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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Dietary supplement: Exogenous Ketone Monoester; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1V 3G1
      • University of British Columbia Okanagan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Dietary supplement: Exogenous Ketone Monoester; 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 Comparator: Placebo; Participants will consume a flavor-matched placebo drink and undergo the same procedures described in the Experimental Arm	Dietary supplement: Placebo; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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)
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)

Other Outcome Measures

Outcome Measure	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	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)	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: 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)	Day 0 (Pre-intervention) and Day 14 (post-intervention)

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Jonathan Little, PhD, University of British Columbia- Okanagan

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2022
• Primary Completion (Actual): February 3, 2023
• Study Completion (Actual): February 3, 2023

Study Registration Dates

• First Submitted: November 30, 2021
• First Submitted That Met QC Criteria: November 30, 2021
• First Posted (Actual): December 13, 2021

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Inflammation; Hyperglycemia; Cognition; Ketones; Glycemic Control; Glucose Control; Immune cell function; 3-Hydroxybutyric Acid
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: H21-01762

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will share individual patient data (de-identified) with researchers upon reasonable request.
• IPD Sharing Time Frame: 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.
• IPD Sharing Access Criteria: 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).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No