title: Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice.
abstract: The cannabinoid 1 receptor (CB1) is an important regulator of energy metabolism. Reports of in vivo and in vitro studies give conflicting results regarding its role in insulin secretion, possibly due to circulatory factors, such as incretins. We hypothesized that this receptor may be a regulator of the entero-insular axis. We found that despite lower food consumption and lower body weight postprandial GLP-1 plasma concentrations were increased in CB1(-/-) mice compared to CB1(+/+) mice administered a standard diet or high fat/sugar diet. Upon exogenous GLP-1 treatment, CB1(-/-) mice had increased glucose-stimulated insulin secretion. In mouse insulinoma cells, cannabinoids reduced GLP-1R-mediated intracellular cAMP accumulation and subsequent insulin secretion. Importantly, such effects were also evident in human islets, and were prevented by pharmacologic blockade of CB1. Collectively, these findings suggest a novel mechanism in which endocannabinoids are negative modulators of incretin-mediated insulin secretion.
authors.affiliation: National Institute on Aging/NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Mariscal
authors.affiliation: National Institute on Aging/NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Krzysik-Walker
authors.affiliation: National Institute on Aging/NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA; Department of Molecular Science and Technology, Ajou University, Suwan 443-749, South Korea. Electronic address: wookkim21@ajou.ac.kr.
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.affiliation: National Institute on Aging/NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rouse
authors.affiliation: National Institute on Aging/NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000096:biosynthesis; D063388:Endocannabinoids / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D000067757:Glucagon-Like Peptide-1 Receptor / Q000502:physiology*; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D005989:Glycerides; D007328:Insulin; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C094503:glyceryl 2-arachidonate; D000242:Cyclic AMP; C078814:anandamide
keywords: Adenylyl cyclase; CB1; GLP-1; Incretin; Insulin secretion; cAMP