Type 2 diabetes mellitus is a chronic condition caused by a deficiency in the secretion of insulin from the islets of Langerhans and/or impaired insulin signalling, resulting in hyperglycaemia. The role of the endocannabinoid system is well-recognised in the CNS and immune system, but its role in glucose homeostasis is poorly understood. The aim of this study was to define the roles of cannabinoids in insulin secretion, to provide insights into their therapeutic potential (or limitation) in the treatment of type 2 diabetes. Isolated islets were used, from Wistar rats, in static incubation studies measuring changes in insulin secretion rates. The endocannabinoid anandamide (AEA) was found to inhibit insulin secretion in a glucose- and concentration-dependent manner, with an IC50 of 1.6μM (95% CI: 227nM to 4.0μM; n= 10). Upon further analysis of the concentration-response data islet sensitivity to AEA appeared to vary, with islets either appearing to be sensative (IC50 220nM; 95% CI: 21.9nM to 2.2μM; n= 5) or less sensative (IC50 12.3μM; 95% CI: 6.8μM to 19.4μM; n= 5) to AEA. Pre-incubation of islets with a fatty acid amide hydrolase inhibitor did not affect islet responsiveness to AEA. AEA-mediated inhibition of insulin secretion was not consistently affected by cannabinoid receptor 1 (CB1) or CB2 antagonism. Surprisingly, the CB1 receptor antagonist AM251 was found to inhibit insulin secretion in a glucose- and concentration-dependent (IC50 1.6μM; 95% CI: 507nM to 3.3μM; n= 6) manner. Results from this study suggest that differences in CB-receptor signalling pathways, rather than endocannabinoid metabolism, could be responsible for the variations in the potency of AEA between islet preparations. Characterisation of cannabinoid signalling in islets was hindered as the CB receptor antagonists used in this study also affected insulin secretion. This study highlights the dynamics of endocannabinoid signalling in islets, which may be linked to their physiological function.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:539187 |
| Date | January 2011 |
| Creators | Anderson, Richard L. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/11760/ |
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