Exogenous Ketosis in a Fed and a Fasted State

The kinetics of circulating βHB following ingestion of the ketone monoester are dependent on several variables that determine the balance between appearance into, and disappearance from, the bloodstream. These dynamics have been well characterised in fasted humans but in the real world the ketone monoester is likely to be ingested in a fed state, pertinently within athletic spheres consumption would proceed a substantial high-carbohydrate meal. Within this, it is unclear how metabolism under exogenous ketosis might be affected in a fed versus fasted state.

This four-arm crossover study looks to characterise the relationship between feeding status, βHB pharmacokinetics, and resting metabolism.

As exogenous ketosis is known to reduce circulating glucose levels, this study will also explored if hepatic metabolism - for example, de novo lipogenesis - might consequently be altered, with implications for metabolic disease states such as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and type II diabetes.

Participants will be asked to consume either the ketone monoester drink or a placebo drink when fasted and when having previously consumed a meal.

Adults free from metabolic disease will be recruited for this randomised-counterbalanced crossover study. Participants will attend four study visits.

Participants will consume a prescribed isocaloric high-carbohydrate diet for two days prior to each visit to standardise dietary intake.

For two of these visits participants will remain 'fasted' throughout, and for the two 'fed' visits they will consume a mixed-nutrient breakfast meal. The breakfast for the 'fed' visits will provide 2g∙kg-1 bodyweight of carbohydrate.

Heavy water (D2O) will be consumed the evening preceding, and during, each fed study visit to achieve \~0.4% plasma enrichment, in order to quantify the contribution of hepatic de novo lipogenesis to VLDL-TG.

At these visits they will consume either a ketone monoester (KME) or taste/volume-matched placebo (PLA) drink. The nature of this drink will be single blinded and consumed after the breakfast meal during the 'fed' visits.

Therefore the four visits will be as follows: fed-KME, fed-PLA, fasted-KME, fasted-PLA.

Blood and breath samples will be collected at fasting and across a 6 hour period after consuming the KME or PLA drink. Subjective measures of gastrointestinal distress and appetite will also be assessed.

This study aims to establish how feeding state might affect the appearance of βHB into the bloodstream, circulating metabolism, and hepatic metabolism.

Eligibility Criteria:
Inclusion Criteria:

* Habitually consuming a mixed macronutrient diet
* Fluent in English, no communication impairments, willing \& able to give informed consent for participation in the study
* Not currently taking any medication (except the contraceptive pill)
* No food allergies incompatible with the supplement drinks or with the standardised breakfast where a suitable substitution cannot be practically made
* Female-only - on contraception (pill/implant/coil/etc); not pregnant/currently breastfeeding; pre-menopausal; not undertaking hormone replacement therapy (HRT)
* In the investigator's opinion - able and willing to comply with all study requirements

Exclusion Criteria:

* Significant cardiovascular disease or metabolic risk factors, or family history of it, on health screening questionnaire
* Food allergies incompatible with the supplement drinks or standardised breakfast
* Having been on a ketogenic diet in the 6 months prior to enrolment
* Any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study/the participant's ability to participate in the study
* Concurrently a participant in any other dietary intervention study/have taken part in one within 1 month of enrolment
* Diabetic
* Pregnant or breastfeeding
* Known history of moderate-to-severe motion sickness