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Post-prandial hyperglycemic excursions induce a cascade of deleterious effects on the body, including increased inflammation, production of reactive oxygen species, and impaired cardiovascular function. Ingestion of an exogenous oral ketone supplement blunts hyperglycemia in response to an oral glucose tolerance test. Accordingly, it is hypothesized that exogenous ketone supplement ingestion prior to a meal could be an effective strategy for blunting postprandial hyperglycemia. Therefore, the purpose of this study is to investigate the effect of short-term (14-days) pre-meal exogenous ketone supplementation on glucose control, cardiovascular function, inflammation, and oxidative stress in individuals at an elevated risk of type 2 diabetes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental | Experimental |
|
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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 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exogenous ketone monoester | Dietary Supplement | Participants will consume 20g 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 | Post-prandial glucose excursions will be measured by continuous glucose monitoring using the iPro2 CGM by Medtronic in both the active and placebo supplement conditions. Post-prandial glucose following breakfast, lunch, and dinner will be averaged together. | 2 hours after a meal |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline flow mediated dilation at 14 days | 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of British Columbia, Okanagan. | Kelowna | British Columbia | V1V 1V7 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34605026 | Derived | Walsh JJ, Caldwell HG, Neudorf H, Ainslie PN, Little JP. Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial. J Physiol. 2021 Nov;599(21):4763-4778. doi: 10.1113/JP281988. Epub 2021 Oct 4. | |
| 33367782 | Derived | Walsh JJ, Neudorf H, Little JP. 14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial. J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1738-e1754. doi: 10.1210/clinem/dgaa925. |
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The investigators will share individual patient data (de-identified) with researchers upon request.
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| ID | Term |
|---|---|
| D006943 | Hyperglycemia |
| D050177 | Overweight |
| D009765 | Obesity |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D044343 | Overnutrition |
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| Change from baseline histone acetylation at 14 days | Histone H3 acetylation status will be quantified by flow cytometry using conjugated acetyl-histone H3 antibody specific for Lys9 (Pacific Blue 445) and the conjugated acetyl-histone H3 antibody specific for Lys14 (Alexa Fluor 488). | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline mitochondrial superoxide production at 14 days | Oxidative Stress will be measured by mitochondrial superoxide production in blood lymphocytes, monocytes, and neutrophils by flow cytometry using the MitoSOX red assay (ThermoFisher #M36008) and total intracellular ROS via the DCFDA assay (Sigma #D6883) | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline cognition (executive functions) at 14 days | Cognition will be assessed using a customized battery of psychometrically validated tests within the domain of executive functions using the iPad-based app BrainBaseline. The tests will be the Stroop test, task-switching test, digit-symbol substitution test, and the n-back test. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline plasma glucose at 14 days | Venous blood samples will be taken and plasma glucose will be measured using a hexokinase method. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline plasma insulin at 14 days | Venous blood samples will be taken and plasma insulin will be measured using a high-sensitivity human insulin ELISA. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline plasma free fatty acids at 14 days | Venous blood samples will be taken and free fatty acids will be measured by colorimetric assay. | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline interleukin-1(IL)-1beta at 14 days | Mature IL-1beta secretion will be quantified by ELISA run in duplicate | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| Change from baseline caspase-1 activation at 14 days | Caspase-1 activation will be quantified by flow cytometry. The fluorescent inhibitor probe FAM-YVAD-FMK binds covalently to activated caspase-1 and emits at 530nm | Day 0 (Pre-intervention) and Day 14 (post-intervention) |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010335 | Pathologic Processes |