Ketosis, Type 2 Diabetes
Conditions
Brief summary
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.
Interventions
DIETARY_SUPPLEMENTKetone monoester
Acute ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate prior to assessment of outcomes.
DIETARY_SUPPLEMENTPlacebo
Acute ingestion of taste-matched placebo prior to assessment of outcomes.
Sponsors
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Placebo masked with flavouring and participants consume in opaque containers.
Eligibility
Sex/Gender
ALL
Age
20 Years to 69 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose | 180 minutes | Plasma glucose concentration after ketone or placebo ingestion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma C-peptide | 180 minutes | C-peptide across concentration after ketone or placebo ingestion |
| Plasma Free Fatty Acids | 180 minutes | Non-esterified fatty acid concentration after ketone or placebo ingestion |
| Plasma Tumour Necrosis Factor Alpha | 180 minutes | Plasma tumour necrosis factor alpha concentration after ketone or placebo ingestion |
| Plasma Tumour Interleukin-1beta | 180 minutes | Plasma tumour interleukin-1beta concentration after ketone or placebo ingestion |
| Plasma Tumour Interleukin-6 | 180 minutes | Plasma tumour interleukin-6 concentration after ketone or placebo ingestion |
| Cerebral Blood Flow | 180 minutes | Intracranial blood flow velocity measured by ultrasound |
| Blood Pressure | 180 minutes | Blood pressure measured manually and by Finipres |
| Plasma Insulin | 180 minutes | Insulin across concentration after ketone or placebo ingestion |
| Brain-derived Neurotrophic Factor | 180 minutes | Brain-derived neurotrophic factor concentrations after ketone or placebo ingestion |
| Number Blood Monocytes (x10^3 Cells/uL) | 180 minutes | Total blood monocytes count (x10\^3 cells/uL) after ketone or placebo ingestion |
| Self Reported Hunger and Fullness | 180 minutes | Self reported hunger and fullness by a 0 to 100 mm Visual Analog Scale (higher scores mean greater hunger or fullness) |
| Gastrointestinal Symptoms | 180 minutes | Gastrointestinal symptom questionnaire scores after ketone or placebo ingestion on a 0 to 100 mm Visual Analog Scale (higher scores mean greater symptoms) |
| Total Energy Consumed | 180 minutes after ketone or placebo ingestion | Total energy consumed in kilocalories in buffet style meal after ketone or placebo ingestion |
| Monocyte Histone Acetylation | 180 minutes | Histone acetylation status of monocytes measured after ketone or placebo ingestion |
| Cognitive Function - Digital Symbol Substitution Task | 180 minutes | Number of Correct Answers on the Digital Symbol Substitution Task. Measure of cognitive function using Brain Baseline battery on an iPad. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Total participants independent of crossover order (Placebo-Ketones and Ketones-Placebo). | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | not eligible | 1 | 0 |
Baseline characteristics
| Characteristic | Overall | — |
|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 8 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Canada | 18 Participants | — |
| Sex: Female, Male Female | 7 Participants | — |
| Sex: Female, Male Male | 11 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Plasma Glucose
Plasma glucose concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Plasma Glucose | 30 minutes | 6.2 mmol/L | Standard Deviation 1.2 |
| Ketone Monoester | Plasma Glucose | 90 minutes | 6.2 mmol/L | Standard Deviation 1.5 |
| Ketone Monoester | Plasma Glucose | Baseline | 7.3 mmol/L | Standard Deviation 1.8 |
| Ketone Monoester | Plasma Glucose | 120 minutes | 5.7 mmol/L | Standard Deviation 1.5 |
| Ketone Monoester | Plasma Glucose | 60 minutes | 6.3 mmol/L | Standard Deviation 1.5 |
| Ketone Monoester | Plasma Glucose | 150 minutes | 5.7 mmol/L | Standard Deviation 1.4 |
| Ketone Monoester | Plasma Glucose | 180 minutes | 5.6 mmol/L | Standard Deviation 1.4 |
| Placebo | Plasma Glucose | 150 minutes | 5.7 mmol/L | Standard Deviation 1.1 |
