Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals

KEY POINTS: The recent development of exogenous ketone supplements allows direct testing of the metabolic effects of elevated blood ketones without the confounding influence of widespread changes experienced with ketogenic diets or prolonged fasting. In the present study, we determined the effect of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester on the glycaemic response and insulin sensitivity index during a 2 h oral glucose tolerance test (OGTT) in humans. The results obtained show that consuming a ketone monoester supplement 30 min prior to an OGTT reduced the glycaemic response and markers of insulin sensitivity without affecting insulin secretion. The findings of the present study provides evidence that ketone supplements could have therapeutic potential for future application as a glucose-lowering nutritional supplement. ABSTRACT: The main objectives of the present study were: (i) to determine whether acute ingestion of ketone monoester (Kme ); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate impacts plasma glucose levels during a standardized oral glucose tolerance test (OGTT) and (ii) to compare changes in insulin concentrations and estimates of insulin sensitivity after acute Kme supplementation. Twenty healthy participants (n = 10 males/females) aged between 18 and 35 years took part in a randomized cross-over study. After an overnight fast, participants consumed a Kme supplement (ΔG®; TΔS Ltd, UK, Oxford, UK; 0.45 ml kg-1 body weight) or placebo (water) 30 min before completing a 75 g OGTT. Blood samples were collected every 15-30 min over 2.5 h. The participants and study personnel performing the laboratory analyses were blinded to the study condition. Kme acutely raised blood d-beta-hydroxybutyrate (β-OHB) to 3.2 ± 0.6 mm within 30 min with levels remaining elevated throughout the entire OGTT. Compared to placebo, Kme significantly decreased the glucose area under the curve (AUC; -16%, P = 0.001), non-esterified fatty acid AUC (-44%, P < 0.001) and C-peptide incremental AUC (P = 0.005), at the same time as improving oral glucose insulin sensitivity index by ∼11% (P = 0.001). In conclusion, a Kme supplement that acutely increased β-OHB levels up to ∼3 mm attenuated the glycaemic response to an OGTT in healthy humans. The reduction in glycaemic response did not appear to be driven by an increase in insulin secretion, although it was accompanied by improved markers of insulin sensitivity. These results suggest that ketone monoester supplements could have therapeutic potential in the management and prevention of metabolic diseases.