BACKGROUND AND PURPOSE:

G-protein coupled receptor (GPR)55 is a novel lipid sensing receptor activated by both cannabinoid endogenous ligands (endocannabinoids) and other non-cannabinoid lipid transmitters. This study assessed the effects of various GPR55 agonists on glucose homeostasis.

EXPERIMENTAL APPROACH:

Insulin secretion and changes in intracellular Ca²⁺ and cAMP in response to glucose and a range of GPR55 agonists (endogenous ligands (OEA, PEA), chemically synthetic CBD analogues (Abn-CBD, 0-1602), an analogue of rimonabant (AM-251) and antagonist (CBD)) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Cytotoxicity was assessed by LDH release, cellular localisation by double-staining immunohistochemistry and in vivo effects assessed in mice.

KEY RESULTS:

The most potent and selective GPR55 agonist was the synthetic CBD analogue, Abn-CBD (pEC₅₀ 10.33), maximum stimulation of 67% at 10^-4 mol/l (p<0.001) in BRIN-BD11 cells. AM-251 (pEC₅₀ 7.0), OEA (pEC₅₀ 7.0), 0-1602 (pEC₅₀ 7.3) and PEA (pEC₅₀ 6.0) stimulated insulin secretion. Results were corroborated by islet studies, with no cytotoxic effects. Concentration-dependent insulin secretion by GPR55 agonists was glucose-sensitive and accompanied by elevations of [Ca²⁺ ]_i (p<0.01-p<0.001) and cAMP (p<0.05-p<0.01). GPR55 agonists exhibited insulinotropic and glucose lowering activity in vivo. GPR55 was expressed on BRIN-BD11 cells and confined to islet beta cells with no distribution on alpha cells.

CONCLUSIONS AND IMPLICATIONS:

These results demonstrate GPR55 is distributed in pancreatic beta cells and is a strong activator of insulin secretion, with glucose-lowering effects in vivo. Development of agents agonising the GPR55 receptor may have therapeutic potential in the treatment of type 2 diabetes.
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PMID:

 23992544
[PubMed – as supplied by publisher]