14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial

Abstract

Context: Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing β-hydroxybutyrate (β-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia.

Objective: We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity.

Methods: In a randomized crossover design, 14 participants with obesity (age = 56 ± 12 years; body mass index = 32.8 ± 7.7 kg/m2) consumed KME (12 g β-OHB) or placebo 15 minutes prior to each meal for 14 days with all meals provided and matched between conditions. Postprandial glycemia was assessed by continuous glucose monitoring. Vascular function and inflammation were assessed before and after treatment periods.

Results: Postprandial glucose was 8.0% lower in KME versus placebo (g = 0.735; P = 0.011) and 24-hour average glucose reduced by 7.8% (g = 0.686; P = 0.0001). Brachial artery flow-mediated dilation increased from 6.2 ± 1.5% to 8.9 ± 3.3% in KME (g = 1.05; P = 0.0004) with no changes in placebo (condition × time interaction, P = 0.004). There were no changes in plasma cytokines; however, lipopolysaccharide-stimulated monocyte caspase-1 activation was lower following KME supplementation versus placebo (stimulation × condition × time interaction; P = 0.004). The KME supplement was well tolerated by participants and adherence to the supplementation regimen was very high.

Conclusions: In adults with obesity, 14 days of premeal KME supplementation improves glucose control, enhances vascular function, and may reduce cellular inflammation. KME supplementation may be a viable, nonpharmacological approach to improving and protecting vascular health in people with heightened cardiometabolic risk.

Trial registration: ClinicalTrials.gov NCT03817749.

Keywords: NLRP3 inflammasome; flow-mediated dilation; glucose-lowering; inflammation; postprandial glucose; β-hydroxybutyrate.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Trial details. A, flow chart of study recruitment and facilitation. B, trial schematic. All pre- and post-intervention measures were made with participants in a fasting, non-supplemented state.

Figure 1.

Trial details. A, flow chart of study recruitment and facilitation. B, trial schematic. All pre- and post-intervention measures were made with participants in a fasting, non-supplemented state.

Figure 2.

Glucose responses to intervention as measured by CGM. A, 2-hour glucose AUC; B, 2-hour glucose iAUC; C, 24-hour average glucose; and D, continuous overall net glycemic action (CONGA). *Significantly different compared to placebo condition, P < 0.05 (paired t test).

Figure 3.

Flow-mediated dilation (FMD) responses before (Pre) and after (Post) 14-day premeal supplementation with either placebo or ketone. Data are not corrected for baseline diameter, as sensitivity analysis revealed no effect of baseline diameter on the FMD response. The time × condition interaction was significant (P < 0.05) in a linear mixed-effect model. *Significantly different compared to Pre within condition, P < 0.05.

Figure 4.

A, Change in monocyte caspase-1 activation after the 14-day intervention (Post minus Pre) measured in whole blood, cultured with lipopolysaccharide (LPS+) or without (LPS−). The stimulation × condition interaction was significant (P < 0.05). B, IL-1β expression following 2-hour of LPS-stimulation before (Pre) and after (Post) the 14-day intervention (time × condition interaction P = 0.053). *Significantly different from placebo condition on preplanned contrast (P < 0.05). Abbreviation: MFI, median fluorescence intensity.