Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

Abstract

There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer ¹¹C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a "super fuel" in cardiac and chronic kidney diseases.

Keywords: acetoacetate; beta-hydroxybutyrate; energy metabolism; ketones; medium chain triglyceride; nicotinamide adenine dinucleotide; positron emission tomography.

Figure 1

Exogenous production of blood ketones by three ketone precursors–MCT, KE, and D-BHB.

Figure 2

Blood ketone kinetics following gram-matched oral doses of D-BHB, D+L-BHB, and MCT in 15 fasted participants at rest. (A) Plasma ketone, (B) D-BHB, (C) AcAc, and (D) L-BHB levels over 4 h. Values are means + SEM.

Figure 3

(A) Plasma ketone iAUC (μM^*h) for D-BHB, D+L BHB and MCT, and (B) their respective ketone production per calorie consumed (iAUC/kcal).

Figure 4

Whole body image after supplementation with two 15 g D-BHB doses, one at −75 min and the other at −30 min prior ¹¹C-AcAc infusion (330 MBq). An 8 min scan (30 s per bed) was acquired 18 min post-injection of the radiotracer.

Figure 5

¹¹C-AcAc organ distribution after D-BHB oral intake.

Figure 6

Heart image: 15 min cardiac-gated acquisition (8 frames) obtained 50 min post-¹¹C-AcAc injection. Left ventricle (LV), right ventricle (RV), horizontal long axis (HLA), vertical long axis (VLA) and short axis (SA) images.