Oral D/L-3-hydroxybutyrate stimulates cholecystokinin and insulin secretion and slows gastric emptying in healthy males

Abstract

Background: D-3-hydroxybutyrate (D-3-OHB) is a ketone body that serves as an alternative nutritional fuel but also as an important signaling metabolite. Oral ketone supplements containing D/L-3-OHB are becoming a popular approach to achieve ketosis. Aim: To explore the gut-derived effects of ketone supplements. Methods: Eight healthy lean male volunteers were investigated on 2 separate occasions: i) Following oral D/L-3-OHB consumption (oral) ii) Following isoketonemic intravenous ketone (D/L-3-OHB) infusion. An acetaminophen test was performed to evaluate gastric emptying and blood samples were obtained consecutively throughout the study period. Results: We show that oral consumption of D/L-3-OHB stimulates cholecystokinin release (P = 0.02), elevates insulin (P = 0.03) and C-peptide (P < 0.001) concentrations, and slows gastric emptying (P = 0.01) compared with matched intravenous D/L-3-OHB administration. Measures of appetite and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were unaffected by interventions. Conclusion: Our findings show that D/L-3-OHB exert incretin effects and indicate luminal sensing in the gut endothelium. This adds to our understanding of ketones as signaling metabolites and displays the important difference between physiological ketosis and oral ketone supplements. (J Clin Endocrinol Metab 105: 1–9, 2020)