title: Endothelial insulin receptor expression in human atherosclerotic plaques: linking micro- and macrovascular disease in diabetes?
abstract: OBJECTIVE
  Exogenous insulin use in patients with type 2 diabetes (DM2) has been associated with an increased risk of cardiovascular events. Through which mechanisms insulin may increase atherosclerotic plaque vulnerability is currently unclear. Because insulin has been suggested to promote angiogenesis in diabetic retinopathy and tumors, we hypothesized that insulin enhances intra-plaque angiogenesis.
  
  
  METHODS
  An in vitro model of pathological angiogenesis was used to assess the potential of insulin to enhance capillary-like tube formation of human microvascular endothelial cells (hMVEC) into a three dimensional fibrin matrix. In addition, insulin receptor expression within atherosclerotic plaques was visualized in carotid endarterectomy specimens of 20 patients with carotid artery stenosis, using immunohistochemical techniques. Furthermore, microvessel density within atherosclerotic plaques was compared between 68 DM2 patients who received insulin therapy and 97 DM2 patients who had been treated with oral glucose lowering agents only.
  
  
  RESULTS
  Insulin, at a concentration of 10(-8)M, increased capillary-like tube formation of hMVEC 1.7-fold (p<0.01). Within human atherosclerotic plaques, we observed a specific distribution pattern for the insulin receptor: insulin receptor expression was consistently higher on the endothelial lining of small nascent microvessels compared to more mature microvessels. There was a trend towards an increased microvessel density by 20% in atherosclerotic plaques derived from patients using insulin compared to plaques derived from patients using oral glucose lowering agents only (p=0.05).
  
  
  CONCLUSIONS
  Exogenous insulin use in DM2 patients may contribute to increased plaque vulnerability by stimulating local angiogenesis within atherosclerotic plaques.
authors.affiliation: Academic Medical Center, Department of Vascular Medicine, Amsterdam, The Netherlands. k.l.rensing@amc.uva.nl
authors.forename: K L
authors.initials: KL
authors.lastname: Rensing
authors.forename: J H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: E M
authors.initials: EM
authors.lastname: Weijers
authors.forename: F M
authors.initials: FM
authors.lastname: Houttuijn Bloemendaal
authors.forename: G W
authors.initials: GW
authors.lastname: van Lammeren
authors.forename: A
authors.initials: A
authors.lastname: Vink
authors.forename: A C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: V W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.forename: C M
authors.initials: CM
authors.lastname: van der Loos
authors.forename: E S
authors.initials: ES
authors.lastname: Stroes
authors.forename: P
authors.initials: P
authors.lastname: Koolwijk
authors.forename: Th B
authors.initials: TB
authors.lastname: Twickler
mesh_terms: D002478:Cells, Cultured; D016894:Endarterectomy, Carotid; D004730:Endothelium, Vascular; D006801:Humans; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use; D055806:Microvessels / Q000166:cytology / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D011972:Receptor, Insulin / Q000096:biosynthesis*
chemical_list: D007328:Insulin; D011972:Receptor, Insulin