DAGL inhibitors have been proposed to treat metabolic disorders due to their effects on the CB1 receptor through 2-AG (Janssen & van der Stelt, 2016).
So far, Anandamide and CB1, CB2 and GPR55 receptors are implicated in the pathophysiology of diabetes type 2 (Jenkin et al., 2014; Jourdan et al., 2014; Troy-Fioramonti et al., 2014). This suggests the endocannabinoid system is a valid target for the treatment of diabetes type 2.
In line with this, CBD and THC were found to help maintain healthy blood-glucose levels and counteract diabetic oxidative stress (Coskun and Bolkent, 2014; Wheal et al., 2014) In mice, CBD was found to prevent β-cell degeneration and insulitis and thus to reduce the incidence and slow-down the development of type 1 diabetes (Weiss et al., 2006, 2008). Similar results were obtained with THC (Li et al., 2001).
Coskun, Z.M., and Bolkent, S. (2014). Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ9-THC. Cell Biochem. Funct. 32, 612–619.
Janssen, F. J., & van der Stelt, M. (2016). Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders. Bioorganic & Medicinal Chemistry Letters, 26(16), 3831-3837. https://doi.org/10.1016/j.bmcl.2016.06.076
Jenkin, K.A., McAinch, A.J., Zhang, Y., Kelly, D.J., and Hryciw, D.H. (2014). Elevated CB1 and GPR55 receptor expression in proximal tubule cells and whole kidney exposed to diabetic conditions. Clin. Exp. Pharmacol. Physiol.
Jourdan, T., Szanda, G., Rosenberg, A.Z., Tam, J., Earley, B.J., Godlewski, G., Cinar, R., Liu, Z., Liu, J., Ju, C., et al. (2014). Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A. 111, E5420–E5428.
Li, X., Kaminski, N.E., and Fischer, L.J. (2001). Examination of the immunosuppressive effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes. Int. Immunopharmacol. 1, 699–712.
Troy-Fioramonti, S., Demizieux, L., Gresti, J., Muller, T., Vergès, B., and Degrace, P. (2014). Acute Activation of cannabinoid Receptors by Anandamide Reduces Gastro-Intestinal Motility and Improves Postprandial Glycemia in Mice. diabetes.
Weiss, L., Zeira, M., Reich, S., Har-Noy, M., Mechoulam, R., Slavin, S., and Gallily, R. (2006). Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39, 143–151.
Weiss, L., Zeira, M., Reich, S., Slavin, S., Raz, I., Mechoulam, R., and Gallily, R. (2008). Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology 54, 244–249.
Wheal, A.J., Cipriano, M., Fowler, C.J., Randall, M.D., and O’Sullivan, S.E. (2014). Cannabidiol improves vasorelaxation in Zucker diabetic fatty rats through cyclooxygenase activation. J. Pharmacol. Exp. Ther. 351, 457–466.