biostudies-literatureAbbas ABritish Heart FoundationMedical Research CouncilWellcome Trust2169-78https://www.ebi.ac.uk/biostudies/studies/S-EPMC3142083biostudies-literatureUnknown60(8)<h4>Objective</h4>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).<h4>Research design and methods</h4>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 andDiabetesThe insulin-like growth factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium.PMC3142083PG/09/042/27518RG/07/003/23133FS/10/028/28252090532Beech DJViswambharan HKearney MTGage MKahn MSukumar PImrie HRajwani ASmith JChannon KMWheatcroft SBCubbon RMXuan SAbbas AGalloway SYuldeshava NGrant PJfalseThe insulin-like growth factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium.<h4>Objective</h4>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).<h4>Research design and methods</h4>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 and2011-01-01T00:00:00Z2011 Aug2025-04-04T12:00:43.518Z2019-03-27T03:07:20ZS-EPMC31420832167728410.2337/db11-0197