Nitrate and Brain Insulin-Sensitivity

Study Overview
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Brief Summary
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Disturbances in brain insulin-sensitivity are not only observed in abdominal obesity and type 2 diabetes mellitus (T2D), but also during brain aging and in dementia. Inorganic nitrate may improve brain insulin-sensitivity, which can be quantified by measuring the gray-matter cerebral blood flow (CBF) response to intranasally administered insulin, through beneficial effects on brain vascular function. Therefore, we now hypothesize that inorganic nitrate, which can be found in several vegetables such as beetroot, improves brain insulin-sensitivity, as assessed by the gray-matter CBF response to intranasally administered insulin, in abdominally obese men.

Official Title
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Acute Effects of Inorganic Nitrate on Brain Insulin-sensitivity in Abdominally Obese Men

Conditions
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Nitrate, Brain Insulin-sensitivity, Vascular Function

Intervention / Treatment
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* Dietary Supplement: Potassium nitrate
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men; Aged between 18 - 60 years; Waist circumference > 102 cm (abdominally obese); Fasting plasma glucose ≤ 7.0 mmol/L; Fasting serum total cholesterol ≤ 8.0 mmol/L; Systolic blood pressure < 160 mmHg and diastolic blood pressure < 100 mmHg; Stable body weight (weight gain or loss < 3 kg in the past three months); Willingness to give up being a blood donor from 8 weeks before the start of the study, during the study and for 4 weeks after completion of the study; Willingness not to use antibacterial mouth wash or toothpaste, chewing-gum and tongue-scraping a week before the study; No difficult venipuncture as evidenced during the screening visit. Exclusion Criteria: Women; Left-handedness; Current smoker, or smoking cessation < 12 months; Diabetic patients; Familial hypercholesterolemia; Abuse of drugs; More than 3 alcoholic consumptions per day; Use of products or dietary supplements known to interfere with the main outcomes as judged by the principal investigators; Use medication to treat blood pressure, lipid or glucose metabolism; Pharmacological treatment advised based on the Dutch general practitioners' association (NHG) for cardiovascular risk management; Use of an investigational product within another biomedical intervention trial within the previous 1-month; Severe medical conditions that might interfere with the study, such as epilepsy, asthma, kidney failure or renal insufficiency, chronic obstructive pulmonary disease, inflammatory bowel diseases, auto inflammatory diseases and rheumatoid arthritis; Active cardiovascular disease like congestive heart failure or cardiovascular event, such as an acute myocardial infarction or cerebrovascular accident; Specific contra-indications for MRI imaging, including pacemakers, surgical clips/material in body, metal splinters in eye, claustrophobia, or tattoos in the facial area, such as permanent make-up.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Potassium nitrate<br>During this experimental day, men will receive 10 mmol of potassium nitrate | Dietary Supplement: Potassium nitrate<br>* Acute intervention (5.5 hours)<br>|
| Placebo Comparator: Placebo<br>During this experimental day, men will receive an isomolar dose of potassium chloride | Dietary Supplement: Placebo<br>* Acute intervention (5.5 hours)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain insulin sensitivity | MRI arterial spin labeling, cerebral blood flow measurements before and after a nasal insulin spray | Change from placebo intervention at 2 hours after supplement intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain vascular function | MRI arterial spin labeling, cerebral blood flow measurements | Change from placebo intervention at 2 hours after supplement intake | 
| Vascular function markers | Flow-mediated vasodilation (FMD) of the brachial and femoral artery | Change from fasting at 4 hours after supplement intake | 
| Cold pressure test | Carotid artery response to cold pressure test | Change from placebo at 4 hours after supplement intake | 
| Cardiometabolic risk markers (1) | Plasma markers for low-grade systemic inflammation (CRP) | Change from placebo at 4 hours after supplement intake | 
| Cardiometabolic risk markers (2) | Plasma marker for endothelial dysfunction (NOx) | Change from placebo at 4 hours after supplement intake | 
| Cardiometabolic risk markers (3) | Office blood pressure | Change from placebo at 4 hours after supplement intake | 
| Cardiometabolic risk markers (4) | Plasma brain derived neurotrophic factor (BDNF) | During the 5.5 hours following supplement intake | 
| Postprandial metabolism (1) | Serum lipid metabolism | During the 5.5 hours following supplement intake | 
| Postprandial metabolism (2) | Plasma glucose metabolism | During the 5.5 hours following supplement intake |