Glucose Transporter Type I Deficiency and Other Glucose Flux Disorders

Pascual, Juan M.; Wang, Dong; Vivo, Darryl C. De

doi:10.1016/b978-0-12-410529-4.00058-9

Cited by 2 publications

(3 citation statements)

References 115 publications

(101 reference statements)

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“…Second, seizures might also result from intrinsic cortical hyperexcitability. Patch‐clamp recordings in acute brain slices evidenced a decrease of excitatory and inhibitory postsynaptic currents in Glut1‐deficient animals compared with controls . This decrease, however, was disproportional between excitatory and inhibitory currents.…”

Section: Glut1 Deficiency Syndromementioning

confidence: 91%

Synaptic energy metabolism and neuronal excitability, in sickness and health

Oyarzábal

Marin‐Valencia

2019

J of Inher Metab Disea

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Most of the energy produced in the brain is dedicated to supporting synaptic transmission. Glucose is the main fuel, providing energy and carbon skeletons to the cells that execute and support synaptic function: neurons and astrocytes, respectively. It is unclear, however, how glucose is provided to and used by these cells under different levels of synaptic activity. It is even more unclear how diseases that impair glucose uptake and oxidation in the brain alter metabolism in neurons and astrocytes, disrupt synaptic activity, and cause neurological dysfunction, of which seizures are one of the most common clinical manifestations. Poor mechanistic understanding of diseases involving synaptic energy metabolism has prevented the expansion of therapeutic options, which, in most cases, are limited to symptomatic treatments. To shed light on the intersections between metabolism, synaptic transmission, and neuronal excitability, we briefly review current knowledge of compartmentalized metabolism in neurons and astrocytes, the biochemical pathways that fuel synaptic transmission at resting and active states, and the mechanisms by which disorders of brain glucose metabolism disrupt neuronal excitability and synaptic function and cause neurological disease in the form of epilepsy.

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Section: Glut1 Deficiency Syndromementioning

confidence: 91%

Synaptic energy metabolism and neuronal excitability, in sickness and health

Oyarzábal

Marin‐Valencia

2019

J of Inher Metab Disea

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“…Other symptoms include mild to severe cognitive impairments, microencephaly, and disordered movements. 2,[4][5][6][7][8][9][10] Impaired Glut1 function reduces glucose transport into the brain, 11 and glucose concentrations in the cerebrospinal fluid (CSF) are lower than normal. 2 This hypoglycorrhachia, along with low CSF lactate levels, is one of the diagnostic criteria for Glut1DS in addition to mutation analysis within the SLC2A1 gene.…”

Section: Introductionmentioning

confidence: 99%

“…Also, mutations within SLC2A1 may play a role in absence epilepsy with early onset. 3 We refer the reader to numerous comprehensive reviews available summarizing the clinical aspects of this disorder and its treatment with ketogenic diet, 2,[4][5][6][7][8][9][10]12 and we extend our apologies to authors not mentioned. Despite dietary treatment and numerous medications available, approximately 30%-50% of persons with Glut1 deficiency have uncontrolled seizures 2,10 and improved treatments to control seizures and other symptoms are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome

Xu,

Borges

2024

Epilepsia

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In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood–brain barrier. This can lead to shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first‐line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ‐aminobutyric acid synthesis, and decanoic acid can also block α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of “ketosis” can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add‐on MCT to ketogenic diets and assessing of short‐ and long‐term outcomes.

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Glucose Transporter Type I Deficiency and Other Glucose Flux Disorders

Cited by 2 publications

References 115 publications

Synaptic energy metabolism and neuronal excitability, in sickness and health

Synaptic energy metabolism and neuronal excitability, in sickness and health

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome

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