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Completed

NCT Number: NCT05155410

Examining the Effect of Exogenous Ketone Supplementation on Glucose Control in Type 2 Diabetes

Ketone bodies are a fuel source and signaling molecule that are produced by the body during prolonged fasting or if an individuals consistently eats a low-carbohydrate "keto" diet. Blood ketones can be used as a source of energy by the body, but they may also act as signals that impact the functioning of different cells in the body. Recently, the availability of ketone supplements that can be taken orally allows for raising blood ketones without having to fast or eat a "keto" diet. The investigators' studies and those of other researchers have shown that ketone supplementation can lower blood sugar without having to make any other dietary changes. Oral ingestion of ketones may therefore be an effective strategy to improve blood sugar control and influence how cells function.

The main objective of this study is to determine if consuming a ketone supplement 3 times per day (before meals) for 14 days lowers blood sugar and impacts how the body's cells function. The results of this study will be used to guide future recommendations on the utility of ketone supplements for improving health in individuals with, or at elevated risk of, type 2 diabetes.

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Key information

Conditions

Diabetes Mellitus, Type 2 Acid-Base Imbalance Acidosis Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Hyperglycemia Inflammation Ketosis Metabolic Diseases Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

30 year–69 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University of British Columbia Okanagan

Kelowna, British Columbia, V1V 3G1, Canada

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Have a type 2 diabetes diagnosis from a physician
  • Have stable use of glucose-lowering medications for at least 3 months

Exclusion criteria

  • Are a competitively trained endurance athlete
  • Are actively attempting to gain or lose weight
  • Have a history of mental illness or existing neurological disease(s), cardiovascular events (i.e., heart attack, stroke) in the last 2 years
  • Have hypoglycemia, irritable bowel syndrome or inflammatory bowel disease
  • Are currently using insulin or SGLT2 inhibitors
  • Are using more than 2 classes of glucose-lowering medication
  • Are currently following a ketogenic diet or taking ketone supplements
  • Are unable to commit for a 29-day trial
  • Are unable to follow a controlled diet

Treatment and study plan

Exogenous Ketone Monoester

Dietary Supplement

Participants will consume 15g of the oral ketone monoester supplement 15 minutes prior to each meal of the day for 14 days. All meals will be provided throughout the 14-day supplementation period.

Other names: KetoneAid KE4 Ketone Ester, D-β-hydroxybutyrate-R 1,3-Butanediol

Placebo

Dietary Supplement

Participants will consume an equivalent volume (30ml) of the active intervention supplement 15 minutes prior to each meal for 14 days. All meals will be provided throughout the 14-day placebo supplementation period.

Other names: Flavor- and volume-matched placebo supplement

Primary outcomes

  1. Glucose Control: Change in Fructosamine

    Time frame: Day 14 (post-intervention)

    Change in glucose control (from pre-intervention Day 0) will be quantified by serum fructosamine obtained by fasting blood sample in both conditions.

Secondary outcomes

  1. Vascular function

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Vascular function will be assessed by flow mediated dilation of the brachial artery using vascular ultrasound. A cuff will affixed on the forearm, distal to the brachial artery and will be inflated for 5 minutes. Flow mediation dilation will be measured over a 3-minute period following cuff release.

  2. Cognition: N-back test

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Cognition will be assessed using a customized battery of psychometrically validated tests within the domain of executive functions using the computer-based app Inqisit6 Lab (Millisecond). The test will be the n-back test.

  3. Cognition: Digit-symbol substitution test

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Cognition will be assessed using a customized battery of psychometrically validated tests within the domain of executive functions using the computer-based app Inquisit6 Lab (Millisecond). The test will be the digit-symbol substitution test.

  4. Change from baseline plasma insulin at 14 days

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Plasma insulin from venous blood samples will be measured using a high-sensitivity human insulin enzyme-like immunosorbent assay (ELISA) run in duplicate.

  5. Change from baseline plasma free fatty acids at 14 days

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Free fatty acids from venous blood samples will be measured by colorimetric assay run in duplicate.

  6. Change from baseline circulating inflammatory cytokines at 14 days

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Key inflammatory cytokines including CRP will be quantified by Mesoscale Discovery U-PLEX run in duplicate.

  7. Phagocytosis

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Phagocytosis of fluorescent-labelled E. coli by immune cells from whole blood will be quantified by flow cytometry

  8. Oxidative Burst

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    LPS-stimulated oxidative burst by immune cells from whole blood will be quantified by flow cytometry

  9. Degranulation

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Immune cell degranulation will be quantified by enzyme-linked immunosorbent assay run in duplicate (quantifying myeloperoxidase and elastase in whole blood cell culture supernatants).

  10. Immune Cell Phenotyping

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Phenotyping of macrophages and T cells will be quantified by surface and intracellular staining by flow cytometry.

  11. Complete blood count

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    A 5-part white blood cell differential and complete blood count will be quantified by hematology analyzer.

  12. Glycemic Control: 2hr postprandial hyperglycemia

    Time frame: Day 1 through to Day 10

    Glycemic control will be measured by continuous glucose monitoring using the G6 CGM (Dexcom) in both the active and placebo supplement conditions. Glycemic control will be quantified by assessing 2hr postprandial hyperglycemia.

