Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation

Abstract

Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic β cells, where they influence insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and Gαi, which inhibits insulin receptor kinase activity in β cells by directly binding to the activation loop in the tyrosine kinase domain of the insulin receptor. Consequently, phosphorylation of pro-apoptotic protein Bad was reduced, leading to activation of Bad and induction of β-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors led to reduced blood glucose and increased β-cell survival after injury due to enhanced insulin receptor signaling and reduced activation of Bad. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and provide a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors.

The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease

“…This mechanism could therefore participate to the hyperinsulinemia typically observed in type 2 diabetes [76]. In addition, CB 1 Rs may regulate b cell health, either indirectly, through the induction of proinflammatory macrophages in the pancreas [77], or directly by stimulating apoptotic activity and b cell death [78]. Conversely, CB 1 R blockade increases b cell proliferation and mass [79].…”

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

“…Although important, sympathetic ligands alone likely do not explain all the PTX-sensitive inhibition of β-cell proliferation, and other Gi-GPCRs, such as Cnr1, along with non-cell-autonomous effects of Gα i/o signaling, surely contribute as well (24,(36)(37)(38).…”

Endocannabinoids and Metabolic Disorders

“…CB 1 receptor blockade also seems to ameliorate β cell function in obesity by increasing β cell proliferation and mass (Kim et al 2011). Indeed, CB 1 receptor activation stimulates apoptotic activity and β cell death (Kim et al 2012). Moreover, macrophage infiltration of pancreatic islets and consequent inflammation, which plays a role in the pathogenesis of diabetes, is a phenomenon recently recognized to be under the control of CB 1 receptor activity.…”