title: Loss of insulin-mediated vasoprotection: early effect of diabetes on pericyte-containing microvessels of the retina.
abstract: OBJECTIVE
  Microvascular cell death is a prominent pathologic feature of the retinopathy associated with insulin-deficient diabetes. The aim of this study was to test the hypothesis that reduced insulin action may contribute to microvascular damage in the diabetic retina.
  
  
  METHODS
  Microvascular complexes were isolated from retinas of healthy rats and those made insulin deficient by streptozotocin. As a model of ischemia, freshly isolated microvessels were maintained in a glucose-free, low-oxygen solution. Cell viability in pericyte-containing retinal microvessels was assayed by trypan blue dye exclusion. Cleaved caspase-3 immunoreactivity and nuclear morphology were used to detect apoptotic cells.
  
  
  RESULTS
  Ischemia significantly increased apoptotic cell death in pericyte-containing microvessels of the normal rat retina. In a dose-dependent (IC(50) = 600 pM) manner, physiological concentrations of insulin markedly decreased ischemic cell death in the retinal microvasculature. This insulin-mediated vasoprotection was prevented by inhibitors of phosphatidylinositol-3-OH kinase and extracellular signal-regulated kinase. Soon after the onset of diabetes, insulin failed to significantly diminish cell death in ischemic retinal microvessels, in contrast to the prosurvival effect of this hormone on nondiabetic microvessels.
  
  
  CONCLUSIONS
  Results of this study support the hypothesis that a physiological concentration of insulin exerts a prosurvival effect on ischemic retinal microvessels and that diabetes impairs the ability of insulin to protect against ischemia-induced microvascular cell death. The authors propose that the loss of insulin-mediated vasoprotection may be a previously unappreciated mechanism by which diabetic retinopathy progresses.
authors: Departments of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA.
authors: Takatoshi
authors: T
authors: Kobayashi
authors: Donald G
authors: DG
authors: Puro
mesh_terms: D000818:Animals; D017209:Apoptosis; D002196:Capillaries; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D007511:Ischemia / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D020318:Rats, Long-Evans; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology
chemical_list: D053148:Caspase 3; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors