The Mechanisms of Insulin Secretion and Calcium Signaling in Pancreatic β-Cells Exposed to Fluoroquinolones

Fluoroquinolones reportedly induce hypoglycemia through stimulation of insulin secretion from pancreatic β-cells via inhibition of KATP channels and activation of L-type voltage-dependent Ca2+ channels. In physiological condition, the cytosolic Ca2+ concentration ([Ca2+]c) is also regulated by release of Ca2+ from intracellular Ca2+ stores. In this study, we investigated the mechanism of insulin secretion induced by fluoroquinolones, with respect to intracellular Ca2+ stores. Even where the absence of supplemental extracellular Ca2+, insulin secretion and [Ca2+]c were increased by gatifloxacin, levofloxacin or tolbutamide. Insulin secretion and the rise of [Ca2+]c induced by fluoroquinolones were reduced by depleting of Ca2+ 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 [Ca2+]c. Destruction of acidic Ca2+ stores such as lysosome and lysosome-related organelles by glycyl-L-phenylalanine-2-nephthylamide (GPN) did not affect insulin secretion and the rise of [Ca2+]c induced by fluoroquinolones. The increase in insulin and [Ca2+]c induced by tolbutamide were reduced by thapsigargin, dantrolene, and GPN but not by xestospongin C. In conclusion, fluoroquinolones induces Ca2+ release from ER mediated by the ryanodine receptor, and the reaction might involve in insulin secretion. Sulfonylureas induce Ca2+ release from GPN-sensitive acidic Ca2+ stores, but fluoroquinolones did not.