title: The mechanisms of insulin secretion and calcium signaling in pancreatic β-cells exposed to fluoroquinolones.
abstract: Fluoroquinolones reportedly induce hypoglycemia through stimulation of insulin secretion from pancreatic β-cells via inhibition of K(ATP) channels and activation of L-type voltage-dependent Ca(2+) channels. In physiological condition, the cytosolic Ca(2+) concentration ([Ca(2+)](c)) is also regulated by release of Ca(2+) from intracellular Ca(2+) stores. In this study, we investigated the mechanism of insulin secretion induced by fluoroquinolones, with respect to intracellular Ca(2+) stores. Even where the absence of supplemental extracellular Ca(2+), insulin secretion and [Ca(2+)](c) were increased by gatifloxacin, levofloxacin or tolbutamide. Insulin secretion and the rise of [Ca(2+)](c) induced by fluoroquinolones were reduced by depleting of Ca(2+) in endoplasmic reticumum (ER) by thapsigargin, and inhibiting ryanodine receptor of ER by dantrolene. Inhibition of inositol 1,4,5-triphosphate receptor of ER by xestospongin C suppressed insulin secretion induced by fluoroquinolones, whereas it did not affect [Ca(2+)](c). Destruction of acidic Ca(2+) stores such as lysosome and lysosome-related organelles by glycyl-L-phenylalanine-2-nephthylamide (GPN) did not affect insulin secretion and the rise of [Ca(2+)](c) induced by fluoroquinolones. The increase in insulin and [Ca(2+)](c) induced by tolbutamide were reduced by thapsigargin, dantrolene, and GPN but not by xestospongin C. In conclusion, fluoroquinolones induces Ca(2+) release from ER mediated by the ryanodine receptor, and the reaction might involve in insulin secretion. Sulfonylureas induce Ca(2+) release from GPN-sensitive acidic Ca(2+) stores, but fluoroquinolones did not.
authors.affiliation: Division of Clinical Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, 1–2–3 Kasumi, Minami-ku, Hiroshima 734–8551, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Bito
authors.forename: Takashi
authors.initials: T
authors.lastname: Tomita
authors.forename: Mika
authors.initials: M
authors.lastname: Komori
authors.forename: Takanori
authors.initials: T
authors.lastname: Taogoshi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kihira
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D024841:Fluoroquinolones / Q000494:pharmacology*; D000077734:Gatifloxacin; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D064704:Levofloxacin; D015242:Ofloxacin / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D007328:Insulin; D064704:Levofloxacin; D014044:Tolbutamide; D015242:Ofloxacin; D000077734:Gatifloxacin