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Recent interest in the endocrine pancreas has revealed the presence of a functional endocannabinoid system in pancreatic islets, however, the effects of endocannabinoids and cannabinoid CB receptor activation on downstream signalling and on insulin release still remains unclear. In the current study, a variety of purported cannabinoid CB receptor agonists and antagonists were evaluated for their effects on insulin secretion. In fresh rat isolated islets, the endocannabinoid anandamide caused a glucose-dependent, concentration-dependent inhibition of insulin release, with two populations of islets being identified based on their sensitivity to anandamide. Methanandamide (a non-hydrolysable analogue of anandamide) elicited similar inhibition of insulin secretion, comparable to the responses obtained with anandamide-sensitive islets, suggesting that the islet responsiveness may be due to differences in local metabolism of anandamide. The antagonists O-2050 (CB1) and AM630 (CB2) failed to reveal the involvement of cannabinoid receptors in the inhibitory activity of anandamide on insulin release. Inhibition of fatty acid amide hydrolase (FAAH) with URB597 did not alter basal or glucose-induced insulin secretion, suggesting that endogenous islet endocannabinoids do not affect insulin release, or that islet FAAH content is low. URB597 also failed to affect the inhibitory actions of anandamide on insulin release in fresh isolated islets. However, in islets following overnight culture, anandamide caused augmentation of basal and glucose-mediated insulin release. The effects of cannabinoid agents on insulin secretion described in this study does not identify a precise mode of action but points to important modulation which may be dependent on local metabolism and prevailing cellular conditions.