title: The insulin-like growth factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium.
abstract: 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).
  
  
  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.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK.
authors.forename: Afroze
authors.initials: A
authors.lastname: Abbas
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.forename: Hema
authors.initials: H
authors.lastname: Viswambharan
authors.forename: Piruthivi
authors.initials: P
authors.lastname: Sukumar
authors.forename: Adil
authors.initials: A
authors.lastname: Rajwani
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.forename: Matthew
authors.initials: M
authors.lastname: Gage
authors.forename: Jessica
authors.initials: J
authors.lastname: Smith
authors.forename: Stacey
authors.initials: S
authors.lastname: Galloway
authors.forename: Nadira
authors.initials: N
authors.lastname: Yuldeshava
authors.forename: Matthew
authors.initials: M
authors.lastname: Kahn
authors.forename: Shouhong
authors.initials: S
authors.lastname: Xuan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: David J
authors.initials: DJ
authors.lastname: Beech
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D001682:Biological Availability; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D010656:Phenylephrine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose