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Title: Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats
Authors: Cardoso, Susana
Moreira, Paula I. 
Keywords: brain cortex; chemically induced diabetes; glucose metabolism; mitochondria; recurrent hypoglycemia; signaling pathways
Issue Date: 15-Dec-2021
Project: European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme 
COMPETE 2020—Operational Programme for Competitiveness 
Healthy Aging 2020 (CENTRO-01-0145-FEDER-000012 
Foundation for Science and Technology under the project PEst-C/SAU/LA0001/2013-2014 and strategic projects UIDB/04539/2020 and UIDP/04539/2020 
ost-Doctoral Researcher Contract DL57/2016 (#SFRH/BPD/95770/2013) from FCT—the Foundation for Science and Technology to S.C. 
Volume: 22
Issue: 24
Abstract: 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 (GSK3β) 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.
ISSN: 1422-0067
DOI: 10.3390/ijms222413470
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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