Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice

Mol Cell Endocrinol. 2016 Mar 5;423:1-10. doi: 10.1016/j.mce.2015.12.015. Epub 2015 Dec 25.

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.

Keywords: Adenylyl cyclase; CB1; GLP-1; Incretin; Insulin secretion; cAMP.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / pharmacology
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cell Line, Tumor
  • Cyclic AMP / biosynthesis
  • Endocannabinoids / pharmacology
  • Genetic Predisposition to Disease
  • Glucagon-Like Peptide-1 Receptor / physiology*
  • Glycerides / pharmacology
  • Humans
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / blood
  • Obesity / genetics
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / genetics*
  • Receptor, Cannabinoid, CB1 / metabolism

Substances

  • Arachidonic Acids
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Endocannabinoids
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Glycerides
  • Insulin
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251
  • glyceryl 2-arachidonate
  • Cyclic AMP
  • anandamide