Zafirlukast promotes insulin secretion by increasing calcium influx through L‐type calcium channels

Abstract

The zafirlukast has been reported to be anti-inflammatory and widely used to alleviate the symptoms of asthma. However, its influence on insulin secretion in pancreatic β-cells has not been investigated. Herein, we examined the effects of zafirlukast on insulin secretion and the potential underlying mechanisms. Among the cysteinyl leukotriene receptor 1 antagonists, zafirlukast, pranlukast, and montelukast, only zafirlukast enhanced insulin secretion in a concentration-dependent manner in both low and high glucose conditions and elevated the level of [Ca ] , further activating Ca /calmodulin-dependent protein kinase II (CaMKII), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) signaling. These effects were nearly abolished by the L-type Ca channel antagonist nifedipine, while treatment with thapsigargin, a sarco/endoplasmic reticulum Ca ATPase inhibitor, did not have the same effect, suggesting that zafirlukast primarily induces the entry of extracellular Ca rather than intracellular Ca from the endoplasmic reticulum. Zafirlukast treatment resulting in a significant drop in glucose levels and increased insulin secretion in C57BL/6J mice. These findings will contribute to an improved understanding of the side effects of zafirlukast and potential candidate for a therapeutic intervention in diabetes.

Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in β Cells

“…However, our further results show that the S1P-stimulated [Ca 2+ ] i levels were reduced compared with those observed in Ca 2+ -containing KRB solution in the absence of extracellular Ca 2+ (chelated by EGTA), suggesting S1P markedly increased [Ca 2+ ] i in pancreatic β cells, mainly through extracellular Ca 2 + influx. And other reports support this notion that extracellular Ca 2+ influx via L-VDCC is crucial for regulating [Ca 2+ ] i in β cells (Bokvist, et al, 1995;Hwang, et al, 2018). In our study, patch clamp results showed that the increase in [Ca 2+ ] i is related to the inhibition of Kv channels by S1P, which prolongs the duration of the action potential, indirectly increases voltage dependent Ca 2+ influx, instead of directly affecting VDCC.…”

Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ

“…In line with these observations, higher doses of montelukast and zafirlukast are effective in several animal models of CVDs were they showed anti-atherosclerotic effects, protected from myocardial infarction and renal perfusion injury in rabbits, rats and mice (Sener et al, 2006; Jawien et al, 2008; Mueller et al, 2008; Ge et al, 2009; Liu et al, 2009). In addition, during treatment with zafirlukast (20 mg, twice daily) rare cases of hypoglycemic events were observed and it was shown recently that the compound increases insulin secretion from pancreatic β cells (Calhoun et al, 1998; Hwang et al, 2018). These findings concerning the beneficial effects on cardiovascular and diabetic disorders clearly argue for an additional, CysLT-unrelated, mechanism of action which can be exploited for therapy in the future.…”

Zafirlukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Reduces the Effect of Advanced Glycation End-Products in Rat Renal Mesangial Cells In Vitro

“…Zafirlukast, an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1), is approved for the treatment of chronic asthma as an anti-inflammatory agent and has also been reported to promote insulin secretion [25]. Zafirlukast is a potential hypoglycemic agent that was investigated in this study for its in vitro effects on renal mesangial cells that were cultured with increasing doses of advanced glycation end-products (AGEs).…”

“…Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1) that is currently prescribed for chronic asthma. Zafirlukast has a dual role in stimulating insulin secretion, and it also has anti-inflammatory effects [16,17]. AGEs that are formed by the glycation of lipids and proteins in conditions of hyperglycemia, including diabetes mellitus, are important inflammatory mediators in diabetes that increase the expression of tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), and IL-6, and induce cell apoptosis [13,18,19].…”

“…Inflammation is involved in the pathogenesis of diabetic nephropathy, and as well as promoting insulin secretion, zafirlukast has previously been shown to have anti-inflammatory effects [25,26]. However, zafirlukast has not previously been studied in diabetic nephropathy.…”