Diabetes Mellitus, Type 2NCT05342012
The Effect of Nitrate on Brown Fat
A study testing Concentrated beetroot juice and Nitrate depleted beetroot juice in people with Diabetes Mellitus, Type 2, run by Bournemouth University at 4 sites in United Kingdom.
Trial summary
Type 2 diabetes mellitus (T2DM) is a metabolic condition characterized by chronic hyperglycemia and progressive insulin resistance, which progressively lead to macro- and microvascular damage. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- Concentrated beetroot juice and Nitrate depleted beetroot juice
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 4 sitesUnited Kingdom
- Study dates
- 30 Jun 2022to 31 Jul 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Males or women with Type 2 Diabetes Mellitus
Who cannot join
- Individuals with a BMI over 30
- Individuals with severe claustrophobia (this would make imaging the BAT less reliable)
- Current smokers (or those that have smoked within 3 months)
- Proton pump inhibitors or phosphodiesterase inhibitor users, as these may affect [cGMP]. Half life of this drug is short. Participants can choose to not use this if they wish to participate.
- Individuals with any other serious medical condition which would interfere with data interpretation or safety will be excluded from participation.
- Unable to give informed consent
Trial locations and contacts
4 sites in 1 country.
United Kingdom4 sites
Bournemouth University
Bournemouth, Dorset, BH12 5BB
Shore Medical
Poole
University of Portsmouth
Portsmouth, Hampshire, PO1 2UP
Southern Health NHS Foundation Trust
Southampton, Hampshire, SO40 8DX
About this study
Official title: The Effect of Inorganic Nitrate Supplementation on Brown Fat Activation and Quantity in People With Type 2 Diabetes Mellitus
Type 2 diabetes mellitus (T2DM) is a metabolic condition characterized by chronic hyperglycemia and progressive insulin resistance, which progressively lead to macro- and microvascular damage. With the number of people with T2DM continuing to rise, this pandemic is expected to reach 700 million people by 2045, such that the costs associated with its clinical management are likely to become unsustainable. Therefore, identifying cost effective alternative interventions is imperative.
Diets rich in fruits and vegetables are well known to have cardiovascular benefits and reduce the risk of getting T2DM. The beneficial effects of vegetables on cardiovascular outcomes are particularly effective in green leafy vegetables and beetroot. This may in part be due to a high concentration of inorganic nitrate, and its beneficial effects on cardiovascular health due to its effect on nitric oxide (NO•). Increased dietary nitrate intake elevates cyclic guanosine monophosphate [(cGMP)]. Importantly, cGMP has also been shown to increase brown fat expression by 'beiging' WAT in mice through an NO• dependent process.
Read more
Recent developments in the ability to non-invasively measure BAT activation using magnetic resonance imaging (MRI) and infrared thermography (ITR) has opened the possibility to study the effects of nitrate on BAT activation in man. BAT depots in humans with T2DM have been identified using MRI but not yet with the more easily accessible technique of IRT.
It is hypothesised that nitrate can increase BAT activation and quantity in people with T2DM.
Read the detailed description
Dietary inorganic nitrate is converted in a reversible, stepwise reaction to nitrite via bacteria on the dorsum of the tongue. Subsequently, small quantities of NO• are produced in the stomach. The remaining nitrite is then absorbed into the circulation where it acts as a storage pool for subsequent NO• production. Production of NO• from nitrite reduction is expedited in hypoxaemia, a phenomenon observed in the vasculature of white adipose tissue (WAT).
WAT is primarily an energy store, whereas brown adipose tissue (BAT) is a metabolically active tissue. BAT is responsible for ~5% of basal metabolic rate and ~15% of total energy expenditure, equating to ~40 g of BAT per day and is used in non-shivering thermogenesis. BAT is used for heat production and is stimulated by cold environments and or diet to cause thermogenesis. To produce heat during cold exposure, uncoupling protein (UCP)-1, an inner mitochondrial protein, is upregulated in BAT ultimately uncoupling the mitochondrial proton gradient, making the cell less energy efficient. Inorganic nitrate supplementation has also been shown to increase UCP-1 expression in BAT.
- Conditions
- Diabetes Mellitus, Type 2
- Being tested
- Concentrated beetroot juice, Nitrate depleted beetroot juice
- Keywords
- Beetroot, Brown Adipose Tissue, Infrared spectrometry, Magnetic Resonance Imaging, Nitrates, Type II Diabetes Mellitus
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Concentrated beetroot juiceDietary supplement
Acute and chronic supplementation of beetroot juice.
