The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium
- Afroze Abbas1,
- Helen Imrie1,
- Hema Viswambharan1,
- Piruthivi Sukumar1,
- Adil Rajwani1,
- Richard M. Cubbon1,
- Matthew Gage1,
- Jessica Smith1,
- Stacey Galloway1,
- Nadira Yuldeshava1,
- Matthew Kahn1,
- Shouhong Xuan2,
- Peter J. Grant1,
- Keith M. Channon3,
- David J. Beech1,
- Stephen B. Wheatcroft1 and
- Mark T. Kearney1⇓
- 1Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, U.K.
- 2Department of Genetics and Development, Columbia University, New York, New York
- 3British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, U.K.
- Corresponding author: Mark T. Kearney, .
A.A., H.I., and H.V. contributed equally to this study.
OBJECTIVE In mice, haploinsufficiency of the IGF-1 receptor (IGF-1R+/−), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1Rαβ and one insulin receptor (IR), IRαβ complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO).
RESEARCH DESIGN AND METHODS Using a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability.
RESULTS IGF-1R+/− mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity.
CONCLUSIONS These data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0197/-/DC1.
- Received February 15, 2011.
- Accepted May 15, 2011.
- © 2011 by the American Diabetes Association.
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