| Placebo | Plasma Glucose | 180 minutes | 6.4 mmol/L | Standard Deviation 1.5 |
| Placebo | Plasma Glucose | Baseline | 7.2 mmol/L | Standard Deviation 1.8 |
| Placebo | Plasma Glucose | 30 minutes | 6.6 mmol/L | Standard Deviation 1.9 |
| Placebo | Plasma Glucose | 60 minutes | 6.2 mmol/L | Standard Deviation 1.8 |
| Placebo | Plasma Glucose | 90 minutes | 5.9 mmol/L | Standard Deviation 1.2 |
| Placebo | Plasma Glucose | 120 minutes | 6.2 mmol/L | Standard Deviation 0.9 |
Secondary
Blood Pressure
Blood pressure measured manually and by Finipres
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Blood Pressure | Systolic blood pressure baseline | 133 mmHg | Standard Deviation 18 |
| Ketone Monoester | Blood Pressure | Systolic blood pressure 180min | 139 mmHg | Standard Deviation 19 |
| Ketone Monoester | Blood Pressure | Diastolic blood pressure baseline | 79 mmHg | Standard Deviation 7 |
| Ketone Monoester | Blood Pressure | Diastolic blood pressure 180min | 83 mmHg | Standard Deviation 11 |
| Placebo | Blood Pressure | Diastolic blood pressure 180min | 78 mmHg | Standard Deviation 14 |
| Placebo | Blood Pressure | Systolic blood pressure baseline | 130 mmHg | Standard Deviation 16 |
| Placebo | Blood Pressure | Diastolic blood pressure baseline | 77 mmHg | Standard Deviation 10 |
| Placebo | Blood Pressure | Systolic blood pressure 180min | 136 mmHg | Standard Deviation 18 |
Secondary
Brain-derived Neurotrophic Factor
Brain-derived neurotrophic factor concentrations after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Brain-derived Neurotrophic Factor | baseline | 7.1 ng/mL | Standard Deviation 13 |
| Ketone Monoester | Brain-derived Neurotrophic Factor | 180 minutes | 4.8 ng/mL | Standard Deviation 6.7 |
| Placebo | Brain-derived Neurotrophic Factor | baseline | 5.5 ng/mL | Standard Deviation 8.1 |
| Placebo | Brain-derived Neurotrophic Factor | 180 minutes | 5.7 ng/mL | Standard Deviation 9 |
Secondary
Cerebral Blood Flow
Intracranial blood flow velocity measured by ultrasound
Time frame: 180 minutes
Population: Procedure not completed due to the unavailability of a specialized research staff. Data was not and will not be obtained and reported.
Secondary
Cognitive Function - Digital Symbol Substitution Task
Number of Correct Answers on the Digital Symbol Substitution Task. Measure of cognitive function using Brain Baseline battery on an iPad.
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Cognitive Function - Digital Symbol Substitution Task | baseline Digit-symbol substitution task | 32.8 number correct | Standard Deviation 8.7 |
| Ketone Monoester | Cognitive Function - Digital Symbol Substitution Task | 180min Digit-symbol substitution task | 35.7 number correct | Standard Deviation 7.5 |
| Placebo | Cognitive Function - Digital Symbol Substitution Task | baseline Digit-symbol substitution task | 32.4 number correct | Standard Deviation 8.2 |
| Placebo | Cognitive Function - Digital Symbol Substitution Task | 180min Digit-symbol substitution task | 34.5 number correct | Standard Deviation 6.9 |
Secondary
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)
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ketone Monoester | Gastrointestinal Symptoms | urge to vomit | 0 mm |
| Ketone Monoester | Gastrointestinal Symptoms | belching | 0 mm |
| Ketone Monoester | Gastrointestinal Symptoms | nausea | 0 mm |
| Ketone Monoester | Gastrointestinal Symptoms | cramping | 0 mm |
| Ketone Monoester | Gastrointestinal Symptoms | bloating | 0 mm |
| Placebo | Gastrointestinal Symptoms | cramping | 0 mm |
| Placebo | Gastrointestinal Symptoms | urge to vomit | 0 mm |
| Placebo | Gastrointestinal Symptoms | bloating | 0 mm |
| Placebo | Gastrointestinal Symptoms | belching | 0 mm |
| Placebo | Gastrointestinal Symptoms | nausea | 0 mm |
Secondary
Monocyte Histone Acetylation
Histone acetylation status of monocytes measured after ketone or placebo ingestion
Time frame: 180 minutes
Population: This assay was not performed due to insufficient sample quantity.
