We have demonstrated previously that mouse and human islets express ECS (endocannabinoid system) elements, and that short-term activation of islet cannabinoid CB1r and CB2r (cannabinoid type 1 and 2 receptors respectively) stimulates insulin secretion in vitro. There is evidence that the ECS is overactive in Type 2 diabetes, impairing glucose homoeostasis, but little is known about whether it is implicated in islet dysfunction. Therefore the aim of the present study was to investigate the effect of chronic exposure of isolated mouse islets to cannabinoid receptor agonists on islet gene expression and function. Quantitative RT–PCR (reverse transcription–PCR) indicated that mRNAs encoding synthesis [NAPE-PLD (N-acyl-phosphatidyl ethanolamide-hydrolysing phospholipase D)] and degradation [FAAH (fatty acid amide hydrolase)] of the endocannabinoid AEA (anandamide) were the most abundant ECS elements in mouse islets, with much lower levels of CB1r, CB2r, DAGL (diacylglycerol lipase) and MAGL (monoacylglycerol lipase) mRNAs. Maintenance of islets for up to 7 days in the presence of the CB1r agonist ACEA [N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eiscosatetraenamide] or the CB2r agonist JWH015 [(2-methyl-1propyl-1H-indol3-yl)-1-napthalenylmethanone] did not compromise islet viability, as assessed by islet morphology and caspase activities, but there were some changes in mRNAs encoding ECS components. Neither glucose-stimulated insulin secretion nor acute insulin secretory responses to ACEA or JWH015 at 16 mM glucose were substantially modified by a 48 h or 7 day pre-exposure to these cannabinoid receptor agonists, but the stimulation of secretion at 3 mM glucose by 100 nM ACEA was significantly reduced after prolonged treatment with ACEA. Despite JWH015-induced reductions in islet glucagon content at 48 h and 7 days, there were no reductions in arginine-induced glucagon secretion from islets pre-exposed to JWH015 or ACEA. These data indicate that treatment of islets with agonists of CB1r and CB2r for up to 7 days does not have any major impact on islet function, suggesting that the impairments in glucose homoeostasis observed following overactivation of the ECS should be sought in relation to insulin resistance rather than β-cell dysfunction.
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Research Article|
December 07 2012
Chronic activation of cannabinoid receptors in vitro does not compromise mouse islet function
Alonso Vilches-Flores;
Alonso Vilches-Flores
*Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, London, U.K.
†Universidad Nacional Autonoma de Mexico, Campus Iztacala, Tlalnepantla, Mexico
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Astrid C. Hauge-Evans;
Astrid C. Hauge-Evans
*Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, London, U.K.
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Peter M. Jones;
Peter M. Jones
*Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, London, U.K.
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Shanta J. Persaud
*Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, London, U.K.
Correspondence: Professor Shanta J. Persaud (email [email protected]).
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Publisher: Portland Press Ltd
Received:
August 17 2012
Revision Received:
October 15 2012
Accepted:
October 19 2012
Accepted Manuscript online:
October 19 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 124 (7): 467–478.
Article history
Received:
August 17 2012
Revision Received:
October 15 2012
Accepted:
October 19 2012
Accepted Manuscript online:
October 19 2012
Citation
Alonso Vilches-Flores, Astrid C. Hauge-Evans, Peter M. Jones, Shanta J. Persaud; Chronic activation of cannabinoid receptors in vitro does not compromise mouse islet function. Clin Sci (Lond) 1 April 2013; 124 (7): 467–478. doi: https://doi.org/10.1042/CS20120447
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