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

J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1738-e1754. doi: 10.1210/clinem/dgaa925.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / administration & dosage
  • Adult
  • Aged
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Blood Glucose Self-Monitoring
  • Blood Pressure / drug effects
  • Cardiovascular Physiological Phenomena / drug effects
  • Cardiovascular System / drug effects*
  • Cross-Over Studies
  • Dietary Supplements
  • Double-Blind Method
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / physiopathology
  • Hyperglycemia / prevention & control
  • Ketones / administration & dosage*
  • Male
  • Middle Aged
  • Obesity* / blood
  • Obesity* / diet therapy
  • Obesity* / physiopathology
  • Postprandial Period
  • Time Factors
  • Vasodilation / drug effects

Substances

  • Blood Glucose
  • Ketones
  • 3-Hydroxybutyric Acid

Associated data

  • ClinicalTrials.gov/NCT03817749