title: Insulin-like growth factor-1 receptor expression masks the antiinflammatory and glucose uptake capacity of insulin in vascular smooth muscle cells.
abstract: OBJECTIVE
  Insulin resistance of vascular smooth muscle cells (VSMCs) has been linked to accelerated atherosclerosis in diabetes; however, the effects of insulin on VSMCs remain controversial. Most VSMC insulin receptors are sequestered into insulin-insensitive hybrids with insulin-like growth factor-1 receptors (IGF1Rs). Thus we hypothesized that regulation of IGF1R expression may impact cellular insulin sensitivity.
  
  
  RESULTS
  IGF1R expression was increased in aortas from diabetic mice. IGF1R overexpression in VSMCs impaired insulin-induced Akt phosphorylation. Conversely, IGF1R downregulation by siRNA allowed assembly of insulin holoreceptors, enhanced insulin-induced phosphorylation of its receptor, Akt, Erk1/2, and further augmented insulin-induced glucose uptake. IGF1R downregulation uncovered an insulin-induced reduction in activation of NF-kappaB and inhibition of MCP-1 upregulation in response to TNF-alpha.
  
  
  CONCLUSIONS
  Downregulation of IGF1R increases the fraction of insulin receptors organized in holoreceptors, which leads to enhanced insulin signaling and unmasks potential antiinflammatory properties of insulin in VSMCs. Therefore, IGF1R, which is susceptible to feedback regulation by its own ligand, may represent a novel target for interventions designed to treat insulin resistance in the vasculature.
authors.affiliation: Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Niels
authors.initials: N
authors.lastname: Engberding
authors.forename: Alejandra
authors.initials: A
authors.lastname: San Martín
authors.forename: Abel
authors.initials: A
authors.lastname: Martin-Garrido
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Koga
authors.forename: Lily
authors.initials: L
authors.lastname: Pounkova
authors.forename: Erin
authors.initials: E
authors.lastname: Lyons
authors.forename: Bernard
authors.initials: B
authors.lastname: Lassègue
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D007328:Insulin; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose