Chronic insulinopenia/hyperglycemia decreases cannabinoid CB₁ receptor density and impairs glucose uptake in the...

Both endocannabinoids and insulin regulate peripheral and cerebral glucose homeostasis via convergent signaling pathways that are impacted by diabetes. Here we asked how glucose metabolism and important facets of insulin signaling are affected in the forebrain of cannabinoid CB₁ receptor knockout mice (CB₁R-KO) and their wild-type (WT) littermates, seven weeks after the induction of insulinopenia/hyperglycemia (diabetes) with intraperitoneal streptozotocin injection. Sham-injected animals served as control. Diabetes caused milder weight loss in the WT mice compared to the phenotypically ˜11% leaner CB₁R-KO, while hyperglycemia was similar. Resting [³H]deoxyglucose uptake was significantly reduced by ˜20% in acute ex vivo frontocortical and hippocampal slices obtained from both the sham-injected CB₁R-KO and the diabetic WT mice. Surprisingly, the third cohort, the diabetic CB₁R-KO showed no further impairment in glucose uptake, as compared to the sham-injected CB₁R-KO. Depolarization-induced [³H]deoxyglucose uptake was proportional to the respective resting values only in the cortex in all four cohorts. The dissipative metabolism of [¹⁴C]-U-glucose remained largely unaffected in all cohorts of animals. However, diabetes reduced cortical CB₁R density by ˜20%, as assessed by Western blotting. Albeit the changes in insulin signaling did not reflect the glucose uptake profile in each cohort, there were significant interactions between diabetes and genotype. In conclusion, a chronic decrease or lack of CB₁R expression reduces glucose uptake in the mouse brain. Additionally, diabetes failed to cause further impairment in cerebral glucose uptake in the CB₁R-KO. These suggest that diabetic encephalopathy may be in part associated with lower CB₁R expression.