Publication
Title
Cannabinoids inhibit insulin receptor signaling in pancreatic -cells
Author
Abstract
OBJECTIVE-Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting beta-cells in the islets of Langerhans. Insulin itself positively regulates beta-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coining 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 beta-cell proliferation and if they influence insulin action. RESEARCH DESIGN AND METHODS-We measured EC production in isolated human and mouse islets and beta-cell line in response to glucose and KC1. We evaluated human and mouse islets, several beta-cell lines, and CB1R-null (CB1R(-/-)) mice for the presence of a fully functioning EC system. We investigated if ECs influence beta-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 beta-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 beta-cells and leads to increased beta-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased beta-cell proliferation and mass, coupled with enhanced IR signaling in beta-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on beta-cells in a G alpha(i)-dependent manner. CONCLUSIONS-These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of beta-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance beta-cell function and proliferation in diabetes. Diabetes 60:1198-1209, 2011
Language
English
Source (journal)
Diabetes / American Diabetes Association. - New York, N.Y., - 2006
Publication
New York, N.Y. : 2011
ISSN
0012-1797
Volume/pages
60:4(2011), p. 1198-1209
ISI
000289496100015
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 06.01.2015
Last edited 18.06.2017