4.7 Article

Attenuated Induction of the Unfolded Protein Response in Adult Human Primary Astrocytes in Response to Recurrent Low Glucose

Journal

FRONTIERS IN ENDOCRINOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2021.671724

Keywords

recurrent low glucose; unfolded protein response; ER stress; human primary astrocytes; transcriptome (RNA-seq)

Funding

  1. Novo Nordisk UK Research Foundation
  2. Mary Kinross Charitable Trust
  3. European Foundation for the Study of Diabetes/Novo Nordisk Programme for Diabetes Research in Europe
  4. Diabetes UK RD Lawrence Fellowship [13/0004647]
  5. JDRF [3-PDF-2020-941-A-N]
  6. Medical Research Council [MR/M008924/1]
  7. Wellcome Trust [WT097835MF, WT101650MA]
  8. BBSRC LOLA award [BB/K003240/1]
  9. National Institute of Health Research Exeter Clinical Research facility
  10. BBSRC [BB/K003240/1] Funding Source: UKRI
  11. MRC [MR/M008924/1] Funding Source: UKRI

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The study found that exposure of human astrocytes to transient low glucose triggers activation of genes related to endoplasmic reticulum stress, while after recurrent low glucose exposure, the activation of stress-related genes decreases, suggesting attenuated endoplasmic reticulum stress. This may be a result of successful metabolic adaptation, better preserving intracellular energy levels.
Aims/hypothesis Recurrent hypoglycaemia (RH) is a major side-effect of intensive insulin therapy for people with diabetes. Changes in hypoglycaemia sensing by the brain contribute to the development of impaired counterregulatory responses to and awareness of hypoglycaemia. Little is known about the intrinsic changes in human astrocytes in response to acute and recurrent low glucose (RLG) exposure. Methods Human primary astrocytes (HPA) were exposed to zero, one, three or four bouts of low glucose (0.1 mmol/l) for three hours per day for four days to mimic RH. On the fourth day, DNA and RNA were collected. Differential gene expression and ontology analyses were performed using DESeq2 and GOseq, respectively. DNA methylation was assessed using the Infinium MethylationEPIC BeadChip platform. Results 24 differentially expressed genes (DEGs) were detected (after correction for multiple comparisons). One bout of low glucose exposure had the largest effect on gene expression. Pathway analyses revealed that endoplasmic-reticulum (ER) stress-related genes such as HSPA5, XBP1, and MANF, involved in the unfolded protein response (UPR), were all significantly increased following low glucose (LG) exposure, which was diminished following RLG. There was little correlation between differentially methylated positions and changes in gene expression yet the number of bouts of LG exposure produced distinct methylation signatures. Conclusions/interpretation These data suggest that exposure of human astrocytes to transient LG triggers activation of genes involved in the UPR linked to endoplasmic reticulum (ER) stress. Following RLG, the activation of UPR related genes was diminished, suggesting attenuated ER stress. This may be a consequence of a successful metabolic adaptation, as previously reported, that better preserves intracellular energy levels and a reduced necessity for the UPR.

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