Nitrate depleted beetroot juiceDietary supplement
(Nitrate depleted beetroot juice
| Study group | Role | What they receive |
|---|---|---|
| Experimental: Beetroot juice then nitrate depleted beetroot juice | Experimental | Participants will be asked to consume 140ml of beetroot juice prior to their first experimental visit. Participants will then be asked to consume 140ml a day for 2 weeks, and finally visit the investigators once more following another 140ml drink. Receives: Dietary Supplement: Concentrated beetroot juice; Dietary Supplement: Nitrate depleted beetroot juice |
| Experimental: Nitrate depleted beetroot juice then beetroot juice | Experimental | Participants will be asked to consume 140ml of placebo prior to their first experimental visit. Participants will then be asked to consume 140ml a day for 2 weeks, and finally visit the investigators once more following another 140ml drink. Receives: Dietary Supplement: Concentrated beetroot juice; Dietary Supplement: Nitrate depleted beetroot juice |
What is being measured
The primary outcome is the main question the study is designed to answer.
MRI Imaging of Supraclavicular BAT
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view.
All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
Measured: MRI on day 14 (Visit 2) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
MRI Imaging of Supraclavicular BAT
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view.
All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
Measured: MRI on day 14 (Visit 2) following 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
MRI Imaging of Supraclavicular BAT
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view.
All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
Measured: MRI on day 35 (visit 3) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
MRI Imaging of Supraclavicular BAT
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view.
All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
Measured: MRI on day 35 (visit 3) following 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
Measured: At start of MRI Imaging of Supraclavicular BAT
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
Measured: At end of MRI Imaging of Supraclavicular BAT
Pixel wise quantification of fat fraction will be performed from fat and water maps.
Pixel wise quantification of fat fraction will be performed from fat and water maps.
Measured: At time of MRI Imaging
Secondary outcomes (7)
IRT Imaging of Supraclavicular BAT
Bilaterally, two regions will be analysed for skin temperature from thermal images using infrared cameras: 1) the skin area overlaying BAT in the SCV fossae on the left and right sides, and; 2) the sternal area considered as a control.
Measured: IRT on day 14 (Visit 2) and day 35 (visit 3), before and after 60 minutes of cold water immersion, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrate
Quantified using a Sievers nitric oxide analyser
Measured: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrite
Quantified using a Sievers nitric oxide analyser
Measured: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - cGMP
Quantified using a Sievers nitric oxide analyser
Measured: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrate
Quantified using commercially available ELISA assays
Measured: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrite
Quantified using commercially available ELISA assays
Measured: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - cGMP
Quantified using commercially available ELISA assays
Measured: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Apr 2022
- Study start30 Jun 2022
- Primary completion31 Jan 2023
- Study completion31 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bournemouth University
- Sponsor type
- University, hospital or other
- Collaborators
- University of Portsmouth, Institute of Bioengineering and Bioimaging (IBB), Loughborough University
- Responsible party
- Sponsor
- Investigators
- Rebecc Neal, Study chair, Senior Lecturer in Exercise Physiology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05342012
- Sponsor's protocol ID
- 306840
- Status last verified
- Oct 2023
- First submitted
- 1 Mar 2022
- Last updated
- 10 Oct 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Inorganic Nitrate Supplementation on Brown Fat Activation and Quantity in People With Type 2 Diabetes Mellitus
- ClinicalTrials.gov ID
- NCT05342012
- Acronym / sponsor ID
- 306840
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- Beetroot, Brown Adipose Tissue, Infrared spectrometry, Magnetic Resonance Imaging, Nitrates, Type II Diabetes Mellitus
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Bournemouth UniversityUniversity, hospital or other
- Collaborators
- University of Portsmouth, Institute of Bioengineering and Bioimaging (IBB), Loughborough University
- Study start
- 30 Jun 2022 (actual)
- Primary completion
- 31 Jan 2023 (actual)
- Study completion
- 31 Jul 2023 (actual)
- First posted
- 22 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Type 2 diabetes mellitus (T2DM) is a metabolic condition characterized by chronic hyperglycemia and progressive insulin resistance, which progressively lead to macro- and microvascular damage. With the number of people with T2DM continuing to rise, this pandemic is expected to reach 700 million people by 2045, such that the costs associated with its clinical management are likely to become unsustainable. Therefore, identifying cost effective alternative interventions is imperative.
Diets rich in fruits and vegetables are well known to have cardiovascular benefits and reduce the risk of getting T2DM. The beneficial effects of vegetables on cardiovascular outcomes are particularly effective in green leafy vegetables and beetroot. This may in part be due to a high concentration of inorganic nitrate, and its beneficial effects on cardiovascular health due to its effect on nitric oxide (NO•). Increased dietary nitrate intake elevates cyclic guanosine monophosphate [(cGMP)]. Importantly, cGMP has also been shown to increase brown fat expression by 'beiging' WAT in mice through an NO• dependent process.
Recent developments in the ability to non-invasively measure BAT activation using magnetic resonance imaging (MRI) and infrared thermography (ITR) has opened the possibility to study the effects of nitrate on BAT activation in man. BAT depots in humans with T2DM have been identified using MRI but not yet with the more easily accessible technique of IRT.
It is hypothesised that nitrate can increase BAT activation and quantity in people with T2DM.
Detailed description
Dietary inorganic nitrate is converted in a reversible, stepwise reaction to nitrite via bacteria on the dorsum of the tongue. Subsequently, small quantities of NO• are produced in the stomach. The remaining nitrite is then absorbed into the circulation where it acts as a storage pool for subsequent NO• production. Production of NO• from nitrite reduction is expedited in hypoxaemia, a phenomenon observed in the vasculature of white adipose tissue (WAT).
WAT is primarily an energy store, whereas brown adipose tissue (BAT) is a metabolically active tissue. BAT is responsible for ~5% of basal metabolic rate and ~15% of total energy expenditure, equating to ~40 g of BAT per day and is used in non-shivering thermogenesis. BAT is used for heat production and is stimulated by cold environments and or diet to cause thermogenesis. To produce heat during cold exposure, uncoupling protein (UCP)-1, an inner mitochondrial protein, is upregulated in BAT ultimately uncoupling the mitochondrial proton gradient, making the cell less energy efficient. Inorganic nitrate supplementation has also been shown to increase UCP-1 expression in BAT.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental: Beetroot juice then nitrate depleted beetroot juice | Experimental | Dietary Supplement: Concentrated beetroot juice, Dietary Supplement: Nitrate depleted beetroot juiceParticipants will be asked to consume 140ml of beetroot juice prior to their first experimental visit. Participants will then be asked to consume 140ml a day for 2 weeks, and finally visit the investigators once more following another 140ml drink. |
| Experimental: Nitrate depleted beetroot juice then beetroot juice | Experimental | Dietary Supplement: Concentrated beetroot juice, Dietary Supplement: Nitrate depleted beetroot juiceParticipants will be asked to consume 140ml of placebo prior to their first experimental visit. Participants will then be asked to consume 140ml a day for 2 weeks, and finally visit the investigators once more following another 140ml drink. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Males or women with Type 2 Diabetes Mellitus
Key exclusion criteria (6 listed)
- Individuals with a BMI over 30
- Individuals with severe claustrophobia (this would make imaging the BAT less reliable)
- Current smokers (or those that have smoked within 3 months)
- Proton pump inhibitors or phosphodiesterase inhibitor users, as these may affect [cGMP]. Half life of this drug is short. Participants can choose to not use this if they wish to participate.
- Individuals with any other serious medical condition which would interfere with data interpretation or safety will be excluded from participation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Concentrated beetroot juiceAcute and chronic supplementation of beetroot juice. | Dietary supplement | Experimental: Beetroot juice then nitrate depleted beetroot juice, Experimental: Nitrate depleted beetroot juice then beetroot juice |
| Nitrate depleted beetroot juice(Nitrate depleted beetroot juice | Dietary supplement | Experimental: Beetroot juice then nitrate depleted beetroot juice, Experimental: Nitrate depleted beetroot juice then beetroot juice |
Primary outcome
MRI Imaging of Supraclavicular BAT
Time frame: MRI on day 14 (Visit 2) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view. All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
MRI Imaging of Supraclavicular BAT
Time frame: MRI on day 14 (Visit 2) following 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view. All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
MRI Imaging of Supraclavicular BAT
Time frame: MRI on day 35 (visit 3) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view. All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
MRI Imaging of Supraclavicular BAT
Time frame: MRI on day 35 (visit 3) following 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
High-resolution 3-dimensional T1-weighted imaging will be acquired using repetition time, echo time and field of view. All imaging sequences will have anatomical coverage of the neck, supraclavicular region and the apices of the lung.
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
Time frame: At start of MRI Imaging of Supraclavicular BAT
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
Time frame: At end of MRI Imaging of Supraclavicular BAT
A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
Pixel wise quantification of fat fraction will be performed from fat and water maps.
Time frame: At time of MRI Imaging
Pixel wise quantification of fat fraction will be performed from fat and water maps.
7 secondary outcomes
IRT Imaging of Supraclavicular BAT
Time frame: IRT on day 14 (Visit 2) and day 35 (visit 3), before and after 60 minutes of cold water immersion, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrate
Time frame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrite
Time frame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - cGMP
Time frame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrate
Time frame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - Nitrite
Time frame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Biomarkers - cGMP
Time frame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rebecc Neal study chair
Senior Lecturer in Exercise Physiology
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Concentrated beetroot juice and Nitrate depleted beetroot juice in people with Diabetes Mellitus, Type 2, run by Bournemouth University at 4 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MRI Imaging of Supraclavicular BAT (time frame: MRI on day 14 (Visit 2) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2023; AzTrials last refreshed its copy on 1 Nov 2026.