Chronic hyperglycaemia increases the vulnerability of the hippocampus to oxidative damage induced during post-hypoglycaemic hyperglycaemia in a mouse model of chemically induced type 1 diabetes.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE

Original Publication: Berlin Springer Verlag

Hyperglycemia*/metabolism ; Diabetes Mellitus, Type 1*/metabolism ; Hypoglycemia*/metabolism ; Diabetes Mellitus, Experimental*/metabolism; Mice ; Animals ; Hypoglycemic Agents ; NF-E2-Related Factor 2/genetics ; Hippocampus ; Oxidative Stress ; Blood Glucose/metabolism

Aims/hypothesis: Chronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent hypoglycaemia in rodent models of chemically induced (streptozotocin [STZ]) diabetes leads to cognitive impairment in memory-related tasks associated with hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic hyperglycaemia in STZ-diabetes exacerbates hippocampal oxidative stress and explored potential contributory mechanisms.
Methods: The hyperinsulinaemic glucose clamp technique was used to induce equivalent hypoglycaemia and to control post-hypoglycaemic glucose levels in mice with and without STZ-diabetes and Nrf2 ^-/- mice (lacking Nrf2 [also known as Nfe2l2]). Subsequently, quantitative proteomics based on stable isotope labelling by amino acids in cell culture and biochemical approaches were used to assess oxidative damage and explore contributory pathways.
Results: Evidence of hippocampal oxidative damage was most marked in mice with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia; these mice also showed induction of Nrf2 and the Nrf2 transcriptional targets Sod2 and Hmox-1. In this group, hypoglycaemia induced a significant upregulation of proteins involved in alternative fuel provision, reductive biosynthesis and degradation of damaged proteins, and a significant downregulation of proteins mediating the stress response. Key differences emerged between mice with and without STZ-diabetes following recovery from hypoglycaemia in proteins mediating the stress response and reductive biosynthesis.
Conclusions/interpretation: There is a disruption of the cellular response to a hypoglycaemic challenge in mice with STZ-induced diabetes that is not seen in wild-type non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, possibly leading to irreversible damage/modification to proteins or synapses between cells. In conclusion, recurrent hypoglycaemia in sub-optimally controlled diabetes may contribute, at least in part, to accelerated cognitive decline through amplifying oxidative damage in key brain regions, such as the hippocampus.
Data Availability: The datasets generated during and/or analysed during the current study are available in ProteomeXchange, accession no. 1-20220824-173727 ( www.proteomexchange.org ). Additional datasets generated during and/or analysed during the present study are available from the corresponding author upon reasonable request.
(© 2023. The Author(s).)

Erratum in: Diabetologia. 2024 Aug;67(8):1724. doi: 10.1007/s00125-024-06188-3. (PMID: 38864888)

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Keywords: Glycaemic variability; Hippocampus; Hyperinsulinaemic glucose clamp; Hypoglycaemia; Mouse; Nfe2l2; Nrf2; Oxidative stress; Proteotoxic stress; Type 1 diabetes

0 (Hypoglycemic Agents)
0 (NF-E2-Related Factor 2)
0 (Blood Glucose)

Date Created: 20230404 Date Completed: 20230608 Latest Revision: 20240615

20250114

PMC10244284

10.1007/s00125-023-05907-6

37015997