Exogenous Ketones in Type 2 Diabetes

Study Overview
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Brief Summary
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Exogenous ketone supplements are proposed to have glucose-lowering potential, provide an alternative fuel for the brain and to enhance cognitive function. No studies have tested whether exogenous ketones can lower blood glucose in people with type 2 diabetes. In addition, the impact of exogenous ketones on brain blood flow, cognitive function or brain-derived neurotrophic factor in humans is unknown. The purpose of this study is to determine if acutely ingesting exogenous ketones, in the form of a ketone monoester drink, can lower glucose and improve measures of brain/cognitive function in humans with type 2 diabetes. Participants will consume a ketone monoester drink or placebo with blood samples, brain blood flow, and cognitive function assessed over 180 minutes. The researchers will also test how the ketone monoester drink impacts appetite and measures of inflammation.

Official Title
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The Effect of Acute Exogenous Oral Ketone Supplementation on Blood Glucose Levels in Type 2 Diabetes

Conditions
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Ketosis, Type 2 Diabetes

Intervention / Treatment
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* Dietary Supplement: Ketone monoester
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: physician-diagnosed type 2 diabetes of ≥1 year current hemoglobin A1C (HbA1c) of 6.5-8.0% treatment with lifestyle or stable (≥3 months) oral glucose-lowering medications blood pressure of <160/99 mm Hg assessed according to guidelines non-smoking no prior history of cardiovascular disease or stroke not on hormone replacement therapy, corticosteroids, or anti-inflammatory medications 20-75 years old Exclusion Criteria: being a competitive endurance athlete taking exogenous insulin or sodium glucose transporter 2 (SGLT2) inhibitors following a ketogenic diet, low-calorie diet, periodic fasting regimen, or consume ketogenic supplements being unable to travel to and from the university being unable to follow the controlled diet instructions being pregnant or planning to become pregnant during the study (if female) disorders of fat metabolism, chronic pancreatitis, had gastric bypass surgery and/or gallbladder disease being unable to read or communicate in English

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketone monoester<br>Acute dose of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (0.3 g/kg body weight) | Dietary Supplement: Ketone monoester<br>* Acute ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate prior to assessment of outcomes.<br>|
| Placebo Comparator: Placebo<br>Acute dose of flavour-matched placebo. | Dietary Supplement: Placebo<br>* Acute ingestion of taste-matched placebo prior to assessment of outcomes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Glucose | Plasma glucose concentration after ketone or placebo ingestion | 180 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Insulin | Insulin across concentration after ketone or placebo ingestion | 180 minutes | 
| Plasma C-peptide | C-peptide across concentration after ketone or placebo ingestion | 180 minutes | 
| Plasma Free Fatty Acids | Non-esterified fatty acid concentration after ketone or placebo ingestion | 180 minutes | 
| Plasma Tumour Necrosis Factor Alpha | Plasma tumour necrosis factor alpha concentration after ketone or placebo ingestion | 180 minutes | 
| Plasma Tumour Interleukin-1beta | Plasma tumour interleukin-1beta concentration after ketone or placebo ingestion | 180 minutes | 
| Plasma Tumour Interleukin-6 | Plasma tumour interleukin-6 concentration after ketone or placebo ingestion | 180 minutes | 
| Cerebral Blood Flow | Intracranial blood flow velocity measured by ultrasound | 180 minutes | 
| Blood Pressure | Blood pressure measured manually and by Finipres | 180 minutes | 
| Cognitive Function | Measures of cognitive function using Brain Baseline battery on an iPad. | 180 minutes | 
| Brain-derived Neurotrophic Factor | Brain-derived neurotrophic factor concentrations after ketone or placebo ingestion | 180 minutes | 
| Blood Monocytes | Total blood monocytes and monocyte subsets after ketone or placebo ingestion | 180 minutes | 
| Self Reported Hunger and Fullness | Self reported hunger and fullness by a 0 to 100 mm Visual Analog Scale (higher scores mean greater hunger or fullness) | 180 minutes | 
| Gastrointestinal Symptoms | Gastrointestinal symptom questionnaire scores after ketone or placebo ingestion on a 0 to 100 mm Visual Analog Scale (higher scores mean greater symptoms) | 180 minutes | 
| Total Energy Consumed | Total energy consumed in kilocalories in buffet style meal after ketone or placebo ingestion | 180 minutes after ketone or placebo ingestion | 
| Monocyte Histone Acetylation | Histone acetylation status of monocytes measured after ketone or placebo ingestion | 180 minutes |