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

Isabel González-Mariscal, Susan M. Krzysik-Walker, Wook Kim*, Michael Rouse, Josephine M. Egan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume423
DOIs
StatePublished - 5 Mar 2016
Externally publishedYes

Keywords

  • Adenylyl cyclase
  • CAMP
  • CB1
  • GLP-1
  • Incretin
  • Insulin secretion

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