Dataset Information

Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats.

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.

SUBMITTER: Cardoso S

PROVIDER: S-EPMC8708764 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundEpisodes of recurrent or severe hypoglycemia can occur in patients with diabetes mellitus, insulinoma, neonatal hypoglycemia, and medication errors. However, little is known about the short-term and long-term effects of repeated episodes of acute severe hypoglycemia on the brain, particularly in relation to hippocampal damage and cognitive dysfunction.MethodsThirty-six wistar rats were randomly assigned to either the experimental or control group. The rats were exposed to severe hypoglycemia, and assessments were conducted to evaluate oxidative stress in brain tissue, cognitive function using the Morris water maze test, as well as histopathology and immunohistochemistry studies. The clinical and histopathological evaluations were conducted in the short-term and long-term.ResultsThe mortality rate attributed to hypoglycemia was 34%, occurring either during hypoglycemia or within 24 h after induction. Out of the 14 rats monitored for 7 to 90 days following severe/recurrent hypoglycemia, all exhibited clinical symptoms, which mostly resolved within three days after the last hypoglycemic episode, except for three rats. Despite the decrease in catalase activity in the brain, the total antioxidant capacity following severe insulin-induced hypoglycemia increased. The histopathology findings revealed that the severity of the hippocampal damage was higher compared to the brain cortex 90 days after hypoglycemia. Memory impairments with neuron loss particularly pronounced in the dentate gyrus region of the hippocampus were observed in the rats with severe hypoglycemia. Additionally, there was an increase in reactive astrocytes indicated by GFAP immunoreactivity in the brain cortex and hippocampus.ConclusionRecurrent episodes of severe hypoglycemia can lead to high mortality rates, memory impairments, and severe histopathological changes in the brain. While many histopathological and clinical changes improved after three months, it seems that the vulnerability of the hippocampus and the development of sustained changes in the hippocampus were greater and more severe compared to the brain cortex following severe and recurrent hypoglycemia. Furthermore, it does not appear that oxidative stress plays a central role in neuronal damage following severe insulin-induced hypoglycemia. Further research is necessary to assess the consequences of repeated hypoglycemic episodes on sustained damage across various brain regions.

Dataset Information

Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets