Clinical trial NCT05342012: The Effect of Nitrate on Brown Fat
Official title: The Effect of Inorganic Nitrate Supplementation on Brown Fat Activation and Quantity in People With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Keywords: Beetroot
Brown Adipose Tissue
Infrared spectrometry
Magnetic Resonance Imaging
Nitrates
Type II Diabetes Mellitus
Lead sponsor: Bournemouth University
Sponsor class: OTHER
Collaborators: name: University of Portsmouth
name: Institute of Bioengineering and Bioimaging (IBB)
name: Loughborough University
First posted: 2022-04-22
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: Inclusion Criteria:

* Males or women with Type 2 Diabetes Mellitus

Exclusion Criteria:

* 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

Primary outcomes:
measure: MRI Imaging of Supraclavicular BAT
timeFrame: MRI on day 14 (Visit 2) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: MRI Imaging of Supraclavicular BAT
timeFrame: MRI on day 14 (Visit 2) following 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: MRI Imaging of Supraclavicular BAT
timeFrame: MRI on day 35 (visit 3) before 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: MRI Imaging of Supraclavicular BAT
timeFrame: MRI on day 35 (visit 3) following 60 minutes of cold exposure, following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
timeFrame: At start of MRI Imaging of Supraclavicular BAT
measure: A 3D multi-point Dixon sequence will be utilized for the water-fat imaging.
timeFrame: At end of MRI Imaging of Supraclavicular BAT
measure: Pixel wise quantification of fat fraction will be performed from fat and water maps.
timeFrame: At time of MRI Imaging
Secondary outcomes:
measure: IRT Imaging of Supraclavicular BAT
timeFrame: 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.
measure: Biomarkers - Nitrate
timeFrame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: Biomarkers - Nitrite
timeFrame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: Biomarkers - cGMP
timeFrame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: Biomarkers - Nitrate
timeFrame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: Biomarkers - Nitrite
timeFrame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
measure: Biomarkers - cGMP
timeFrame: Blood sampling on day 14 (Visit 2) and day 35 (visit 3) following 14-days beetroot/placebo supplementation with 7-day washout between crossover.
Other outcomes:
Locations:
city: Bournemouth
country: United Kingdom
facility: Bournemouth University
state: Dorset
city: Portsmouth
country: United Kingdom
facility: University of Portsmouth
state: Hampshire
city: Southampton
country: United Kingdom
facility: Southern Health NHS Foundation Trust
state: Hampshire
city: Poole
country: United Kingdom
facility: Shore Medical
Study officials:
affiliation: Senior Lecturer in Exercise Physiology
name: Rebecc Neal
role: STUDY_CHAIR
References: