Aortic Stiffness, Glucose Intolerance, Vasodilation
Conditions
Keywords
Oral glucose tolerance test, Flow mediated dilatation, Aortal pulse wave velocity, Finger-fold capillary density by capillaroscopy
Brief summary
The purpose of this study is to determine whether dietary inducers of glyoxalase 1 are effective in improving metabolic and vascular health.
Detailed description
The aim of the study is to evaluate dietary inducers of glyoxalase 1 for effects on metabolic and vascular health in overweight volunteers at risk of developing type 2 diabetes. The research objectives are: (i) To evaluate dietary inducers of glyoxalase 1 for effects on markers of glucose metabolism during an oral glucose tolerance test (oGTT), (ii) To evaluate dietary inducers of glyoxalase 1 for effects on vascular function on three levels, using finger fold capillary density by capillaroscopy (FFCD), arterial stiffness by aortal pulse wave velocity (aPWV) and flow mediated dilatation (FMD); and effects on metabolic and pro-inflammatory markers in circulating blood and urine.
Interventions
DIETARY_SUPPLEMENTGlyoxalase 1 (Glo1) inducer
Dietary bioactive
DIETARY_SUPPLEMENTPlacebo
Mannitol, 108 mg
Sponsors
Technology Strategy Board, United Kingdom
Unilever R&D
University of Warwick
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI 25 - 40 kg/m2 (\>23 kg/m2 for Asians), with normal, impaired fasting or impaired postprandial glucose. * No other relevant morbidities. * Women will be preferably post-menopausal.
Exclusion criteria
* Severe hypertriglyceridemia. * Uncontrolled hypertension, cardiovascular disease, relevant renal or hepatic disease, diabetes, and other relevant morbidity. * Excess alcohol consumption, smoking, acute pharmacological treatment with drugs affecting glucose metabolism such as steroids and antibiotics. * Anticoagulants. * Intake of herbal remedies. * Food allergies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve for Oral Glucose Tolerance Test (oGGT) | Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention) | A standard 75 g glucose oGTT will be performed, as routinely used in clinical practice. Participants will be instructed to eat carbohydrate rich diet (\> 150 g/day) for at least three days before the test, followed by an overnight fast. Participants will be instructed to have comparable macronutrient composition of the dinner before the respective study days in the metabolic unit. During the oGTT both capillary and venous blood samples will be collected after 0, 15, 30, 60, 90 and 120 min. To minimize the inconvenience of repeated blood tests during the oGTT, a venous cannula will be inserted, under sterile conditions, prior to the test, for blood sampling. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Finger-fold Capillary Density by Capillaroscopy | Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention) | After 20 min seated at rest, measurements are made with the subject seated and the left hand at heart level. Nail-fold capillaries in the dorsal skin of the third finger are visualized using a stereo microscope linked to a monochrome digital camera. Capillary density is defined as the number of capillaries per mm2 of nail-fold skin and is computed as the mean of 4 measurements. |
| Flow-mediated Dilatation (FMD) | Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention) | Brachial artery FMD will be assessed. Ultrasound imaging of the brachial artery will be performed. Percent FMD will be calculated using the averaged minimum mean brachial artery diameter at baseline compared to the largest mean values obtained after either release of the forearm occlusion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Aortal Pulse Wave Velocity (aPWV) | Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention) | Aortal pulse wave velocity is measured by a non-invasive oscillometric device. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glyoxalase 1 Inducer Then Placebo Glyoxalase 1 inducer (90 mg trans-resveratrol & 120 mg hesperetin), once daily, 8 weeks; then Placebo (excipient: 108 mg mannitol), once daily, 8 weeks. | 15 |
| Placebo Then Glyoxalase 1 Inducer Placebo (excipient: 108 mg mannitol), once daily, 8 weeks; then Glyoxalase 1 inducer (90 mg trans-resveratrol & 120 mg hesperetin), once daily, 8 weeks. | 17 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (8 Weeks) | Withdrawal by Subject | 1 | 0 |
| Second Intervention (8 Weeks) | Protocol Violation | 1 | 0 |
| Second Intervention (8 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Glyoxalase 1 Inducer Then Placebo | Placebo Then Glyoxalase 1 Inducer | Total |
|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 12 | 44 years STANDARD_DEVIATION 13 | 45 years STANDARD_DEVIATION 13 |
| Gender Female | 10 Participants | 12 Participants | 22 Participants |
| Gender Male | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment United Kingdom | 15 participants | 17 participants | 32 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Curve for Oral Glucose Tolerance Test (oGGT)
A standard 75 g glucose oGTT will be performed, as routinely used in clinical practice. Participants will be instructed to eat carbohydrate rich diet (\> 150 g/day) for at least three days before the test, followed by an overnight fast. Participants will be instructed to have comparable macronutrient composition of the dinner before the respective study days in the metabolic unit. During the oGTT both capillary and venous blood samples will be collected after 0, 15, 30, 60, 90 and 120 min. To minimize the inconvenience of repeated blood tests during the oGTT, a venous cannula will be inserted, under sterile conditions, prior to the test, for blood sampling.
Time frame: Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention)
Population: Highly overweight/obese (BMI\>27.5 kg/m2) subgroup, based on subject BMI at study entry.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glyoxalase 1 Inducer | Area Under the Curve for Oral Glucose Tolerance Test (oGGT) | Baseline | 10.8 mM h | Standard Error 0.7 |
| Glyoxalase 1 Inducer | Area Under the Curve for Oral Glucose Tolerance Test (oGGT) | Post-8 weeks treatment | 9.9 mM h | Standard Error 0.6 |
| Placebo | Area Under the Curve for Oral Glucose Tolerance Test (oGGT) | Baseline | 11.0 mM h | Standard Error 0.7 |
| Placebo | Area Under the Curve for Oral Glucose Tolerance Test (oGGT) | Post-8 weeks treatment | 10.6 mM h | Standard Error 0.6 |
Secondary
Finger-fold Capillary Density by Capillaroscopy
After 20 min seated at rest, measurements are made with the subject seated and the left hand at heart level. Nail-fold capillaries in the dorsal skin of the third finger are visualized using a stereo microscope linked to a monochrome digital camera. Capillary density is defined as the number of capillaries per mm2 of nail-fold skin and is computed as the mean of 4 measurements.
Time frame: Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention)
Population: All subjects with where baseline and post-8 treatment data were obtained.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Glyoxalase 1 Inducer | Finger-fold Capillary Density by Capillaroscopy | Baseline | 115 number of capillaries per mm2 |
| Glyoxalase 1 Inducer | Finger-fold Capillary Density by Capillaroscopy | Post-8 weeks treatment | 125 number of capillaries per mm2 |
| Placebo | Finger-fold Capillary Density by Capillaroscopy | Baseline | 119 number of capillaries per mm2 |
| Placebo | Finger-fold Capillary Density by Capillaroscopy | Post-8 weeks treatment | 128 number of capillaries per mm2 |
Secondary
Flow-mediated Dilatation (FMD)
Brachial artery FMD will be assessed. Ultrasound imaging of the brachial artery will be performed. Percent FMD will be calculated using the averaged minimum mean brachial artery diameter at baseline compared to the largest mean values obtained after either release of the forearm occlusion.
Time frame: Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention)
Population: All subjects completing the study per protocol
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Glyoxalase 1 Inducer | Flow-mediated Dilatation (FMD) | Baseline | 0.17 percentage of baseline value |
| Glyoxalase 1 Inducer | Flow-mediated Dilatation (FMD) | Post-8 weeks treatment | 0.12 percentage of baseline value |
| Placebo | Flow-mediated Dilatation (FMD) | Baseline | 0.18 percentage of baseline value |
| Placebo | Flow-mediated Dilatation (FMD) | Post-8 weeks treatment | 0.26 percentage of baseline value |
Other Pre-specified
Aortal Pulse Wave Velocity (aPWV)
Aortal pulse wave velocity is measured by a non-invasive oscillometric device.
Time frame: Week 0 and Week 8 (first intervention); Week 14 and Week 22 (second intervention)
Population: Subjects for which PWV data were obtained at baseline and post 8-weeks treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Glyoxalase 1 Inducer | Aortal Pulse Wave Velocity (aPWV) | Baseline | 7.9 m/s |
| Glyoxalase 1 Inducer | Aortal Pulse Wave Velocity (aPWV) | Post-8 weeks treatment | 8.0 m/s |
| Placebo | Aortal Pulse Wave Velocity (aPWV) | Baseline | 8.3 m/s |
| Placebo | Aortal Pulse Wave Velocity (aPWV) | Post-8 weeks treatment | 8.5 m/s |