D-BHB Supplementation Before Moderate-intensity Exercise Suppresses Lipolysis and Selectively Blunts Exercise-induced Long-chain Acylcarnitine Increase in Pilot Study of Patients with Long-chain Fatty Acid Oxidation Disorders

Patients with long-chain fatty acid oxidation disorders (LC-FAOD) have impaired endogenous ketone production due to defects in the beta-oxidation pathway. We explored supplementation of exogenous D-beta-hydroxybutyrate (D-BHB) as an alternative source of energy in a randomized, double-blinded crossover pilot study. Participants ≥18 years of age with a diagnosis of LC-FAOD completed two moderate-intensity treadmill exercises following an oral supplementation of D-BHB salts or an isocaloric maltodextrin beverage. Five subjects (1 VLCADD, 2 CPT2D, 2 LCHADD), 60 % male, mean age = 33 years were enrolled. Mild to moderate GI symptoms were related to ingestion of D-BHB. Plasma D-BHB was increased after oral D-BHB compared to maltodextrin (p < .001) with an average concentration of 0.43 mM in the post-exercise period. During exercise, free fatty acids (p = .01), fold change in long-chain acylcarnitine species (LC-AC) (p ≤ .03) and systolic BP (p = .02) were lower after D-BHB compared to the maltodextrin beverage. D-BHB suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitines. There were no differences between beverages in acetylcarnitine, blood glucose, creatine kinase, VO2, HR, RPE or respiratory exchange ratio. Consumption of the D-BHB beverage was safe and well-tolerated. Plasma D-BHB levels achieved mild ketosis and suppressed lipolysis and the associated rise in LC-AC, but fell short of stimulating the energetic effects that might have resulted in altered exercise parameters such as RER, or HR. In conclusion, our results provide a strong rationale for future studies aimed toward defining the optimal multiple-dose regimen of D-BHB per day that might improve exercise tolerance and understanding the long-term impact of treatment in LC-FAOD subjects.