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

Abstract

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; -17%, 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.

Keywords: d-beta-hydroxybutyrate; glycemic response; insulin sensitivity; ketone bodies; non-esterified fatty acids.

© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Figures

Figure 1. β‐OHB, glucose, insulin and C‐peptide responses following a single dose of Kme supplement or placebo

Supplements were consumed in the fasted state followed 30 min later by a 75 g OGTT. A, β‐OHB, B, glucose. C, insulin. D, C‐peptide. *P < 0.001 vs. placebo within time point, Bonferroni adjusted post hoc. †P < 0.001, significant main effect of condition.

Figure 2. Two hour AUC following a single dose of Kme supplement or placebo

Supplements were consumed in the fasted state followed 30 min later by a 75 g OGTT. A, β‐OHB AUC. B, glucose AUC. C, insulin AUC. D, C‐peptide AUC. Continuous lines represent individual male participants and dashed lines represent individual female participants. *P = 0.001 vs. placebo.

Figure 3. Two‐hour iAUC following a single dose of Kme supplement or placebo

Supplements were consumed in the fasted state followed 30 min later by a 75 g OGTT. A, glucose iAUC. B, insulin iAUC. C, C‐peptide iAUC. Continuous lines represent individual male participants and dashed lines represent individual female participants. **P < 0.01 vs. placebo, *P < 0.05 vs. placebo.

Figure 4. Oral glucose insulin sensitivity index following a single dose of Kme supplement or placebo

Supplements were consumed in the fasted state followed 30 min later by a 75 g OGTT. Continuous lines represent individual male participants and dashed lines represent individual female participants. *P = 0.001 vs. placebo.

Figure 5. NEFA following a single dose of Kme supplement or placebo

Supplements were consumed in the fasted state followed 30 min later by a 75 g OGTT. A, NEFA response over time. B, 2 h AUC. Continuous lines represent individual male participants and dashed lines represent individual female participants. **P < 0.001 vs. placebo. *P < 0.01 vs. placebo within time point, Bonferroni adjusted post hoc.

Figure 6. GLP‐1 and adiponectin responses following a single dose of Kme supplement or placebo

Supplements were consumed in the fasted state followed 30 min later by a 75 g OGTT. A, GLP‐1. B, adiponectin. *P < 0.01 vs. placebo within time point, Bonferroni adjusted post hoc.