title: Insulin therapy modulates mitochondrial dynamics and biogenesis, autophagy and tau protein phosphorylation in the brain of type 1 diabetic rats.
abstract: The main purpose of this study was to examine whether streptozotocin (STZ)-induced type 1 diabetes (T1D) and insulin (INS) treatment affect mitochondrial function, fission/fusion and biogenesis, autophagy and tau protein phosphorylation in cerebral cortex from diabetic rats treated or not with INS. No significant alterations were observed in mitochondrial function as well as pyruvate levels, despite the significant increase in glucose levels observed in INS-treated diabetic rats. A significant increase in DRP1 protein phosphorylated at Ser616 residue was observed in the brain cortex of STZ rats. Also an increase in NRF2 protein levels and in the number of copies of mtDNA were observed in STZ diabetic rats, these alterations being normalized by INS. A slight decrease in LC3-II levels was observed in INS-treated rats when compared to STZ diabetic animals. An increase in tau protein phosphorylation at Ser396 residue was observed in STZ diabetic rats while INS treatment partially reversed that effect. Accordingly, a modest reduction in the activation of GSK3β and a significant increase in the activity of phosphatase 2A were found in INS-treated rats when compared to STZ diabetic animals. No significant alterations were observed in caspases 9 and 3 activity and synaptophysin and PSD95 levels. Altogether our results show that mitochondrial alterations induced by T1D seem to involve compensation mechanisms since no significant changes in mitochondrial function and synaptic integrity were observed in diabetic animals. In addition, INS treatment is able to normalize the alterations induced by T1D supporting the importance of INS signaling in the brain.
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: R X
authors.initials: RX
authors.lastname: Santos
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
authors.forename: S C
authors.initials: SC
authors.lastname: Correia
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: M G
authors.initials: MG
authors.lastname: Alves
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: P F
authors.initials: PF
authors.lastname: Oliveira
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Cardoso
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Carvalho
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
authors.forename: A I
authors.initials: AI
authors.lastname: Duarte
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: M S
authors.initials: MS
authors.lastname: Santos
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: venta@ci.uc.pt.
authors.forename: P I
authors.initials: PI
authors.lastname: Moreira
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D053148:Caspase 3; D053453:Caspase 9; D034281:Dynamins; D005947:Glucose; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; D019289:Pyruvic Acid; D016875:tau Proteins; C526109:Anxa3 protein, rat; C489131:Mapt protein, rat; C495637:Nfe2l2 protein, rat; C000605508:Gsk3b protein, rat; C505410:Casp3 protein, rat; C519851:Dnm1l protein, rat
keywords: Autophagy; Cerebral cortex; Insulin treatment; Mitochondrial fission, fusion and biogenesis; Tau protein phosphorylation; Type 1 diabetes