PMID- 34948265
OWN - NLM
STAT- MEDLINE
DCOM- 20220131
LR  - 20220131
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 24
DP  - 2021 Dec 15
TI  - Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the 
      Brain Cortex of Chemically Induced Diabetic Rats.
LID - 10.3390/ijms222413470 [doi]
LID - 13470
AB  - Diabetes is a chronic metabolic disease that seriously compromises human 
      well-being. Various studies highlight the importance of maintaining a sufficient 
      glucose supply to the brain and subsequently safeguarding cerebral glucose 
      metabolism. The goal of the present work is to clarify and disclose the metabolic 
      alterations induced by recurrent hypoglycemia in the context of long-term 
      hyperglycemia to further comprehend the effects beyond brain harm. To this end, 
      chemically induced diabetic rats underwent a protocol of repeatedly 
      insulin-induced hypoglycemic episodes. The activity of key enzymes of glycolysis, 
      the pentose phosphate pathway and the Krebs cycle was measured by 
      spectrophotometry in extracts or isolated mitochondria from brain cortical 
      tissue. Western blot analysis was used to determine the protein content of 
      glucose and monocarboxylate transporters, players in the insulin signaling 
      pathway and mitochondrial biogenesis and dynamics. We observed that recurrent 
      hypoglycemia up-regulates the activity of mitochondrial hexokinase and Krebs 
      cycle enzymes (namely, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase 
      and succinate dehydrogenase) and the protein levels of mitochondrial 
      transcription factor A (TFAM). Both insults increased the nuclear factor 
      erythroid 2-related factor 2 (NRF2) protein content and induced divergent effects 
      in mitochondrial dynamics. Insulin-signaling downstream pathways were found to be 
      down-regulated, and glycogen synthase kinase 3 beta (GSK3beta) was found to be 
      activated through both decreased phosphorylation at Ser9 and increased 
      phosphorylation at Y216. Interestingly, no changes in the levels of cAMP response 
      element-binding protein (CREB), which plays a key role in neuronal plasticity and 
      memory, were caused by hypoglycemia and/or hyperglycemia. These findings provide 
      experimental evidence that recurrent hypoglycemia, in the context of chronic 
      hyperglycemia, has the capacity to evoke coordinated adaptive responses in the 
      brain cortex that will ultimately contribute to sustaining brain cell health.
FAU - Cardoso, Susana
AU  - Cardoso S
AUID- ORCID: 0000-0002-9866-933X
AD  - CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 
      Coimbra, Portugal.
AD  - IIIU-Institute for Interdisciplinary Research, University of Coimbra, 3030-789 
      Coimbra, Portugal.
AD  - CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 
      3004-504 Coimbra, Portugal.
FAU - Moreira, Paula I
AU  - Moreira PI
AUID- ORCID: 0000-0001-5177-6747
AD  - CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 
      Coimbra, Portugal.
AD  - CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 
      3004-504 Coimbra, Portugal.
AD  - Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-370 
      Coimbra, Portugal.
LA  - eng
GR  - CENTRO-01-0145-FEDER-000012/COMPETE 2020 - Operational Programme for 
      Competitiveness and Healthy Aging 2020/
GR  - PEst-C/SAU/LA0001/2013-2014/FCT - Foundation for Science and Technology/
GR  - UIDB/04539/2020 and UIDP/04539/2020./FCT - Foundation for Science and Technology/
PT  - Journal Article
DEP - 20211215
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Blood Glucose)
RN  - 0 (Insulin)
RN  - 5W494URQ81 (Streptozocin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - Brain/metabolism
MH  - Cerebral Cortex/*metabolism
MH  - Diabetes Mellitus, Experimental/metabolism
MH  - Energy Metabolism
MH  - Glucose/*metabolism
MH  - Glycolysis/physiology
MH  - Hyperglycemia/metabolism
MH  - Hypoglycemia/*metabolism/physiopathology
MH  - Insulin/metabolism
MH  - Male
MH  - Mitochondria/metabolism
MH  - Neuronal Plasticity/drug effects
MH  - Rats
MH  - Rats, Wistar
MH  - Streptozocin/pharmacology
PMC - PMC8708764
OTO - NOTNLM
OT  - brain cortex
OT  - chemically induced diabetes
OT  - glucose metabolism
OT  - mitochondria
OT  - recurrent hypoglycemia
OT  - signaling pathways
COIS- The authors declare no conflict of interest.
EDAT- 2021/12/25 06:00
MHDA- 2022/02/01 06:00
PMCR- 2021/12/15
CRDT- 2021/12/24 01:17
PHST- 2021/10/29 00:00 [received]
PHST- 2021/12/12 00:00 [revised]
PHST- 2021/12/13 00:00 [accepted]
PHST- 2021/12/24 01:17 [entrez]
PHST- 2021/12/25 06:00 [pubmed]
PHST- 2022/02/01 06:00 [medline]
PHST- 2021/12/15 00:00 [pmc-release]
AID - ijms222413470 [pii]
AID - ijms-22-13470 [pii]
AID - 10.3390/ijms222413470 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Dec 15;22(24):13470. doi: 10.3390/ijms222413470.