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

This is the authors' abstract. We don't add key points for this paper.

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.