Exogenous Ketones in People With Type 1 Diabetes

Ketosis, Diabetic Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04487678
• Other study ID #: KEsupplements
• Status: Withdrawn
• Phase: N/A
• Start date: August 2023
• Est. completion date: December 2023

Study information

• Verified date: August 2023
• Source: Insel Gruppe AG, University Hospital Bern
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2023
• Est. primary completion date: November 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

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)

Related Conditions & MeSH terms

• Diabetic Ketoacidosis
• Ketosis, Diabetic

Intervention

Dietary Supplement:
• Ketone ester supplement
Participants taking part in this study will receive a drink containing either 141 or 282 mg/kg bodyweight of ketone esters in a randomised order. These doses are in line with recommendations by the company HVMN from which the supplements for this study will be obtained.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Insel Gruppe AG, University Hospital Bern

References & Publications (13)

Balasse EO, Fery F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989 May;5(3):247-70. doi: 10.1002/dmr.5610050304. — View 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. — View Citation

Cox PJ, Clarke K. Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem Physiol Med. 2014 Oct 29;3:17. doi: 10.1186/2046-7648-3-17. eCollection 2014. — View Citation

Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27. — View Citation

Egan B, D'Agostino DP. Fueling Performance: Ketones Enter the Mix. Cell Metab. 2016 Sep 13;24(3):373-375. doi: 10.1016/j.cmet.2016.08.021. — View Citation

Egan B. The glucose-lowering effects of exogenous ketones: is there therapeutic potential? J Physiol. 2018 Apr 15;596(8):1317-1318. doi: 10.1113/JP275938. Epub 2018 Mar 24. No abstract available. — View Citation

Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol. 2017 May 1;595(9):2857-2871. doi: 10.1113/JP273185. Epub 2016 Dec 7. — View Citation

Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord. 2000 Jan;24(1):38-48. doi: 10.1038/sj.ijo.0801083. — View Citation

Kesl SL, Poff AM, Ward NP, Fiorelli TN, Ari C, Van Putten AJ, Sherwood JW, Arnold P, D'Agostino DP. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Nutr Metab (Lond). 2016 Feb 4;13:9. doi: 10.1186/s12986-016-0069-y. eCollection 2016. — View 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. Erratum In: J Physiol. 2019 Nov;597(22):5515. Abstract corrected. — View Citation

Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Sports Med. 2017 Mar;47(3):383-391. doi: 10.1007/s40279-016-0577-y. — View Citation

Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980 Jan;60(1):143-87. doi: 10.1152/physrev.1980.60.1.143. No abstract available. — View 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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in venous blood pH	Change in blood pH over a 3 hour period from baseline following ingestion of a ketone ester drink	Over a 3 hour period from baseline following ingestion of a ketone ester drink in people with type 1 diabetes.
Secondary	Blood total ketone level /beta hydroxy butyrate level		3 hours
Secondary	Blood glucose concentration		3 hours
Secondary	Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio)		3 hours
Secondary	Gastro-intestinal distress symptoms via a questionnaire		3 hours