Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β-Cells
- Wook Kim1,
- Máire E. Doyle2,
- Zhuo Liu1,
- Qizong Lao1,
- Yu-Kyong Shin1,
- Olga D. Carlson1,
- Hee Seung Kim1,
- Sam Thomas1,
- Joshua K. Napora1,
- Eun Kyung Lee1,
- Ruin Moaddel1,
- Yan Wang1,
- Stuart Maudsley1,
- Bronwen Martin1,
- Rohit N. Kulkarni3 and
- Josephine M. Egan1⇓
- 1National Institute on Aging, National Institutes of Health, Baltimore, Maryland
- 2Division of Endocrinology, Johns Hopkins Medical Institutes, Baltimore, Maryland
- 3Department of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Corresponding author: Josephine M. Egan, .
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.
RESEARCH DESIGN AND 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 Gαi-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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1550/-/DC1.
- Received November 9, 2010.
- Accepted January 4, 2011.
- © 2011 by the American Diabetes Association.
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