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Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)

Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon do...

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Autores principales: Avila, Adrian, Málaga, Ignacio, Sirsi, Deepa, Kayani, Saima, Primeaux, Sharon, Kathote, Gauri A., Jakkamsetti, Vikram, Kallem, Raja Reddy, Putnam, William C., Park, Jason Y., Shinnar, Shlomo, Pascual, Juan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238483/
https://www.ncbi.nlm.nih.gov/pubmed/37268656
http://dx.doi.org/10.1038/s41598-023-36001-x
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author Avila, Adrian
Málaga, Ignacio
Sirsi, Deepa
Kayani, Saima
Primeaux, Sharon
Kathote, Gauri A.
Jakkamsetti, Vikram
Kallem, Raja Reddy
Putnam, William C.
Park, Jason Y.
Shinnar, Shlomo
Pascual, Juan M.
author_facet Avila, Adrian
Málaga, Ignacio
Sirsi, Deepa
Kayani, Saima
Primeaux, Sharon
Kathote, Gauri A.
Jakkamsetti, Vikram
Kallem, Raja Reddy
Putnam, William C.
Park, Jason Y.
Shinnar, Shlomo
Pascual, Juan M.
author_sort Avila, Adrian
collection PubMed
description Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet. ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.
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spelling pubmed-102384832023-06-04 Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D) Avila, Adrian Málaga, Ignacio Sirsi, Deepa Kayani, Saima Primeaux, Sharon Kathote, Gauri A. Jakkamsetti, Vikram Kallem, Raja Reddy Putnam, William C. Park, Jason Y. Shinnar, Shlomo Pascual, Juan M. Sci Rep Article Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet. ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017. Nature Publishing Group UK 2023-06-02 /pmc/articles/PMC10238483/ /pubmed/37268656 http://dx.doi.org/10.1038/s41598-023-36001-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Avila, Adrian
Málaga, Ignacio
Sirsi, Deepa
Kayani, Saima
Primeaux, Sharon
Kathote, Gauri A.
Jakkamsetti, Vikram
Kallem, Raja Reddy
Putnam, William C.
Park, Jason Y.
Shinnar, Shlomo
Pascual, Juan M.
Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)
title Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)
title_full Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)
title_fullStr Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)
title_full_unstemmed Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)
title_short Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D)
title_sort combination of triheptanoin with the ketogenic diet in glucose transporter type 1 deficiency (g1d)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238483/
https://www.ncbi.nlm.nih.gov/pubmed/37268656
http://dx.doi.org/10.1038/s41598-023-36001-x
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