Endocrine Abstracts (2018) 59 P108 | DOI: 10.1530/endoabs.59.P108

Nrf2 mediated protection against hypoglycaemia induced cognitive deficits in type 1 diabetes

Alison Mc Neilly, Jennifer Gallagher & Rory McCrimmon

University of Dundee, Dundee, UK.

Background: Hypoglycaemia in Type 1 diabetes (T1D) and type 2 diabetes is associated with long-term cognitive dysfunction. We have previously demonstrated that recurrent hypoglycaemia (RH) in a rodent model of T1D induces oxidative stress and inflammation in the hippocampus, associated with impaired cognitive function. This study sought to investigate whether pre-treatment with a potent inducer of the antioxidant response would ameliorate these cognitive deficits.

Methods: A chronic stable model of chronic insulin-treated TD1 was achieved using streptozotocin (125 mg/kg i.p) and insulin implants (Linbit®). Diabetic (male C57bl6 mice n=8–10/group) mice were randomly allocated to one of 3 groups: (i) T1D, (ii) T1D+RH, (iii) T1D+RH+AO and subjected to repeated episodes of insulin-induced hypoglycemia (3 episodes per week for 4 weeks). Sulforaphane(50 mg/kg i.p.) or Vehicle (1% DMSO/PBS) was administered 24hr prior to each hypoglycaemic episode. Cognition was subsequently assessed by novel object recognition (NOR) and spontaneous alternation tasks.

Results: Pre-treatment with the antioxidant had no impact upon body weight (P=ns) or fasting blood glucose (P=ns). In contrast HbA1c levels were significantly lower in SFN treated animals (P<0.01). Furthermore, SFN significantly improved cognitive performance in the 24hr NOR task (P<0.01) and the spontaneous alternation task (P<0.01) when compared to those receiving vehicle.

Conclusions: Treatment with the SFN significantly improves RH induced cognitive impairments in a rodent model of T1D. These improvements were associated with a significant improvement in HbA1c levels. Therefore, activation of antioxidant pathways offer a novel therapeutic target for the treatment of cognitive impairments associated with RH in T1D.

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