title: Insulin-like growth factor type 1 prevents hyperglycemia-induced uncoupling protein 3 down-regulation and oxidative stress.
abstract: Uncoupling proteins (UCPs) have been reported to decrease the mitochondrial production of reactive oxygen species (ROS) by lowering the mitochondrial inner membrane potential (MMP). We have previously shown that UCP3 expression is positively regulated by insulin-like growth factor-1 (IGF-1). The aim of this study was to investigate the role of UCPs in IGF-1-mediated protection from hyperglycemia-induced oxidative stress and neurodegeneration. Human neuroblastoma SH-SY5Y cells were differentiated with retinoic acid for 6 days, after which exposure to 8, 30, or 60 mM glucose with or without 10 nM IGF-1 was started. After 48-72 hr, the number of neurites per cell, UCP3 protein expression, MMP, and intracellular levels of ROS and total glutathione were examined. These studies showed that glucose concentration-dependently reduced the number of neurites per cell, with a 50% reduction at 60 mM. In parallel, the UCP3 protein expression was down-regulated, and the MMP was raised 3.5-fold, compared with those in cells incubated with 8 mM glucose. Also, the ROS levels were increased, showing a twofold maximum at 60 mM glucose. This was accompanied by a twofold elevation of total glutathione levels, confirming an altered cellular redox state. IGF-1 treatment prevented the glucose-induced neurite degeneration and UCP3 down-regulation. Furthermore, the MMP and the intracellular levels of ROS and glutathione were normalized to those of control cells. These data indicate that IGF-1 may protect from hyperglycemia-induced oxidative stress and neuronal injuries by regulating MMP, possibly by the involvement of UCP3.
authors.affiliation: Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden. helena@neurochem.su.se
authors.forename: Helena
authors.initials: H
authors.lastname: Gustafsson
authors.forename: Therése
authors.initials: T
authors.lastname: Söderdahl
authors.forename: Gunn
authors.initials: G
authors.lastname: Jönsson
authors.forename: Jan-Ove
authors.initials: JO
authors.lastname: Bratteng
authors.forename: Anna
authors.initials: A
authors.lastname: Forsby
mesh_terms: D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002477:Cells; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D007473:Ion Channels; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D007334:Insulin-Like Growth Factor I; D005978:Glutathione; D005947:Glucose