title: Cannabinoids inhibit insulin receptor signaling in pancreatic β-cells.
abstract: OBJECTIVE
  Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action.
  
  
  METHODS
  We measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KCl. We evaluated human and mouse islets, several β-cell lines, and CB1R-null (CB1R(-/-)) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice.
  
  
  RESULTS
  ECs are generated within β-cells, which also express CB1Rs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased β-cell proliferation and mass, coupled with enhanced IR signaling in β-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on β-cells in a Gα(i)-dependent manner.
  
  
  CONCLUSIONS
  These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes.
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.forename: Máire E
authors.initials: ME
authors.lastname: Doyle
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Liu
authors.forename: Qizong
authors.initials: Q
authors.lastname: Lao
authors.forename: Yu-Kyong
authors.initials: YK
authors.lastname: Shin
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.forename: Hee Seung
authors.initials: HS
authors.lastname: Kim
authors.forename: Sam
authors.initials: S
authors.lastname: Thomas
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Napora
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D010880:Piperidines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007211:Indoles; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D011189:Potassium Chloride; D011972:Receptor, Insulin; D051960:GTP-Binding Protein alpha Subunit, Gi2; D005947:Glucose; C094023:iodopravadoline