Clinical trial NCT04487678: Exogenous Ketones in People With Type 1 Diabetes
Official title: A Single-centre, Randomised, Single-blinded Crossover Study Evaluating the Metabolic Effects of a Ketone Ester Food Supplement in People With Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Ketosis, Diabetic
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2020-07-27
Enrollment: 0
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Single-centre, randomised, single blinded, crossover study in 6 individuals with type 1 diabetes (see inclusion/exclusion criteria)
Primary purpose: PREVENTION

Brief summary: The aim of this pilot study is to investigate the metabolic effects of exogenous ketone ester food supplements, by assessing the change in blood acid-base balance, and the level of blood beta-hydroxy-butyrate in people with type 1 diabetes during resting conditions.

Detailed description: The ketone bodies acetoacetate, β-hydroxybutyrate (βHB) and acetone are small lipid-derived molecules that are produced in the liver under certain conditions such as starvation, very low carbohydrate intake and prolonged glycogen-depleting exercise. Ketone bodies serve as an alternative energy substrate for the brain and other metabolically active tissues under periods of low glucose availability, and can modulate carbohydrate and lipid metabolism. Previously, controlled physiological ketosis required a low carbohydrate diet, starvation or administration of acetoacetate (AcAc) salts which were all unpleasant or potentially harmful. The development of ketone esters provides an alternative method to increase βHB levels, and has been shown to be well tolerated in rodents and humans. Two examples are the R,S-1,3-butanediol acetoacetate diester and the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester. Ingestion of either have been shown to result in short-term (0.5-6 hours) nutritional ketosis (βHB \>1mM). Nutritional ketosis can therefore be achieved without the need for the impracticality of ketogenic dieting or fasting.

In recent years there has been considerable interest in ketone body food supplements due to their potential for improved exercise performance and therapeutic glucose lowering effects in people with type 2 diabetes. Exogenous ketone supplements may be of particular interest for individuals living with type 1 diabetes by serving as an alternative fuel substrate to reduce the reliance on glucose utilisation and spare endogenous glycogen and reduce the risk of hypoglycaemia in certain situations, such as exercise. Stubbs et al. (2017) found that drinks containing exogenous ketones were a practical and efficacious way to raise blood βHB levels with only a modest change in acid-base balance in healthy individuals without diabetes (after 60 min, blood pH declined from 7.41 to 7.31 following a ketone ester drink). To date, no studies have investigated the metabolic effects of ketone in people with type 1 diabetes.

Eligibility criteria: Inclusion Criteria:

* Type 1 diabetes for \>1 year
* Male and female aged 18-45 years old
* HbA1c \<8.5% (69 mmol/mol) based on analysis from the central laboratory unit of Bern University Hospital
* Using either continuous subcutaneous insulin infusion or multiple daily injections
* Wearing a continuous glucose monitor (CGM) or flash glucose monitor (fGM)
* Written informed consent

Exclusion Criteria:

* Physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the results as judged by the investigator
* Current treatment with drugs known to interfere with metabolism e.g. systemic corticosteroids, statins, SGLT2 inhibitors, GLP1 agonists
* Relevant diabetic complications as judged by the investigator
* Body mass index \> 30 kg/m2
* Uncontrolled hypertension (\>180/100 mmHg)

Primary outcomes:
measure: Change in venous blood pH
timeFrame: Over a 3 hour period from baseline following ingestion of a ketone ester drink in people with type 1 diabetes.
Secondary outcomes:
measure: Blood total ketone level /beta hydroxy butyrate level
timeFrame: 3 hours
measure: Blood glucose concentration
timeFrame: 3 hours
measure: Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio)
timeFrame: 3 hours
measure: Gastro-intestinal distress symptoms via a questionnaire
timeFrame: 3 hours
Other outcomes:
Locations:
Study officials:
affiliation: University of Bern
name: Christoph Stettler, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3.
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citation: Myette-Cote E, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018 Apr 15;596(8):1385-1395. doi: 10.1113/JP275709. Epub 2018 Mar 2.
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citation: Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848. doi: 10.3389/fphys.2017.00848. eCollection 2017.