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Sci. Signal., 20 March 2012
Vol. 5, Issue 216, p. ra23
[DOI: 10.1126/scisignal.2002519]


Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation

Wook Kim1, Qizong Lao1, Yu-Kyong Shin1, Olga D. Carlson1, Eun Kyung Lee2, Myriam Gorospe1, Rohit N. Kulkarni3, and Josephine M. Egan1*

1 National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2 Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul 137-701, Republic of Korea.
3 Department of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

Abstract: Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic β cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate–binding protein α subunit Gαi. Gαi inhibited the kinase activity of the insulin receptor in β cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad was reduced and its apoptotic activity was stimulated, leading to β-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors enhanced insulin receptor signaling after injury, leading to reduced blood glucose concentrations and activation of Bad, which increased β-cell survival. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and suggest a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors.

* To whom correspondence should be addressed. E-mail: eganj{at}

Citation: W. Kim, Q. Lao, Y.-K. Shin, O. D. Carlson, E. K. Lee, M. Gorospe, R. N. Kulkarni, J. M. Egan, Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation. Sci. Signal. 5, ra23 (2012).

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