Vagal complex monocarboxylate transporter-2 expression during hypoglycemia

Vavaiya, Kamlesh V.; Paranjape, Sachin A.; Patil, Gopal D.; Briski, Karen P.

doi:10.1097/01.wnr.0000224766.07702.51

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Furthermore, the use of these monocarboxylates might contribute to reduce the risk of hypoglycaemia-induced brain injury in intensively treated diabetic patients. Interestingly, insulin-induced hypoglycaemia was shown to up-regulate neuronal monocarboxylate transporter MCT2 and glucose transporter GLUT-3 through an estrogen-mediated mechanism in lactate-sensitive chemosensory neurons (Vavaiya et al 2006;Vavaiya and Briski 2008b, a). These studies provided further evidence on the existence of mechanisms to enhance lactate and glucose transport mechanisms and promote local lactate utilization during hypoglycaemia in neurons.…”

Section: Ketone Bodiesmentioning

confidence: 85%

Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose

Amaral

2012

J of Inher Metab Disea

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Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes.

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Section: Ketone Bodiesmentioning

confidence: 85%

Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose

Amaral

2012

J of Inher Metab Disea

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“…This is the case in the hypothalamus, an important region for nutrient sensing and metabolic homeostasis. Thus, an injection of insulin to induce an hypoglycemic episode altered MCT2 expression of the vagal complex in opposite direction between male rats and estrogen-treated oviarectomized female rats [178] . Recurrent insulin-induced hypoglycemia enhanced MCT2 expression in the dorsal vagus complex, whereas acute hypoglycemia suppressed MCT2 expression in the ventromedial hypothalamus [179] .…”

Section: Mcts In the Central Nervous Systemmentioning

confidence: 93%

Monocarboxylate transporters in the brain and in cancer

Pérez-Escuredo

Hée

Sboarina

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

325

289

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Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1–4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1–4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

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“…The current evidence for elevated DVC MCT2 and GLUT3 mRNA in insulin‐injected female rats underscores gender differences in these gene responses, in that IIH does not modify these transcripts in testes‐intact male rats (Vavaiya et al,2007), and suggests that net neuronal lactate and glucose uptake may be correspondingly increased in this brain site in response to IIH. We speculate that these measures of increased mRNA yield coincide with net augmentation of mean cellular transporter protein levels, but the possibility that individual mRNA and protein expression patterns may diverge in an as yet undetermined proportion of DVC neurons cannot be dismissed.…”

Section: Discussionmentioning

confidence: 67%

“…The DVC was bilaterally microdissected from frozen sections with calibrated hollow needles of 0.76 mm diameter (catalog No. 57401; Stoelting, Inc., Kiel, WI), by using neuroanatomical landmarks depicted in Brain maps: structure of the rat brain (Swanson, 1999) as a guide, over an approximate interval of −12.88 to −14.68 mm posterior to bregma (Vavaiya et al,2007). qPCR was performed as previously described from our laboratory (Paranjape et al,2006; Kale et al,2006).…”

Section: Methodsmentioning

confidence: 99%

Effects of caudal hindbrain lactate infusion on insulin‐induced hypoglycemia and neuronal substrate transporter glucokinase and sulfonylurea receptor‐1 gene expression in the ovariectomized female rat dorsal vagal complex: Impact of estradiol

Vavaiya

Briski

2007

J of Neuroscience Research

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The monocarboxylate, lactate, is produced by astrocytic glycolysis and is trafficked to neurons as a substrate fuel for aerobic respiration. This molecule is a critical monitored metabolic variable in hindbrain detection of cellular energy imbalance, because diminished uptake and/or oxidative catabolism of lactate in this part of the brain activates neural mechanisms that increase systemic glucose availability. Lactate-sensitive chemosensory neurons occur in the hindbrain dorsal vagal complex (DVC). Estradiol (E) enhances expression of the neuronal monocarboxylate transporter MCT2 in the DVC during insulin-induced hypoglycemia (IIH), evidence that this hormone may promote local lactate utilization during systemic glucose shortages. We investigated the hypothesis that E regulates basal and IIH-associated patterns of DVC MCT2 and neuronal glucose transporter gene expression and that caudal fourth ventricular (CV4) lactate infusion exerts divergent effects on blood glucose levels and DVC energy transducer gene profiles in hypoglycemic E- vs. oil (O)-implanted ovariectomized (OVX) rats. Insulin-induced decrements in circulating glucose were significantly augmented by lactate, albeit to a greater extent in the presence of E. DVC MCT2, GLUT3, GLUT4, glucokinase (GCK), and sulfonylurea receptor-1 (SUR1) mRNA levels did not differ between saline-injected OVX + E and OVX + O rats. IIH elevated MCT2 and GLUT3 gene profiles in both E- and O-implanted groups, but up-regulation of MCT2 transcripts was reversed by CV4 lactate infusion during hypoglycemia in E- but not O-implanted animals. DVC GLUT4 and GK mRNA were decreased by insulin alone in OVX + O but not OVX + E, but were suppressed by lactate plus insulin treatment in the latter group. Expression of the SUR1 subunit of the energy-dependent potassium channel K(ATP) was significantly decreased by IIH in both E- and O-treated rats and further suppressed in response to lactate delivery during hypoglycemia in OVX + E. These data reveal that E does not control baseline DVC substrate fuel transporter or energy transducer gene profiles or local MCT2, GLUT3, or SUR1 transcriptional responses to IIH but prevents IIH-associated decreases in GLUT4 and GCK mRNA in this brain site. The results also show that, in the presence of E, intensifying effects of CV4 lactate infusion on hypoglycemia are correlated with reversal of IIH enhancement of DVC MCT2 gene expression, augmented IIH inhibition of SUR1 transcripts, and reductions in GLUT4 and GCK mRNA levels relative to baseline. This work implies that IIH may enhance specific neuronal lactate and glucose transport mechanisms in the female rat DVC and that, in the presence of E, caudal hindbrain lactate repletion may normalize neuronal lactate but not glucose internalization by local neurons. The results also suggest that putative IIH-associated reductions in K(ATP)-mediated regulation of membrane voltage in this brain site may be causally related to diminished glucose availability.

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Vagal complex monocarboxylate transporter-2 expression during hypoglycemia

Cited by 6 publications

References 23 publications

Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose

Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose

Monocarboxylate transporters in the brain and in cancer

Effects of caudal hindbrain lactate infusion on insulin‐induced hypoglycemia and neuronal substrate transporter glucokinase and sulfonylurea receptor‐1 gene expression in the ovariectomized female rat dorsal vagal complex: Impact of estradiol

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