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

Adrian Avila, Ignacio Málaga, Deepa Sirsi, Saima Kayani, Sharon Primeaux, Gauri A Kathote, Vikram Jakkamsetti, Raja Reddy Kallem, William C Putnam, Jason Y Park, Shlomo Shinnar, Juan M Pascual, Adrian Avila, Ignacio Málaga, Deepa Sirsi, Saima Kayani, Sharon Primeaux, Gauri A Kathote, Vikram Jakkamsetti, Raja Reddy Kallem, William C Putnam, Jason Y Park, Shlomo Shinnar, Juan M Pascual

Abstract

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.

Conflict of interest statement

The authors declare no competing interests.

© 2023. The Author(s).

Figures

Figure 1
Figure 1
Study procedures. BHB beta-hydroxybutyric acid, Glu glucose.
Figure 2
Figure 2
Beta-hydroxybutyrate levels independent of, before, during and after C7 ingestion. Left panel: Non C7: Percent change in 224 beta-hydroxybutyrate levels from 20 G1D individuals not receiving C7 and not treated in this study; C7 Compatible: change in G1D individuals that exhibited beta-hydroxybutyrate values indicative of compatibility with C7. C7 Non compatible: change in G1D individuals where the ketogenic diet was estimated non compatible with C7; The variability in sample-to-sample change for non-C7 treated subjects was not significantly different from the variability in G1D patients who received C7 in whom C7 was compatible with the ketogenic diet. Welch's ANOVA (for unequal variances) with Dunnett's correction for multiple comparisons. *p 

Figure 3

C5 ketonemia in select subjects…

Figure 3

C5 ketonemia in select subjects before and after C7 administration. Left panel: Beta-hydroxy…

Figure 3
C5 ketonemia in select subjects before and after C7 administration. Left panel: Beta-hydroxy pentanoate values in relation to C7 administration times (4 doses, administered on day 2). Right panel: values for beta-keto pentanoate.
Figure 3
Figure 3
C5 ketonemia in select subjects before and after C7 administration. Left panel: Beta-hydroxy pentanoate values in relation to C7 administration times (4 doses, administered on day 2). Right panel: values for beta-keto pentanoate.

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