PMID- 27411381
OWN - NLM
STAT- MEDLINE
DCOM- 20170519
LR  - 20240214
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 65
IP  - 10
DP  - 2016 Oct
TI  - Nrf2-Mediated Neuroprotection Against Recurrent Hypoglycemia Is Insufficient to 
      Prevent Cognitive Impairment in a Rodent Model of Type 1 Diabetes.
PG  - 3151-60
LID - 10.2337/db15-1653 [doi]
AB  - It remains uncertain whether recurrent nonsevere hypoglycemia (Hypo) results in 
      long-term cognitive impairment in type 1 diabetes (T1D). 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.
CI  - (c) 2016 by the American Diabetes Association.
FAU - McNeilly, Alison D
AU  - McNeilly AD
AD  - Division of Molecular and Clinical Medicine, School of Medicine, Ninewells 
      Hospital and Medical School, Dundee, U.K.
FAU - Gallagher, Jennifer R
AU  - Gallagher JR
AD  - Division of Molecular and Clinical Medicine, School of Medicine, Ninewells 
      Hospital and Medical School, Dundee, U.K.
FAU - Dinkova-Kostova, Albena T
AU  - Dinkova-Kostova AT
AD  - Division of Cancer Research, School of Medicine, Ninewells Hospital and Medical 
      School, Dundee, U.K.
FAU - Hayes, John D
AU  - Hayes JD
AD  - Division of Cancer Research, School of Medicine, Ninewells Hospital and Medical 
      School, Dundee, U.K.
FAU - Sharkey, John
AU  - Sharkey J
AD  - Division of Molecular and Clinical Medicine, School of Medicine, Ninewells 
      Hospital and Medical School, Dundee, U.K. Division of Neuroscience, School of 
      Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
FAU - Ashford, Michael L J
AU  - Ashford ML
AD  - Division of Molecular and Clinical Medicine, School of Medicine, Ninewells 
      Hospital and Medical School, Dundee, U.K.
FAU - McCrimmon, Rory J
AU  - McCrimmon RJ
AD  - Division of Molecular and Clinical Medicine, School of Medicine, Ninewells 
      Hospital and Medical School, Dundee, U.K. r.mccrimmon@dundee.ac.uk.
LA  - eng
GR  - MR/N009851/1/MRC_/Medical Research Council/United Kingdom
GR  - 12/0004531/DUK_/Diabetes UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160713
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Animals
MH  - Cognitive Dysfunction/metabolism/*physiopathology
MH  - Diabetes Mellitus, Type 1/genetics/immunology/*metabolism
MH  - Hippocampus/immunology/metabolism
MH  - Hypoglycemia/*metabolism/*physiopathology
MH  - Inflammation/metabolism
MH  - Lipid Peroxidation/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Oxidative Stress/physiology
MH  - Polymerase Chain Reaction
MH  - Random Allocation
EDAT- 2016/07/15 06:00
MHDA- 2017/05/20 06:00
CRDT- 2016/07/15 06:00
PHST- 2015/12/09 00:00 [received]
PHST- 2016/07/07 00:00 [accepted]
PHST- 2016/07/15 06:00 [entrez]
PHST- 2016/07/15 06:00 [pubmed]
PHST- 2017/05/20 06:00 [medline]
AID - db15-1653 [pii]
AID - 10.2337/db15-1653 [doi]
PST - ppublish
SO  - Diabetes. 2016 Oct;65(10):3151-60. doi: 10.2337/db15-1653. Epub 2016 Jul 13.