Abbas, A, Imrie, H orcid.org/0000-0002-1940-6604, Viswambharan, H orcid.org/0000-0002-7616-5026 et al. (14 more authors) (2011) The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium. Diabetes, 60 (8). pp. 2169-2178. ISSN 0012-1797
Abstract
OBJECTIVE—In mice, haploinsufficiency of the IGF-1 receptor (IGF-1R+/2), 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-1Rab and one insulin receptor (IR), IRab 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 IGF1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability.
RESULTS—IGF-1R+/2 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.