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

Aims/ Hypothesis: Chronic hyperglycemia 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 on tasks related to memory, 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 STZdiabetes and Nrf2-/- mice and subsequently SILAC-based quantitative proteomics and biochemical approaches were used to assess oxidative damage and to explore contributory pathways.

Results: Evidence of hippocampal oxidative damage was most marked in rodents with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia, who 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 alternate fuel provision, reductive biosynthesis, and degradation of damaged proteins, and a significant down-regulation 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 WT non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, which may in turn lead 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.