Secondary
Number Blood Monocytes (x10^3 Cells/uL)
Total blood monocytes count (x10\^3 cells/uL) after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Number Blood Monocytes (x10^3 Cells/uL) | baseline Monocytes | 408 x10^3 cells/uL | Standard Deviation 171 |
| Ketone Monoester | Number Blood Monocytes (x10^3 Cells/uL) | 180min Monocytes | 445 x10^3 cells/uL | Standard Deviation 181 |
| Placebo | Number Blood Monocytes (x10^3 Cells/uL) | baseline Monocytes | 442 x10^3 cells/uL | Standard Deviation 152 |
| Placebo | Number Blood Monocytes (x10^3 Cells/uL) | 180min Monocytes | 447 x10^3 cells/uL | Standard Deviation 179 |
Secondary
Plasma C-peptide
C-peptide across concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ketone Monoester | Plasma C-peptide | baseline | 4,384 pg/mL |
| Ketone Monoester | Plasma C-peptide | 180 minutes | 3,908 pg/mL |
| Placebo | Plasma C-peptide | baseline | 4,438 pg/mL |
| Placebo | Plasma C-peptide | 180 minutes | 3,918 pg/mL |
Secondary
Plasma Free Fatty Acids
Non-esterified fatty acid concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Plasma Free Fatty Acids | baseline | 0.42 mmol/L | Standard Deviation 0.14 |
| Ketone Monoester | Plasma Free Fatty Acids | 180 minutes | 0.18 mmol/L | Standard Deviation 0.11 |
| Placebo | Plasma Free Fatty Acids | baseline | 0.40 mmol/L | Standard Deviation 0.18 |
| Placebo | Plasma Free Fatty Acids | 180 minutes | 0.43 mmol/L | Standard Deviation 0.16 |
Secondary
Plasma Insulin
Insulin across concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Plasma Insulin | baseline | 26.7 pg/mL | Standard Deviation 17.4 |
| Ketone Monoester | Plasma Insulin | 180minutes | 24.3 pg/mL | Standard Deviation 17.2 |
| Placebo | Plasma Insulin | baseline | 28.2 pg/mL | Standard Deviation 18.2 |
| Placebo | Plasma Insulin | 180minutes | 21.4 pg/mL | Standard Deviation 15.4 |
Secondary
Plasma Tumour Interleukin-1beta
Plasma tumour interleukin-1beta concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Plasma Tumour Interleukin-1beta | baseline | 253 fg/mL | Standard Deviation 450 |
| Ketone Monoester | Plasma Tumour Interleukin-1beta | 180min | 106 fg/mL | Standard Deviation 105 |
| Placebo | Plasma Tumour Interleukin-1beta | baseline | 115 fg/mL | Standard Deviation 74 |
| Placebo | Plasma Tumour Interleukin-1beta | 180min | 102 fg/mL | Standard Deviation 41 |
Secondary
Plasma Tumour Interleukin-6
Plasma tumour interleukin-6 concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Plasma Tumour Interleukin-6 | 180min | 2.7 pg/mL | Standard Deviation 1.6 |
| Ketone Monoester | Plasma Tumour Interleukin-6 | baseline | 1.5 pg/mL | Standard Deviation 0.8 |
| Placebo | Plasma Tumour Interleukin-6 | baseline | 2.7 pg/mL | Standard Deviation 1.6 |
| Placebo | Plasma Tumour Interleukin-6 | 180min | 2.7 pg/mL | Standard Deviation 1.6 |
Secondary
Plasma Tumour Necrosis Factor Alpha
Plasma tumour necrosis factor alpha concentration after ketone or placebo ingestion
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Plasma Tumour Necrosis Factor Alpha | baseline | 1.1 pg/mL | Standard Deviation 0.5 |
| Ketone Monoester | Plasma Tumour Necrosis Factor Alpha | 180min | 1.0 pg/mL | Standard Deviation 0.4 |
| Placebo | Plasma Tumour Necrosis Factor Alpha | baseline | 1.2 pg/mL | Standard Deviation 0.4 |
| Placebo | Plasma Tumour Necrosis Factor Alpha | 180min | 1.1 pg/mL | Standard Deviation 0.4 |
Secondary
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)
Time frame: 180 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketone Monoester | Self Reported Hunger and Fullness | baseline how hungry | 46 mm | Standard Deviation 26 |
| Ketone Monoester | Self Reported Hunger and Fullness | 180 minutes how hungry | 58 mm | Standard Deviation 21 |
| Placebo | Self Reported Hunger and Fullness | baseline how hungry | 42 mm | Standard Deviation 31 |
| Placebo | Self Reported Hunger and Fullness | 180 minutes how hungry | 60 mm | Standard Deviation 23 |
Secondary
Total Energy Consumed
Total energy consumed in kilocalories in buffet style meal after ketone or placebo ingestion
Time frame: 180 minutes after ketone or placebo ingestion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketone Monoester | Total Energy Consumed | 823 kcal | Standard Deviation 377 |
| Placebo | Total Energy Consumed | 948 kcal | Standard Deviation 455 |