A peripherally restricted cannabinoid-1 receptor inverse agonist promotes insulin secretion and protects from cytokine toxicity in human pancreatic islets

The Cannabinoid Receptor CB1R is expressed in pancreatic β-cells; CB1R increased activity is associated with diabetes, obesity, cardiovascular disorders as well as decreased Insulin secretion and Insulin resistance. CB1R was shown to signal through G-protein coupling as well as β-arrestins in β-cells. Peripherally restricted CB1R inverse agonists purportedly have beneficial effects on Insulin secretion in β-cells, without the unwanted effects in the central nervous system. Here we show that a peripherally restricted CB1R inverse agonist, MRI-1891, augments glucose stimulated Insulin secretion in isolated human pancreatic islets and mouse islets. The Insulin secretion enhancing effect of MRI-1891 is comparable to exendin-4, an analogue of the glucagon like peptide-1 (GLP1). Moreover, MRI-1891 treatment protects isolated human islet cells against cytokine-induced Apoptosis, similar to exendin-4. Thus, MRI-1891, a new class of CB1R inverse agonist, may be considered a potential therapeutic for both type 1 and type 2 diabetes because of its ability to protect pancreatic β-cells from cytokine toxicity and to promote Insulin secretion.