Background

We previously demonstrated that ingesting a ketone monoester (KME) supplement before a single meal delays the rate of exogenous glucose appearance, leading to lower postprandial glycaemia in individuals with type 2 diabetes. This occurred despite a concomitant rise in endogenous glucose appearance later in the postprandial period, suggesting that the effect may not persist during subsequent meals in the day, and underlining that the origin of endogenous glucose remains unknown. We aimed to test the hypothesis that pre-meal KME ingestion consistently delays rate of exogenous glucose appearance and decreases postprandial glycaemia across consecutive meals. We also sought to investigate the contribution of glycogenolysis and gluconeogenesis to endogenous glucose appearance.

 

Methods

Twelve participants with type 2 diabetes (age 61±2 years, 4 females/8 males, BMI 30.9±0.5 kg/m², HbA_1c 63±3 mmol/mol [7.9±0.3%]) completed two consecutive 4-hour mixed-meal tolerance tests (MMTT1 and MMTT2) on two separate visits. Participants consumed either 0.5 g/kg body mass KME or a non-caloric, taste-matched placebo 30 minutes prior to each MMTT in a randomised, double-blind, crossover design. Primed continuous [²H₂]-glucose infusions were used to trace rates of total glucose appearance (Ra-T) and disappearance (Rd-T), combined with orally ingested [¹³C₆]-glucose to derive exogenous (Ra-Exo) and endogenous (Ra-Endo) glucose appearance. Orally ingested ²H₂O enabled determination of the contribution of gluconeogenesis and glycogenolysis to Ra-Endo. Blood samples were collected regularly to quantify circulating glucose and ketone (beta-hydroxybutyrate; bOHB) concentrations and isotope enrichments. Differences between condition and time were analysed by 2-way ANOVAs (statistical significance P<0.05).

 

Results

Plasma bOHB concentration was 13±1-fold higher with KME versus placebo, and remained elevated at all timepoints throughout each MMTT (interaction P<0.001). Blood glucose concentration increased during each MMTT, but peak concentration was 12±2% and 16±2% lower during MMTT1 and MMTT2, respectively, with KME versus placebo (P<0.001). This suppression remained for up to 2 h in MMTT1 and 2.5 h in MMTT2 (interaction P<0.001). Rd-T increased during each MMTT but was unaffected by KME (time P<0.001). Ra-T increased during each MMTT, but was 27±9% and 32±8% lower with KME at 0.5 h following MMTT1 and MMTT2, respectively, persisting for 1 h after each MMTT (interaction P<0.001). Ra-Exo increased during each MMTT but was 31±6% and 37±8% lower with KME at 0.5 h following MMTT1 and MMTT2, respectively, persisting for 1 h after each MMTT (interaction P<0.001). Ra-Endo decreased during each MMTT (time P<0.001) but was unaffected by KME during each MMTT (interaction P>0.05) though tended to be greater across the entire 8-hour visit with KME (condition P=0.05). Glycogenolysis and gluconeogenesis decreased during each MMTT (time effects P<0.001). Although KME did not affect this change (interactions P>0.05), gluconeogenesis was 12±4% greater across the trial with KM (condition P<0.05).

 

Conclusion

We show for the first time that ingesting a ketone monoester supplement before consecutive meals consistently delays exogenous glucose appearance and lowers postprandial blood glucose concentration, without a substantial change in endogenous glucose production or disposal. Exogenous ketones show promise as an effective nutritional tool to manage blood glucose homeostasis in people living with type 2 diabetes.