Comparison of Exogenous Ketone Administration versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial

Figures

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  FIGURE 1.. KEETO-CROSS study design. Participants were assigned in random order to KE and 24/72-h KD arms, and after at least a 1-wk washout period, participants returned for remaining arm. Visit time points in hours depicted. KD = ketogenic diet; KE = ketone ester.

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  FIGURE 2.. Biomarker levels by study arm. Box-and-whisker plots for ketone (A), insulin (B), glucagon (C), and NEFA (D) levels are displayed by study visit for the 18 participants included in the modified intention-to-treat analysis. Whiskers depict minimum and maximum values. P values corrected for multiple testing.

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  FIGURE 3.. Primary and secondary endpoints of KEETO-CROSS study shown for the 18 participants who completed all study visits. (A) Percentages of primary endpoint achievement (complete myocardial glucose suppression). (B) Box-and-whisker plots of secondary outcome (average SUV of myocardium to blood pool).

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  FIGURE 4.. Receiver-operating-characteristic curve analysis for BHB, insulin, glucagon, NEFA, and glucose to predict myocardial glucose suppression in all participants during ketogenic diet.

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  FIGURE 5.. Myocardial 18F-FDG uptake patterns in healthy volunteers. Representative images (displayed using same window width 0–5) of most common myocardial 18F-FDG uptake patterns encountered in our healthy cohort, with their corresponding BHB levels. Patterns C–E can be potentially mistaken as myocardial inflammation; however, accompanying BHB levels should raise concern for incomplete suppression. LV = left ventricular.

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  FIGURE 6.. Relationship between endogenous ketone levels and myocardial glucose uptake. Continuous spline analysis with 4 knots depicts relationship between endogenous ketone levels (BHB) and secondary outcome (SUV ratio of myocardium to blood pool).

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  FIGURE 7.. Proposed molecular mechanisms associated with myocardial 18F-FDG suppression between acute exogenous ketone administration (lower left) and endogenous ketosis induced by dietary modification (lower right). Posttranslational protein acetylation and attenuation of insulin signaling are both required mechanisms for successful inhibition of glucose transporter member 4 (GLUT4) translocation. Acute administration of KE drink leads to a severalfold increment in β-hydroxybutyrate (βHB) levels but also appears to decrease free fatty acid (FFA) levels, which may ultimately affect modulation of insulin signaling and process of acetylation. In contrast, although KD yields lower βHB levels after 24–72 h, it increases FFA and glucagon and lowers insulin levels on a sustained fashion, eventually augmenting fatty acid oxidation (FAO) over glucose oxidation (“Randle effect”), increasing protein acetylation, and limiting insulin signaling. These molecular differences in substrate handling may explain why myocardial 18F-FDG suppression rates were 44% for KE and 81% for KD. Adapted from “Insulin Mechanism,” by BioRender.com (2021 (17)).