Hyperglycemia in a type 1 Diabetes Mellitus model causes a shift in mitochondria coupled-glucose phosphorylation and redox metabolism in rat brain

Silva-Rodrigues, Thaia; de‐Souza‐Ferreira, Eduardo; Machado, Caio M.; Cabral, Bruno; Rodrigues-Ferreira, Clara; Galina, Antônio

doi:10.1016/j.freeradbiomed.2020.09.017

Cited by 18 publications

(7 citation statements)

References 54 publications

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“…Oscillating glucose lowered the activity of aconitase, an enzyme of the Krebs cycle, and suppressed mitochondrial respiratory chain complex I [103]. At the same time, a reduction in the mitochondrial complex I activity was observed in the rat brain in a model of T1D [104]. Therefore, this effect may be induced by hyperglycemia per se, rather than increased GV.…”

Section: Altered Mitochondrial Homeostasismentioning

confidence: 94%

Glucose Variability: How Does It Work?

Климонтов

Saik

Korbut

2021

IJMS

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A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.

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Section: Altered Mitochondrial Homeostasismentioning

confidence: 94%

Glucose Variability: How Does It Work?

Климонтов

Saik

Korbut

2021

IJMS

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“…A recent study of diabetes mellitus has also implicated mitochondrial H 2 O 2 in inhibition NF-κB activation. 53 A role for NF-κB in IRF4 gene expression was reported earlier. 54 Similar to our findings, immune suppression by nasal DCs in response to inhaled antigen was attributed to ROS production in DCs 55 suggesting that DCs in the upper airways may utilize a common mechanism of mitochondrial ROS/H 2 O 2 to prevent unwarranted allergic responses to inhaled antigens.…”

Section: Discussionmentioning

confidence: 65%

Early life exposure to house dust mite allergen prevents experimental allergic asthma requiring mitochondrial H2O2

Yuan

Chen

et al. 2022

Mucosal Immunology

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Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo . In line with our previous finding of increased mitochondrial H 2 O 2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H 2 O 2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia and increased airway hyperreactivity. WT Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naïve mice. In contrast, the lungs of MCAT Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H 2 O 2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.

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“…Those rats had severe epileptic seizures, increased mortality, and neuronal damage in the CA3 area of the hippocampus 24 h after lithium–pilocarpine administration. 8 In the hippocampus, diabetic hyperglycemia can promote structural and functional changes due to various factors such as alterations in mitochondrial energy metabolism as consequence of increased mitochondrial ROS, alterations in the NF‐κB pathway, variations in the function of the PTEN protein, 29 modifications in the integrity of the blood–brain barrier, gliosis, microgliosis, increased expression of pro‐inflammatory markers such as TNF‐α, IL‐6 as well as OS. 30 , 31 , 32 , 33 The chronic elevation of glucose in DM2 can contribute to increased neurodegeneration in the hippocampus when a severe insult like SE occurs.…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes mellitus facilitates status epilepticus in adult rats: Seizure severity, neurodegeneration, and oxidative stress

Ramos‐Riera,

Beltrán‐Parrazal,

Morgado‐Valle

et al. 2024

Epilepsia Open

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ObjectiveThe goal of this research was to evaluate the effect of DM type 2 (DM2) on SE severity, neurodegeneration, and brain oxidative stress (OS) secondary to seizures.MethodsDM2 was induced in postnatal day (P) 3 male rat pups by injecting streptozocin (STZ) 100 mg/kg; control rats were injected with citrate buffer as vehicle. At P90, SE was induced by the lithium–pilocarpine administration and seizure latency, frequency, and severity were evaluated. Neurodegeneration was assessed 24 h after SE by Fluoro‐Jade B (F‐JB) staining, whereas OS was estimated by measuring lipid peroxidation and reactive oxygen species (ROS).ResultsDM2 rats showed an increase in latency to the first generalized seizure and SE onset, had a higher number and a longer duration of seizures, and displayed a larger neurodegeneration in the hippocampus (CA3, CA1, dentate gyrus, and hilus), the piriform cortex, the dorsomedial nucleus of the thalamus and the cortical amygdala. Our results also show that only SE, neither DM2 nor the combination of DM2 with SE, caused the increase in ROS and brain lipid peroxidation.SignificanceDM2 causes higher seizure severity and neurodegeneration but did not exacerbate SE‐induced OS under these conditions.Plain Language SummaryOur research performed in animal models suggests that type 2 diabetes mellitus (DM2) may be a risk factor for causing higher seizure severity and seizure‐induced neuron cell death. However, even when long‐term seizures promote an imbalance between brain pro‐oxidants and antioxidants, DM2 does not exacerbate that disproportion.

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Hyperglycemia in a type 1 Diabetes Mellitus model causes a shift in mitochondria coupled-glucose phosphorylation and redox metabolism in rat brain

Cited by 18 publications

References 54 publications

Glucose Variability: How Does It Work?

Glucose Variability: How Does It Work?

Early life exposure to house dust mite allergen prevents experimental allergic asthma requiring mitochondrial H2O2

Type 2 diabetes mellitus facilitates status epilepticus in adult rats: Seizure severity, neurodegeneration, and oxidative stress

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