Introduction: Ketone monoester (KME) ingestion has been shown to attenuate postprandial glycaemia in young healthy individuals and those with Type 2 diabetes. This appears to be mediated by a reduced exogenous rate of glucose appearance, without affecting whole-body glucose disposal. However, the effect of KME ingestion on glucose handling within muscle, and its relation to ketone and non-esterified fatty acid (NEFA) handling, is less well characterised. This study investigated the effect of KME ingestion, prior to a mixed meal (MTT), on postprandial concentrations of β-Hydroxybutyrate (β-OHB), glucose, NEFA, and insulin, utilising a forearm arterialised-venous deep-venous (AV) balance model to characterise skeletal muscle substrate handling.

Methods: Seven young healthy individuals (m=5, f=2; age 27±5 y; BMI 24.3±1.8 kg∙m^-2) completed two trials, in a randomised, double-blind, placebo-controlled, crossover design. Participants consumed KME [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 0.5 g∙kg^-1 body weight] or a noncaloric taste-matched placebo (CON), 30 min before consuming an MTT (1.1, 0.3 and 0.2 g∙kg^-1 body weight carbohydrate, protein, and fat, respectively) at t=0 min. Circulating arterialised-venous and deep-venous β-OHB, glucose, NEFA, and insulin concentrations were subsequently measured over 3 hours, with fractional extraction calculated for glucose and β-OHB  (the AV difference relative to arterialised-venous concentration).

Results: Circulating β-OHB concentration remained at baseline during CON (0.2±0.0 mM), whereas it increased to a peak of 3.5±0.4 mM at t=30 in KME, averaging 2.2±1.1 mM throughout the postprandial period (P<0.0001). In turn, fractional β-OHB extraction was elevated in KME, but not CON (P=0.0060), peaking at t=0 before returning to baseline at t=60. Arterialised-venous blood glucose concentration increased from 4.4±0.3 mM in the postabsorptive state to a peak of 7.0±0.5 mM at t=15 in CON, whereas this rise was attenuated in KME, increasing from 4.1±0.3 mM to 5.9±0.5 mM (P=0.007), equating to a 44±29% suppression in postprandial glucose iAUC. Fractional glucose extraction increased following the MTT (P<0.0001), peaking at t=45, but was not different between conditions (P=0.4514). NEFA concentrations were suppressed more rapidly and to a greater extent in KME compared with CON (P=0.0063), which corresponded to a 49±20% suppression in NEFA iAUC. Circulating lactate concentrations increased in both conditions, but to a greater extent in KME (P=0.0244), averaging 0.75 mM in CON and 0.92 mM in KME. Serum insulin concentrations increased similarly in both trials, peaking at 87±16 mU and 81±19 mU at t=15 min in CON and KME, respectively.

Conclusion: The ingestion of KME before a mixed meal robustly increased circulating β-OHB concentrations, which was associated with a marked attenuation of postprandial glucose and NEFA concentrations in young healthy individuals, occurring independently of insulin. KME did not alter relative glucose extraction across the vascular bed of the forearm musculature, although it did increase relative β-OHB extraction, suggesting that β-OHB uptake in muscle does not significantly affect muscle glucose metabolism. This evidence implies KME attenuates postprandial glucose concentrations via mechanisms independent of skeletal muscle glucose uptake.