Arachidonic acid signaling is involved in the mechanism of imidazoline-induced KATP channel-independent stimulation of insulin secretion

Abstract

The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated. The roles of KATP channels, alpha2-adrenoreceptors, the I1-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied. Using SUR1(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on alpha2-adrenoreceptors, I1-imidazoline receptors or PC-PLC. BL11282 significantly increased [3H]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.

Dissection of mechanisms that account for imidazoline-induced lowering of blood glucose in mice

“…This provided a plausible alternative explanation for promotion of insulin release, as further supported by evidence that idazoxan is a less effective K ATP channel blocker than the insulinotropic imidazolines phentolamine and efaroxan (Chan and Morgan, 1990;Östenson et al, 1989;Rustenbeck et al, 1999;Shepherd et al, 1996). But again, the whole matter became complicated by evidence for another site of action distal to Ca 2 þ influx into the β-cell, which some regarded as the truly important mechanism of insulinotropic action Efendic et al, 2002;Meidute-Abaraviciene et al, 2009;Sharoyko et al, 2007;Zaitsev et al, 1996). More recently, evidence arose that variations in or near the gene encoding the α 2A -adrenoceptor (ADRA2A) may pre-dispose individuals to type 2 diabetes, which led to speculations that α 2A -antagonists could be a treatment tailored to those carrying the at-risk mutations (Gribble, 2010;Liggett, 2009;Rosengren et al, 2010;Wess, 2010).…”

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…More recently, the cardioprotective effect of EETs administered prior to ischemia was attributed to the activation of the eNOS and increased NO production, whereas K ATP channel activation and the mitochondrial permeability transition pore were involved in the beneficial effects of the EETs when administered just prior to reperfusion (Gross et al, 2013). The actions of EETs in other organs, such as insulin secretion in pancreatic islets, may also be linked to K ATP channel activation (Sharoyko et al, 2007).…”

AHNAK KO Mice are Protected from Diet-Induced Obesity but are Glucose Intolerant

“…In the presence of AA, AHNAK is also known to activate PLCγ [19]. There are studies that report involvement of AA signaling in calcium mobilization in beta cells and stimulated insulin secretion [35][36][37]. Thus, AHNAK KO might lead to impairment in insulin secretion via impaired calcium influx.…”