title: Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson's disease.
abstract: Clinical evidence has shown a correlation between Parkinson's disease (PD) and Type 2 Diabetes (T2D), as abnormal glucose tolerance has been reported in >50% of PD patients. The development of insulin resistance and the degeneration of nigrostriatal dopamine (DA) neurons are both mediated by oxidative mechanisms, and oxidative stress is likely a mechanistic link between these pathologies. Although glucose uptake in neuronal tissues is primarily non-insulin dependent, proteins involved in insulin signaling, such as insulin receptor substrate 2 (IRS2) and glucose transporter 4 (GLUT4), are present in the basal ganglia. The purpose of this study was to determine whether nigrostriatal DA depletion affects measures of insulin resistance in the striatum. Six weeks after 6-hydroxydopamine (6-OHDA) infusion into the medial forebrain bundle, rats were classified as having either partial (20-65%) or severe (90-99%) striatal DA depletion. Increased IRS2 serine phosphorylation, a marker of insulin resistance, was observed in the DA-depleted striatum. Additionally, severe depletion resulted in decreased total IRS2, indicating possible degradation of the protein. Decreased phosphorylation of AKT and expression of the kinase glycogen synthase kinase-3 alpha (GSK3-alpha) was also measured in the striatum of severely DA-depleted animals. Finally, expression of heat shock protein 25 (Hsp25), which is protective against oxidative damage and can decrease stress kinase activity, was decreased in the striatum of lesioned rats. Together, these results support the hypothesis that nigrostriatal DA depletion impairs insulin signaling in the basal ganglia.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Morris
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: A A
authors.initials: AA
authors.lastname: Gupte
authors.forename: G L
authors.initials: GL
authors.lastname: Bomhoff
authors.forename: J A
authors.initials: JA
authors.lastname: Stanford
authors.forename: P C
authors.initials: PC
authors.lastname: Geiger
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012694:Serine / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D055551:HSP27 Heat-Shock Proteins; C486114:Hspb1 protein, rat; D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D012694:Serine; D016627:Oxidopamine; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha