981:Diazoxide / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology; D010180:Pancreatectomy; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D051040:Vesicle-Associated Membrane Protein 3 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D050683:R-SNARE Proteins; D050600:SNARE Proteins; C498858:Snap23 protein, rat; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D050988:Vesicle-Associated Membrane Protein 2; D051040:Vesicle-Associated Membrane Protein 3; D033921:Vesicular Transport Proteins; D009543:Nifedipine; D005947:Glucose; D003981:Diazoxide