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Model describing adaption of cerebral metabolism during severe hypoglycemia. Under normoglycemic conditions, glucose is metabolized to pyruvate and can enter the tricarboxylic acid (TCA) cycle through the action of either pyruvate dehydrogenase or (in the case of glia) pyruvate carboxylase. Under conditions of severe hypoglycemia, the availability of pyruvate is limited. Cerebral tissue is able to maintain a limited ability for oxidative phosphorylation by the production of reducing compounds (NADH and FADH 2 ) by metabolizing glutamate (and glutamine) using enzymes from part of the TCA cycle. This model removes reactions involving the six-carbon intermediates (citrate , cis-aconitate and isocitrate) with limited entry of carbon from pyruvate, but can only partially sustain metabolism so long as a source of glutamate is available.
Source publication
There is a misconception that hypoglycemic nerve cell death occurs easily, and can happen in the absence of coma. In fact, coma is the prerequisite for neuronal death, which occurs via metabolic excitatory amino acid release. The focus on nerve cell death does not explain how most brain neurons and all glia survive. Brain metabolism was interrogate...
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Citations
... However, AGC1/Aralar could participate in a possible truncated TCA cycle [81,86,88], in which mitochondria is energized thanks to Glu oxidation in mitochondria up to OAA, leaving out the reactions in which acetylCoA is incorporated from citrate synthase to isocitrate dehydrogenase. This truncated TCA cycle is proposed to function typically under glucose deprivation conditions [89] and results in the accumulation of Asp at the expense of Glu, an abundant amino acid in neurons. A similar situation arises in astrocytes in which GDH, the major Glu oxidative pathway, is deleted [86] and in retina upon inhibition of the mitochondrial pyruvate carrier by zaprinast [90]. ...
AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named “early infantile epileptic encephalopathy 39” (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.
... We can speculate that the TCA cycle in hyperglycemic animals is truncated at the aconitase steps, but there is an attempt to maintain the functionality of this pathway from α-KGDH onwards, as we did not notice alterations in SDH activity. In agreement with [45], a similar situation may occur in hypoglycemic rats, in which aconitase activity is also decreased [13], but the activities of PDH, α-KGDH and SDH are increased. ...
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.
... [23,25] Thus, both may have similar movement disorders; for example, abnormal movements that have not yet been reported with hypoglycemia but have been reported with hyperglycemia may in the future be reported in a patient with hypoglycemia, and vice versa. Ballism Chorea and ballism, [4] paroxysmal bilateral ballism [5] Chorea and ballism, [6] hemiballism [7] Chorea Chorea, [8] choreoathetosis, [9] paroxysmal choreoathetosis [10] Chorea, [11] choreoathetosis, [12] hemichorea [7] Dystonia Paroxysmal exercise-induced Dystonia [13] Paroxysmal kinesigenic dystonic choreoathetosis [14] Myoclonus [15] Opsoclonus-myoclonus [16] Parkinsonism [17] [ 18] No clearly defined Jerky head movements, [1] jerky leg movement, [19] paroxysmal nonkinesigenic dyskinesias, [20] tremor is a commonly reported symptom [24] The hypothesis for the increased excitatory substances in hypoglycemia was proposed by Sutherland et al. [26] They explained that in the occurrence of hypoglycemia there will be a truncation of the Krebs cycle. In this context, the decreased levels of pyruvate, under severe hypoglycemia, would lead to the metabolism of oxaloacetate directly to α-ketoglutarate with the use of glutamate [ Figure 2]. ...
We read the article entitled “Sudden jerky head movement in hypoglycemia” on the esteemed Annals of Movement Disorders with great interest. Shah and Sardana reported a case of an elderly female who developed two episodes of hemiparesis and a single episode of jerky head movement. She was diabetic and had a low blood sugar level in both times. It is noteworthy that according to Shah and Sardana their report was the first to describe the occurrence of jerky head movement secondary to hypoglycemia.
... 37 Intracellular aspartate's increase was partially caused by the low oxygen availability and augmentation of the flux through the truncated TCA cycle. 38 ...
Introduction
Lactate accumulation in the brain is caused by the anaerobic metabolism induced by ischemic damages, which always accompanies intracerebral hemorrhages (ICH). Our former findings showed that microglia's movement was always directly toward hemorrhagic center with the highest lactate concentration, and penumbra area has the largest density of compactly arrayed microglia. However, the relationship between microglia and lactate concentration has not been well documented.
Methods
Cerebral hemorrhage model was successfully achieved by injecting collagenase VII (causing stabile localized bleeding) in CPu (striatum) of SD rats. Emodin was used as a potential therapeutic for ICH. The function of the lactate was examined with in vitro culture studies. Then, the effect of lactate on the proliferation, cell survival, migration, and phagocytosis property of microglia was investigated by in vitro culture studies.
Results
Lactate accumulation was observed with in vivo MRS method, and its concentration was monitored during the recovery of ICH and treatment of emodin. Lactate concentration significantly increased in the core and penumbra regions of hemorrhagic foci, and it decreased after the treatment of emodin. The in vitro culture study was verified that lactate was beneficial for the proliferation, cell survival, migration, and phagocytosis property of the microglia.
