title: Central nervous system endoplasmic reticulum stress in a murine model of type 2 diabetes.
abstract: OBJECTIVE
  Type 2 diabetes is associated with complications in the central nervous system (CNS), including learning and memory, and an increased risk for neurodegenerative diseases. The mechanism underlying this association is not understood. The aim of this study was to gain greater insight into the possible mechanisms of diabetes-induced cognitive decline.
  
  
  METHODS
  We used microarray technology to identify and examine changes in gene expression in the hippocampus of a murine model of type 2 diabetes, the db/db mouse. Bioinformatics approaches were then used to investigate the biological significance of these genes. To validate the biological significance we evaluated mRNA and protein levels.
  
  
  RESULTS
  At 8 and 24 weeks, 256 and 822 genes, respectively, were differentially expressed in the db/db mice. The most significantly enriched biological functions were related to mitochondria, heat shock proteins, or the endoplasmic reticulum (ER), the majority of which were downregulated. The ER-enriched cluster was one of the clusters that contained the highest number of differentially expressed genes. Several of the downregulated genes that were differentially expressed at 24 but not at 8 weeks are directly involved in the unfolded protein response (UPR) pathway and include two heat shock proteins (encoded by Hspa5 and Hsp90b1), a transcriptional factor (x-box binding protein 1, encoded by Xbp1), and an apoptotic mediator (DNA-damage inducible transcript 3, encoded by Ddit3).
  
  
  CONCLUSIONS
  The changes that we observed in the UPR pathway due to ER stress may play a role in the pathogenesis of CNS complications in diabetes. The results of this study are a foundation for the development of pharmacological targets to reduce ER stress in diabetic hippocampi.
authors.affiliation: Department of Neurology, University of Michigan, 5017 AATBSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sims-Robinson
authors.forename: S
authors.initials: S
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Hur
authors.forename: E L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D012333:RNA, Messenger