Nrf2-mediated neuroprotection response to recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes

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Abstract

It remains uncertain whether recurrent non-severe hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). Both T1D and Hypo can compromise host defenses against oxidative stress. This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2-/- ±T1D and ±Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1. In Nrf2-/-mice, both T1D and Hypo independently resulted in impaired cognitive performance and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.
Original languageEnglish
Pages (from-to)3151-3160
Number of pages10
JournalDiabetes
Volume65
Issue number10
Early online date13 Jul 2016
DOIs
Publication statusPublished - 1 Oct 2016

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Type 1 Diabetes Mellitus
Hypoglycemia
Rodentia
Oxidative Stress
Inflammation
Long-Term Memory
Cognitive Dysfunction
Neuroprotection
Cognition
Hippocampus
Antioxidants
Insulin
Control Groups
Injections
Brain
Genes

Cite this

@article{bb57b005d3fd4b528c7db22392b7e774,
title = "Nrf2-mediated neuroprotection response to recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes",
abstract = "It remains uncertain whether recurrent non-severe hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). Both T1D and Hypo can compromise host defenses against oxidative stress. This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2-/- ±T1D and ±Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1. In Nrf2-/-mice, both T1D and Hypo independently resulted in impaired cognitive performance and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.",
author = "McNeilly, {Alison D.} and Gallagher, {Jennifer R.} and Dinkova-Kostova, {Albena T.} and Hayes, {John D.} and John Sharkey and Ashford, {Michael L. J.} and McCrimmon, {Rory J.}",
note = "This work was supported by an award from the University of Dundee/Wellcome Trust Translational Medical Research Fund (RJM), Diabetes UK (12/0004531) and Juvenile Diabetes Research Foundation (5-2011-464)",
year = "2016",
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T1 - Nrf2-mediated neuroprotection response to recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes

AU - McNeilly, Alison D.

AU - Gallagher, Jennifer R.

AU - Dinkova-Kostova, Albena T.

AU - Hayes, John D.

AU - Sharkey, John

AU - Ashford, Michael L. J.

AU - McCrimmon, Rory J.

N1 - This work was supported by an award from the University of Dundee/Wellcome Trust Translational Medical Research Fund (RJM), Diabetes UK (12/0004531) and Juvenile Diabetes Research Foundation (5-2011-464)

PY - 2016/10/1

Y1 - 2016/10/1

N2 - It remains uncertain whether recurrent non-severe hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). Both T1D and Hypo can compromise host defenses against oxidative stress. This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2-/- ±T1D and ±Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1. In Nrf2-/-mice, both T1D and Hypo independently resulted in impaired cognitive performance and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.

AB - It remains uncertain whether recurrent non-severe hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). Both T1D and Hypo can compromise host defenses against oxidative stress. This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2-/- ±T1D and ±Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1. In Nrf2-/-mice, both T1D and Hypo independently resulted in impaired cognitive performance and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.

U2 - 10.2337/DB15-1653

DO - 10.2337/DB15-1653

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