Conclusion
Results from in vitro verification study, investigations from the recovery of ICH, and treatment of emodin verify that lactate plays an important role during the recovery of ICH. This could provide a novel therapeutic approach for ICH.
... energy fuels (Moheet, Emir, et al., 2014;Moheet, Kumar, et al., 2014;Terpstra et al., 2014), are consistently observed in humans and other mammals (Behar et al., 1985;Choi, Lee, Kim, & Gruetter, 2001;Fernandez, Barton, & Spotswood, 2009;Norberg & Siesio, 1976;Rao et al., 2010;Sutherland, Tyson, & Auer, 2008). Hypoglycemiainduced metabolic changes may impair hypoglycemia awareness and lead to the development of hypoglycemia-associated autonomic failure (HAAF). ...
... This study sought valuable information on the estimation of the degrees of hypoglycemia severity. We extended previously reported limited energy substrates in the entire brain (Behar et al., 1985;Choi et al., 2001) and some in vitro studies (Sutherland et al., 2008) with short-echo 1 H MRS measurements of abundant metabolites in conjunction with continuous arterial spin labeling (CASL) of blood flow in rodent cortex upon euglycemia, three hypoglycemic phases and glycemia recovery from severe hypoglycemia. were obtained from Charles-River (France) 2 weeks before experiments. ...
... A typical experimental scheme is shown in Figure 1. Since the sharp rise in cCBF and some metabolites during severe hypoglycemia are beyond 100% (Ghajar, Plum, & Duffy, 1982;Lewis, Ljunggren, Norberg, & Siesjo, 1974;Sutherland et al., 2008) and when assuming a 10% deviation of the corresponding mean (e.g., 40 ± 4 versus 80 ± 8 ml/100 g/ min of cCBF and 1 ± 0.1 versus. 2 ± 0.2 μ mol/g of metabolic concentration), the number of animals (> 1) for the hypoglycemia III group in this study would be sufficient to reach statistical significant level of p < .05 with 80% power (www.lasec.cuhk.edu.hk/sampl e-size-calcu lation.html). ...
Hypoglycemia is critical condition during diabetic treatment that involves intensive insulin therapy, and it may impair brain function. We aimed to compare cortical responses of three hypoglycemic phases and the restoration of glycemia to control levels after a severe episode in rats using non‐invasive perfusion magnetic resonance (MR) imaging and localized ¹H MR spectroscopy. Under light α‐chloralose anesthesia, cortical blood flow (cCBF) was 42 ± 3 ml/100 g/min at euglycemia (~ 5 mM plasma glucose), was not altered at mild hypoglycemia I (42 ± 4 ml/100 g/min, 2–3.5 mM), increased to 60 ± 8 ml/100 g/min under moderate hypoglycemia II (1–2 mM) and amplified to 190 ± 35 ml/100 g/min at severe hypoglycemia III (< 1 mM). ¹H MRS revealed metabolic changes at hypoglycemia I without any perfusion alteration. At hypoglycemia III, glutamine and glutamate decreased, whereas aspartate increased. When animals subsequently regained glycemic control, not all metabolites returned to their control levels, for example, glutamine. Meanwhile, ascorbate was increased with amplified hypoglycemic severity, whereas glutathione was reduced; these compounds did not return to normal levels upon the restoration of glycemia. Our study is the first to report cCBF and neurochemical changes in cortex upon five glycemic stages. The cortical responses of different hypoglycemic phases would explain variable neuronal damages after hypoglycemia and might help identify the degrees of hypoglycemic insults and further improve alternative therapies.
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... Truncation of the TCA cycle is also possible in certain disease states, including hypoglycaemia and in various cancers, in which specific steps are no longer functional and are bypassed. During hypoglycaemia, for example, glutamate can become the primary source of carbon, allowing OAA to be generated from αKG instead of citrate [35]. Loss of FH function, as found in some cancers, results in the accumulation of fumarate and a corresponding decrease in NADH generation [36]. ...
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD.
... However, hypoglycemia in type 1 diabetic subjects caused increase in TCA cycle flux in comparison to heathy subjects, possibly due to cerebral adaptations to RH [89]. During the substantial decline in brain energy production associated with severe hypoglycemia, a modified form of TCA cycle continues to work which involves aspartate aminotransferase-mediated formation of αketoglutarate from oxaloacetate and supports neurons during hypoglycemia-associated energy deprivation [90]. Using a radio-labeled lactate microdialysis study followed by nuclear magnetic resonance analysis of microdialysate, Gallagher et al. showed that lactate may be directly used as a TCA cycle substrate [91]. ...
... While RH decreases glucose metabolism during an eventual episode of hypoglycemia, acetate metabolism remains unchanged [70]. During hypoglycemia, an increase in aspartate, and decrease in glutamine and glutamate levels is associated with a low energy status of brain [90,191]. Glutamine [86] serves as an alternate source of energy for neurons during recovery from hypoglycemia. ...
