Pharmacokinetics and metabolic effects of ketone monoester supplementation: The first simultaneous CKM and CGM study under normal diet and activities

Exogenous ketone supplementation has gained attention for its potential health and performance benefits, yet its real-world pharmacokinetics and metabolic effects remain underexplored. This study investigated the pharmacokinetics of ketone monoester (KME) supplementation during normal diet and activities, leveraging simultaneous interstitial fluid (ISF) continuous ketone and glucose monitoring (CKM and CGM). In this single-group observational study, twenty healthy adults underwent a 10-day KME supplementation protocol following a 4-day baseline period. Weight-based KME dosing rapidly elevated ISF β-hydroxybutyrate (BHB) levels, peaking within 1 h and sustaining ketosis for approximately 5 h. Exploratory correlational analyses revealed a two-stage influence pattern: larger skeletal/adipose mass slowed and blunted peak BHB levels (<i>r</i> = -.52 to -.63, <i>p</i> = .04-.08), whereas higher habitual activity, better baseline glucose regulation and greater protein intake prolonged BHB elevation and associated glucose-suppression window (<i>r</i> = .47-.58, <i>p</i> = .05-.09). Granger causality analysis confirmed that KME supplementation acutely suppressed ISF glucose, with an initial effect at 5 min and a sustained post-dose suppression phase between 25 and 55 min. Surprisingly, fasting glucose levels increased after 10 days of KME supplementation, suggesting compensatory metabolic adaptation. Additionally, sleep efficiency and quality declined during the intervention phase. These findings highlight the complex metabolic effects of KME use, emphasizing the need for personalized approaches to optimize its benefits. This study demonstrates the feasibility of CKM/CGM for capturing real-time metabolic dynamics and underscores the importance of further research into the physiological implications of exogenous ketone supplementation.