Exogenous Ketones in People With Type 1 Diabetes

Study Overview
=================
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.

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

Conditions
-----------------
Ketosis, Diabetic

Intervention / Treatment
-----------------
* Dietary Supplement: Ketone ester supplement


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Single-centre, randomised, single blinded, crossover study in 6 individuals with type 1 diabetes (see inclusion/exclusion criteria)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose KE<br>141 mg/kg bodyweight of ketone esters | Dietary Supplement: Ketone ester supplement<br>* 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.<br>* Other names: H.V.M.N Ketone Ester food supplement;|
| Experimental: High-dose KE<br>282 mg/kg bodyweight of ketone esters | Dietary Supplement: Ketone ester supplement<br>* 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.<br>* Other names: H.V.M.N Ketone Ester food supplement;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood total ketone level /beta hydroxy butyrate level |  | 3 hours | 
| Blood glucose concentration |  | 3 hours | 
| Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio) |  | 3 hours | 
| Gastro-intestinal distress symptoms via a questionnaire |  | 3 hours |