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 8-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 8-arrestins in 8-cells. Peripherally restricted CB1R inverse agonists purportedly have beneficial effects on insulin secretion in 8-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 8-cells from cytokine toxicity and to promote insulin secretion.

Automated summary

MRI-1891, a peripherally restricted CB1R inverse agonist, enhances glucose stimulated insulin secretion in isolated human and mouse pancreatic islets, and protects islet cells from cytokine-induced apoptosis, showing potential as a therapeutic for both type 1 and type 2 diabetes.