title: DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice β cells.
abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single β-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptin for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.
authors.affiliation: Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo, Japan. shinya@ks.kyorin-u.ac.jp
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagamatsu
authors.forename: Mica
authors.initials: M
authors.lastname: Ohara-Imaizumi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Kyota
authors.initials: K
authors.lastname: Aoyagi
authors.forename: Chiyono
authors.initials: C
authors.lastname: Nishiwaki
mesh_terms: D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011719:Pyrazines / Q000493:pharmacokinetics*; D014230:Triazoles / Q000493:pharmacokinetics*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D011719:Pyrazines; D014230:Triazoles