  13. Glycemic Control: 24hr average glucose area under the curve (AUC)

    Time frame: Day 1 through to Day 10

    Glycemic control will be measured by continuous glucose monitoring using the G6 CGM (Dexcom) in both the active and placebo supplement conditions. Glycemic control will be quantified by assessing 24hr average glucose AUC.

  14. Glycemic Control: Fasting glucose

    Time frame: Day 1 through to Day 10

    Glycemic control will be measured by continuous glucose monitoring using the G6 CGM (Dexcom) in both the active and placebo supplement conditions. Glycemic control will be quantified by assessing fasting plasma glucose.

  15. Glycemic Control: Change in Fasting Plasma glucose

    Time frame: Day 14

    Change in fasting plasma glucose (from pre-intervention Day 0) will be measured by fasting blood sample in both the active and placebo supplement conditions.

  16. Glycemic Control: Glycemic variability

    Time frame: Day 1 through to Day 10

    Glycemic control will be measured by continuous glucose monitoring using the G6 CGM (Dexcom) in both the active and placebo supplement conditions. Glycemic control will be quantified by assessing glycemic variability.

  17. Glycemic Control: Time in Target Range

    Time frame: Day 1 through to Day 10

    Glycemic control will be measured by continuous glucose monitoring using the G6 CGM (Dexcom) in both the active and placebo supplement conditions. Glycemic control will be quantified by assessing time in target range.

  18. Glycemic Control: HbA1c

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Glycemic control will be measured by assessing HbA1c using a point-of-care analyzer.

  19. Lipid Panel

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Lipid panel (total cholesterol, high-density cholesterol, low-density cholesterol, triglycerides, non-HDL cholesterol, cholesterol/HDL ratio) will be measured using a point-of-care analyzer.

  20. Body weight

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Change in body weight will be measured using a body weight scale.

  21. Blood pressure

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Change in blood pressure will be measured using an automated blood pressure device. Both systolic and diastolic blood pressure will be measured.

  22. Blood beta-hydroxybutyrate

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Change in fasting blood beta-hydroxybutyrate will be measured using a standard assay.

  23. Physical activity

    Time frame: Day 0 (pre-intervention) to Day 14 (post-intervention)

    Physical activity will be assessed using an accelerometer (activePal) worn throughout the entire intervention period.

  24. Sedentary time

    Time frame: Day 0 (pre-intervention) to Day 14 (post-intervention)

    Sedentary time will be assessed using an accelerometer (activePal) worn throughout the entire intervention period.

  25. Sleeping time

    Time frame: Day 0 (pre-intervention) to Day 14 (post-intervention)

    Sleeping time will be assessed using an accelerometer (activePal) worn throughout the entire intervention period.

  26. Resting heart rate

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Change resting heart rate will be measured using an automated heart rate monitor device.

  27. Waist circumference

    Time frame: Day 0 (pre-intervention) and Day 14 (post-intervention)

    Change in waist circumference will be measures using a measurement tape.

Other outcomes

  1. Supplement acceptability

    Time frame: Day 14

    Acceptability of the supplement (easy of compliance, taste etc.) will be assessed via questionnaire. A 7-point Likert scale will be used.

  2. Hunger and fullness cravings questionnaire

    Time frame: Day 0 (Pre-intervention) through to Day 3

    Perceived hunger will be measured on a visual analogue scale questionnaire assessing hunger and fullness. The questions assessed are:

    • How hungry do you feel? (0 = I am not hungry at all; 10 = I have never been more hungry)
    • How satisfied do you feel? (0 = I am completely empty; 10 = I cannot eat another bite)
    • How full do you feel? (0 = Not at all full; 10 = Totally full)
    • How much more do you think you can eat? (0 = Nothing at all; 10 = A lot)

  3. T cell Activation

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Markers of T cell activation in whole blood will be quantified by flow cytometry.

  4. Cravings

    Time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)

    Participants will be asked to report their desire to eat a particular type of food. A visual analogue scale will be used. The questions assessing cravings are:

    • How often do you experience strong urges to eat particular types of food? (0 = Never; 10 = All the time)
    • On average how often do you experience a strong urge to eat a particular type of food? (0 = Several times per day; 10 = Once per month)
    • How strong are these urges you experience to eat particular types of food? (0 = Extremely weak; 10 = Extremely strong)
    • Are the experiences of strong urges to eat a particular food always of the same strength? (0 = Never; 10 = Always)
    • How easy is it to ignore this strong urge to eat a particular food? (0 = Very easy; 10 = Impossible)
    • Is a strong urge to eat a particular food the same as a craving for food? (0 = No; 10 = Yes)

Sponsors and collaborators

Lead sponsor

University of British Columbia

Other

Registry information

Official study title

Effect of 14 Days of Exogenous Ketone Supplementation on Glycemic Control in Type 2 Diabetes: a Randomized Placebo-controlled Crossover Trial

Important dates

Study start
2022
Primary completion
2023
Study completion
2023
First posted
Dec 13, 2021
Registry last updated
Apr 13, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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