Transient Gain of Function of Cannabinoid CB ₁ Receptors in the Control of Frontocortical Glucose Consumption in a Rat Model of Type-1 Diabetes

Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB₁ receptor (CB₁R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB₁R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB₁R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB₁R agonists, WIN55212-2 (500 nM) and the CB₁R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB₁R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB₁Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKβ levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB₁R density within a month after T1D induction resolves previous controversial reports on forebrain CB₁R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.

Keywords: Cannabinoid CB(1)receptor; Cerebral glucose metabolism; Frontal cortex; Goto-Kakizaki rat; Wistar rat; type-1 diabetes.