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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental | Experimental | Participants will consume 15 g of an active oral exogenous ketone monoester supplement 15 minutes prior to each meal of the day for a 14-day period. Pre-intervention (baseline) and post-intervention measurements will be obtained before and immediately after the 14-day period. All meals will be provided throughout the supplementation period Participants will wear a continuous glucose monitor for the first 10 consecutive days during the supplementation period. |
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| Placebo | Placebo Comparator | Participants will consume a flavor-matched placebo drink and undergo the same procedures described in the Experimental Arm |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Glucose Control: Change in Fructosamine | Change in glucose control (from pre-intervention Day 0) will be quantified by serum fructosamine obtained by fasting blood sample in both conditions. | Day 14 (post-intervention) |
| Measure | Description | Time Frame |
|---|---|---|
| Vascular function | 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. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Measure | Description | Time Frame |
|---|---|---|
| Supplement acceptability | Acceptability of the supplement (easy of compliance, taste etc.) will be assessed via questionnaire. A 7-point Likert scale will be used. | Day 14 |
| Hunger and fullness cravings questionnaire |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jonathan Little, PhD | University of British Columbia- Okanagan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of British Columbia Okanagan | Kelowna | British Columbia | V1V 3G1 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39804761 | Derived | Baranowski BJ, Oliveira BF, Falkenhain K, Little JP, Mohammad A, Beaudette SM, Finch MS, Caldwell HG, Neudorf H, MacPherson REK, Walsh JJ. Effect of exogenous beta-hydroxybutyrate on BDNF signaling, cognition, and amyloid precursor protein processing in humans with T2D and insulin-resistant rodents. Am J Physiol Cell Physiol. 2025 Feb 1;328(2):C541-C556. doi: 10.1152/ajpcell.00867.2024. Epub 2025 Jan 13. |
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The investigators will share individual patient data (de-identified) with researchers upon reasonable request.
The de-identified data and associated documents will be made available to researchers upon reasonable request for the duration that is required by the researchers.
Researchers from accredited institutions will be granted access to the de-identified data and associated documents provided they can show that it will be used for a research-related purpose (e.g., meta-analysis).
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D006943 | Hyperglycemia |
| D007662 | Ketosis |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D005421 | Flavoring Agents |
| ID | Term |
|---|---|
| D010592 | Pharmaceutic Aids |
| D004364 | Pharmaceutical Preparations |
| D005503 | Food Additives |
| D000074385 | Food Ingredients |
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|
| 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. |
|
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| Cognition: N-back test | 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. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Cognition: Digit-symbol substitution test | 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. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline plasma insulin at 14 days | Plasma insulin from venous blood samples will be measured using a high-sensitivity human insulin enzyme-like immunosorbent assay (ELISA) run in duplicate. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline plasma free fatty acids at 14 days | Free fatty acids from venous blood samples will be measured by colorimetric assay run in duplicate. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline circulating inflammatory cytokines at 14 days | Key inflammatory cytokines including CRP will be quantified by Mesoscale Discovery U-PLEX run in duplicate. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Phagocytosis | Phagocytosis of fluorescent-labelled E. coli by immune cells from whole blood will be quantified by flow cytometry | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Oxidative Burst | LPS-stimulated oxidative burst by immune cells from whole blood will be quantified by flow cytometry | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Degranulation | Immune cell degranulation will be quantified by enzyme-linked immunosorbent assay run in duplicate (quantifying myeloperoxidase and elastase in whole blood cell culture supernatants). | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Immune Cell Phenotyping | Phenotyping of macrophages and T cells will be quantified by surface and intracellular staining by flow cytometry. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Complete blood count | A 5-part white blood cell differential and complete blood count will be quantified by hematology analyzer. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Glycemic Control: 2hr postprandial hyperglycemia | 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. | Day 1 through to Day 10 |
| Glycemic Control: 24hr average glucose area under the curve (AUC) | 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. | Day 1 through to Day 10 |
| Glycemic Control: Fasting glucose | 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. | Day 1 through to Day 10 |
| Glycemic Control: Change in Fasting Plasma glucose | 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. | Day 14 |
| Glycemic Control: Glycemic variability | 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. | Day 1 through to Day 10 |
| Glycemic Control: Time in Target Range | 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. | Day 1 through to Day 10 |
| Glycemic Control: HbA1c | Glycemic control will be measured by assessing HbA1c using a point-of-care analyzer. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
| Lipid Panel | 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. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
| Body weight | Change in body weight will be measured using a body weight scale. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
| Blood pressure | Change in blood pressure will be measured using an automated blood pressure device. Both systolic and diastolic blood pressure will be measured. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
| Blood beta-hydroxybutyrate | Change in fasting blood beta-hydroxybutyrate will be measured using a standard assay. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
| Physical activity | Physical activity will be assessed using an accelerometer (activePal) worn throughout the entire intervention period. | Day 0 (pre-intervention) to Day 14 (post-intervention) |
| Sedentary time | Sedentary time will be assessed using an accelerometer (activePal) worn throughout the entire intervention period. | Day 0 (pre-intervention) to Day 14 (post-intervention) |
| Sleeping time | Sleeping time will be assessed using an accelerometer (activePal) worn throughout the entire intervention period. | Day 0 (pre-intervention) to Day 14 (post-intervention) |
| Resting heart rate | Change resting heart rate will be measured using an automated heart rate monitor device. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
| Waist circumference | Change in waist circumference will be measures using a measurement tape. | Day 0 (pre-intervention) and Day 14 (post-intervention) |
Perceived hunger will be measured on a visual analogue scale questionnaire assessing hunger and fullness. The questions assessed are:
| Day 0 (Pre-intervention) through to Day 3 |
| T cell Activation | Markers of T cell activation in whole blood will be quantified by flow cytometry. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Cravings | 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:
| Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| D004700 | Endocrine System Diseases |
| D000138 | Acidosis |
| D000137 | Acid-Base Imbalance |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D020313 |
| Specialty Uses of Chemicals |
| D020164 | Chemical Actions and Uses |
| D005502 | Food |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019602 | Food and Beverages |