The Effect of Nitrate on Brown Fat

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.

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