Article ; Online: A peripherally restricted cannabinoid-1 receptor inverse agonist promotes insulin secretion and protects from cytokine toxicity in human pancreatic islets.
European journal of pharmacology
2023 Volume 944, Page(s) 175589
Abstract: 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- ... ...
Abstract | 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. |
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MeSH term(s) | Mice ; Animals ; Humans ; Insulin Secretion ; Drug Inverse Agonism ; Insulin/metabolism ; Cytokines/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Exenatide/pharmacology ; Cannabinoid Receptor Agonists/pharmacology ; Islets of Langerhans ; Insulin-Secreting Cells ; Cannabinoids/pharmacology |
Chemical Substances | Insulin ; Cytokines ; Exenatide (9P1872D4OL) ; Cannabinoid Receptor Agonists ; Cannabinoids |
Language | English |
Publishing date | 2023-02-09 |
Publishing country | Netherlands |
Document type | Journal Article |
ZDB-ID | 80121-5 |
ISSN | 1879-0712 ; 0014-2999 |
ISSN (online) | 1879-0712 |
ISSN | 0014-2999 |
DOI | 10.1016/j.ejphar.2023.175589 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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