A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial

Abstract

Background: Exogenous ketones make it possible to reach a state of ketosis that may improve metabolic control in humans.

Objectives: The main objective of this study was to determine whether the ingestion of a ketone monoester (KE) drink before a 2-h oral-glucose-tolerance test (OGTT) would lower blood glucose concentrations. Secondary objectives were to determine the impact of KE on nonesterified fatty acid (NEFA) concentration and glucoregulatory hormones.

Methods: We conducted a randomized controlled crossover experiment in 15 individuals with obesity (mean ± SD age: 47 ± 10 y; BMI: 34 ± 5 kg/m2). After an overnight fast, participants consumed a KE drink [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 0.45 mL/kg body weight] or taste-matched control drink 30 min before completing a 75-g OGTT. Participants and study personnel performing laboratory analyses were blinded to each condition.

Results: The KE increased d-β-hydroxybutyrate to a maximum of ∼3.4 mM (P < 0.001) during the OGTT. Compared with the control drink, KE reduced glucose (-11%, P = 0.002), NEFA (-21%, P = 0.009), and glucagon-like peptide 1 (-31%, P = 0.001) areas under the curve (AUCs), whereas glucagon AUC increased (+11%, P = 0.030). No differences in triglyceride, C-peptide, and insulin AUCs were observed after the KE drink. Mean arterial blood pressure decreased and heart rate increased after the KE drink (both P < 0.01).

Conclusions: A KE drink consumed before an OGTT lowered glucose and NEFA AUCs with no increase in circulating insulin. Our results suggest that a single drink of KE may acutely improve metabolic control in individuals with obesity. Future research is warranted to examine whether KE could be used safely to have longer-term effects on metabolic control. This trial was registered at clinicaltrials.gov as NCT03461068.

Keywords: carbohydrate metabolism; glycemic control; insulin resistance; ketone supplement; obesity; β-hydroxybutyrate.

Copyright © American Society for Nutrition 2019.

Figures

FIGURE 1

CONSORT flow diagram. CVD, cardiovascular disease; OGTT, oral-glucose-tolerance test.

FIGURE 2

Changes over time and 2-h AUC after a single drink of KE supplement or Ctrl drink. Drinks were consumed in the fasted state followed 30 min later by a 75-g oral-glucose-tolerance test. Linear mixed-effects models (condition and time as fixed factors and subject as a random factor) were used to determine the treatment effects. Significant interactions were followed up with preplanned contrasts comparing Ctrl drink with KE within each time point using Bonferroni corrections for multiple comparisons. AUCs were compared between experimental conditions using paired Student's t tests. (A) βHB. Condition-by-time interaction P < 0.001. *P < 0.001 compared with Ctrl drink within time point, Bonferroni adjusted post hoc (n = 15). (B) βHB AUC. ‡P < 0.001 compared with Ctrl drink (n = 15). (C) Glucose. Condition-by-time interaction P = 0.354, main effects of time P < 0.001 and condition **P < 0.001 (n = 15). (D) Glucose AUC. †P = 0.002 compared with Ctrl drink (n = 15). Dotted lines represent the Ctrl drink and solid lines the KE drink. Data are presented as mean ± SD in changes over time figures and as individual data and mean in AUC figures. Ctrl, control; KE, ketone monoester; βHB, β-hydroxybutyrate.

FIGURE 3

Changes over time and 2-h AUC after a single drink of KE supplement or Ctrl drink. Drinks were consumed in the fasted state followed 30 min later by a 75-g oral-glucose-tolerance test. Linear mixed-effects models (condition and time as fixed factors and subject as a random factor) were used to determine the treatment effects. Significant interactions were followed up with preplanned contrasts comparing Ctrl drink with KE within each time point using Bonferroni corrections for multiple comparisons. AUCs were compared between experimental conditions using paired Student's t tests. (A) Insulin. Condition-by-time interaction P = 0.989, main effects of time P < 0.001 and condition P < 0.401 (n = 14). (B) Insulin AUC (n = 14). (C) C-peptide, condition-by-time interaction P = 0.702, main effects of time P < 0.001 and condition P = 0.990 (n = 14). (D) C-peptide AUC (n = 14). Dotted lines represent the Ctrl drink and solid lines the KE drink. Data are presented as mean ± SD in changes over time figures and as individual data and mean in AUC figures. Ctrl, control; KE, ketone monoester.

FIGURE 4

Changes over time and 2-h AUC after a single drink of KE supplement or Ctrl drink. Drinks were consumed in the fasted state followed 30 min later by a 75-g oral-glucose-tolerance test. Linear mixed-effects models (condition and time as fixed factors and subject as a random factor) were used to determine the treatment effects. Significant interactions were followed up with preplanned contrasts comparing Ctrl drink with KE within each time point using Bonferroni corrections for multiple comparisons. AUCs were compared between experimental conditions using paired Student's t tests. (A) NEFAs. Condition-by-time interaction P < 0.001. *P < 0.005 compared with Ctrl drink within time point, Bonferroni adjusted post hoc (n = 15). (B) NEFA AUC. **P < 0.01 compared with Ctrl drink (n = 15). (C) GLP-1. Condition-by-time interaction P = 0.144, main effects of time P < 0.001 and condition †P < 0.001 (n = 14). (D) GLP-1 AUC. ‡P < 0.001 compared with Ctrl drink (n = 14). Dotted lines represent the Ctrl drink and solid lines the KE drink. Data are presented as mean ± SD in changes over time figures and as individual data and mean in AUC figures. Ctrl, control; GLP-1, glucagon-like peptide 1; KE, ketone monoester; NEFA, nonesterified fatty acid.

FIGURE 5

Changes over time and 2-h AUC after a single drink of KE supplement or Ctrl drink. Drinks were consumed in the fasted state followed 30 min later by a 75-g oral-glucose-tolerance test. Linear mixed-effects models (condition and time as fixed factors and subject as a random factor) were used to determine the treatment effects. Significant interactions were followed up with preplanned contrasts comparing Ctrl drink with KE within each time point using Bonferroni corrections for multiple comparisons. AUCs were compared between experimental conditions using paired Student's t tests. (A) Lactate. Condition-by-time interaction P = 0.462, main effects of time P < 0.001 and condition †P = 0.038 (n = 15). (B) Triglycerides, condition-by-time interaction P = 0.992, main effect of time P = 0.210 and condition P = 0.572 (n = 15). (C) Glucagon, condition-by-time interaction P = 0.826, main effect of time P < 0.001 and condition †P = 0.049 (n = 13). (D) Glucagon AUC. *P < 0.05 compared with Ctrl drink (n = 13). Dotted lines represent the Ctrl drink and solid lines the KE drink. Data are presented as mean ± SD in changes over time figures and as individual data and mean in AUC figures. Ctrl, control; KE, ketone monoester.