Gatifloxacin Induces Augmented Insulin Release and Intracellular Insulin Depletion of Pancreatic Islet Cells

Abstract

Many hypoglycemic and hyperglycemic episodes associated with clinical use of gatifloxacin (GFLX), a novel fluoroquinolone antimicrobial agent, have been reported in recent years. Some have reported hypoglycemia induced by fluoroquinolones, indicating that these agents may stimulate insulin secretion from pancreatic islet cells. In this study, we investigated the effect of GFLX on insulin homeostasis in islet cells using the insulin secreting cell line, HIT-T15. After 1 h incubation with over 100 m mM of GFLX, insulin secretion from the cells was significantly augmented. However, the augmentation of insulin release induced by GFLX subsequently reached a plateau. Coincidentally, cellular insulin was decreased by 120 h incubation, and reactivity to re-stimulation by sulfonylurea was suppressed. The GFLX insulin depletion effect was stronger than the effects produced by such other fluoroquinolones as levofloxacin and ciprofloxacin. This study suggests that GFLX should induce insulin oversecretion from pancreatic islet cells in the short-term, and decrease insulin productivity or increase insulin disintegration in the long-term. These results are consistent with the clinical results of GFLX finding that hypoglycemic episodes were seen after a first single administration, and most hyperglycemic episodes were seen more than 2 d after the start of administration.

Clinicopathological Aspect of Dysglycemia in Naive and Diabetic Rats induced by the Fluoroquinolone Antibacterial Gatifloxacin

“…On the basis of fluctuations of blood glucose concentrations in naive and diabetic rats given GFLX, our nonclinical results resembled somewhat previous in vitro and clinical profiles showing that hypoglycemic episodes were seen after an initial single exposure [19], and that most hyperglycemic episodes were seen in patients with diabetes mellitus more than 2 days after the start of administration [3].…”

“…GFLX has been reported to largely affect insulin secretion [17,19,22], and to inhibit pancreatic K ATP channel currents, especially via the pore-forming subunit Kir6.2 [17].…”

“…Yamada et al [22] reported that GFLX acutely stimulated insulin secretion associated with hypoglycemia, and chronic GFLX exposure decreased islet insulin content by inhibiting insulin biosynthesis related to hyperglycemia in mouse pancreatic islets. Tomita et al [19] reported that GFLX induced insulin oversecretion in the short-term, and decreased insulin productivity or increased insulin disintegration in the long-term using the insulin-secreting cell line HIT-T15. Based on the in vivo studies, Ishiwata et al [10] reported that serum glucose concentrations decreased and increased in normal and streptozotocin-induced diabetic rats, respectively, given a single intravenous injection of GFLX at 50 mg/kg, with elevations in both serum insulin and epinephrine (adrenaline) concentrations.…”

The insulinotropic effect of fluoroquinolones

“…Fluoroquinolones may have effects on the B-cell in addition to K ATP channel blockade, but not effects which can stimulate insulin secretion independently of the K ATP channel activity. It is unclear whether the decrease of insulin content by gatifloxacin [17,26] is such an additional effect, since sulfonylureas are also able to degranulate B-cells [27] Depolarizing effect…”

“…Finally, gatifloxacin is also associated with the induction of hyperglycemic episodes in diabetic and non-diabetic patients [15,16]. The hyperglycemic episodes, which are even more frequent than the hypoglycemic episodes [1] are not easily explained by a block of K ATP channels [17].…”