Central nervous system endoplasmic reticulum stress in a murine model of Type 2 diabetes

C. Sims-Robinson, S. Zhao, J. Hur, E. L. Feldman

Research output: Contribution to journalReview article

28 Citations (Scopus)

Abstract

Aims/hypothesis: 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/ interpretation: 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.

Original languageEnglish (US)
Pages (from-to)2276-2284
Number of pages9
JournalDiabetologia
Volume55
Issue number8
DOIs
StatePublished - Aug 1 2012

Fingerprint

Endoplasmic Reticulum Stress
Type 2 Diabetes Mellitus
Central Nervous System
Unfolded Protein Response
Heat-Shock Proteins
Endoplasmic Reticulum
Genes
Hippocampus
Down-Regulation
Diabetes Complications
Computational Biology
Neurodegenerative Diseases
DNA Damage
Carrier Proteins
Mitochondria
Learning
Pharmacology
Technology
Gene Expression
Messenger RNA

Keywords

  • Brain
  • ER stress
  • Gene expression
  • Hippocampus
  • Microarray
  • Type 2 diabetes
  • Unfolded protein response

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Central nervous system endoplasmic reticulum stress in a murine model of Type 2 diabetes. / Sims-Robinson, C.; Zhao, S.; Hur, J.; Feldman, E. L.

In: Diabetologia, Vol. 55, No. 8, 01.08.2012, p. 2276-2284.

Research output: Contribution to journalReview article

Sims-Robinson, C. ; Zhao, S. ; Hur, J. ; Feldman, E. L. / Central nervous system endoplasmic reticulum stress in a murine model of Type 2 diabetes. In: Diabetologia. 2012 ; Vol. 55, No. 8. pp. 2276-2284.
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