Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells

Abstract

Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse beta-cell lines, human islets and CB1R-null (CB1R(-/-) ) mice, we have now investigated the role of CB1Rs in modulating beta-cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP-1-mediated cAMP accumulation and insulin secretion as well as glucose-stimulated insulin secretion in mouse beta-cell lines and human islets. In addition, silencing CB1R in mouse beta cells resulted in an increased expression of pro-insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in beta cells lacking insulin receptor. Furthermore, CB1R(-/-) mice had increased pro-insulin, GCK and GLUT2 expression in beta cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve beta-cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to beta-cell function in type 2 diabetes.