Diabetes is a metabolic disease afflicting millions of people worldwide. A substantial fraction of world’s total healthcare expenditure is spent on treating diabetes. Hypoglycemia is a serious consequence of anti-diabetic drug therapy, because it induces metabolic alterations in the brain. Metabolic alterations are one of the central mechanisms mediating hypoglycemia-related functional changes in the brain. Acute, chronic, and/or recurrent hypoglycemia modulate multiple metabolic pathways, and exposure to hypoglycemia increases consumption of alternate respiratory substrates such as ketone bodies, glycogen, and monocarboxylates in the brain. The aim of this review is to discuss hypoglycemia-induced metabolic alterations in the brain in glucose counterregulation, uptake, utilization and metabolism, cellular respiration, amino acid and lipid metabolism, and the significance of other sources of energy. The present review summarizes information on hypoglycemia-induced metabolic changes in the brain of diabetic and non-diabetic subjects and the manner in which they may affect brain function.
... The return of released transmitter GABA to glutamine is complex [4,6] and will not be discussed in the present paper. The fluxes in the two directions are approximately equal ( Figure 1) and a truncated TCA cycle with build-up and release of aspartate is in vivo only seen during hypoglycemia, when conversion of glutamate-derived α-KG to oxaloacetate and aspartate provides some metabolic energy [42]. ...
The glutamine-glutamate cycle provides neurons with astrocyte-generated glutamate/γ-aminobutyric acid (GABA) and oxidizes glutamate in astrocytes, and it returns released transmitter glutamate/GABA to neurons after astrocytic uptake. This review deals primarily with the glutamate/GABA generation/oxidation, although it also shows similarity between metabolic rates in cultured astrocytes and intact brain. A key point is identification of the enzyme(s) converting astrocytic α-ketoglutarate to glutamate and vice versa. Most experiments in cultured astrocytes, including those by one of us, suggest that glutamate formation is catalyzed by aspartate aminotransferase (AAT) and its degradation by glutamate dehydrogenase (GDH). Strongly supported by results shown in Table 1 we now propose that both reactions are primarily catalyzed by AAT. This is possible because the formation occurs in the cytosol and the degradation in mitochondria and they are temporally separate. High glutamate/glutamine concentrations abolish the need for glutamate production from α-ketoglutarate and due to metabolic coupling between glutamate synthesis and oxidation these high concentrations render AAT-mediated glutamate oxidation impossible. This necessitates the use of GDH under these conditions, shown by insensitivity of the oxidation to the transamination inhibitor aminooxyacetic acid (AOAA). Experiments using lower glutamate/glutamine concentration show inhibition of glutamate oxidation by AOAA, consistent with the coupled transamination reactions described here.
... The activation of glutamine oxidation through this pathway has previously been described for neurons during hypoglycemia, 47e50 and prolongs neuronal survival under these conditions. 48 Given that glutaminases, BCAT1, and AST2 are mainly neuronal enzymes in normal brain, 51 whereas astrocytes are net producers of glutamine, it seems likely that glutamine oxidation would be mostly up-regulated in neurons in Npc1 À/À cerebellum, and be supported by increased glutamine transport from astrocytes. Moreover, our immunohistochemical analyses showed decreased PDH levels in neurons, including PCs, supporting our hypothesis of deficient neuronal pyruvate oxidation and up-regulation of compensatory pathways. ...
The fatal neurodegenerative disorder Niemann-Pick type C (NPC) is caused in most cases by mutations in NPC1, which encodes the late endosomal NPC1 protein. Loss of NPC1 disrupts cholesterol trafficking from late endosomes to the endoplasmic reticulum and plasma membrane, causing cholesterol accumulation in late endosomes/lysosomes. Neurons are particularly vulnerable to this cholesterol trafficking defect, but the pathogenic mechanisms through which NPC1 deficiency causes neuronal dysfunction remain largely unknown. Herein, we have investigated amino acid metabolism in cerebella of NPC1-deficient mice at different stages of NPC disease. Imbalances in amino acid metabolism were evident from increased branched chain amino acid and asparagine levels and altered expression of key enzymes of glutamine/glutamate metabolism in presymptomatic and early symptomatic NPC1-deficient cerebellum. Increased levels of several amino acid intermediates of one-carbon metabolism indicated disturbances in folate and methylation pathways. Alterations in DNA methylation were apparent in decreased expression of DNA methyltransferase 3a and methyl-5′-cytosine-phosphodiester-guanine-domain binding proteins, reduced 5-methylcytosine immunoreactivity in the molecular and Purkinje cell layers, demethylation of genome-wide repetitive LINE-1 elements, and hypermethylation in specific promoter regions of single-copy genes in NPC1-deficient cerebellum at early stages of the disease. Alterations in amino acid metabolism and epigenetic changes in the cerebellum at presymptomatic stages of NPC disease represent previously unrecognized mechanisms of NPC pathogenesis.
... Substratem energetycznym neuronów jest L-Gln przekształcana w L-Glu, a następnie α-ketoglutaran. Produktem końcowym tego szlaku analogicznego do glutaminolizy w komórkach szybko dzielących się jest L-Asp [51]. ...
Aspartate aminotransferase is an organ - nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms - cytoplasmic (AST1) and mitochondrial (AST2), that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys – 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp) in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs.
