Nitrate and Brain Insulin-Sensitivity (NO-BRAINS)

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

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.

Study Overview

• Status: Completed
• Conditions: Vascular Function; Nitrate; Brain Insulin-sensitivity
• Intervention / Treatment: Dietary supplement: Potassium nitrate; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 ER
      • Maastricht University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Potassium nitrate; During this experimental day, men will receive 10 mmol of potassium nitrate	Dietary supplement: Potassium nitrate; Acute intervention (5.5 hours)
PLACEBO_COMPARATOR: Placebo; During this experimental day, men will receive an isomolar dose of potassium chloride	Dietary supplement: Placebo; Acute intervention (5.5 hours)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Ronald P.M. Mensink, Dr, Maastricht University

Publications and helpful links

General Publications

• Kleinloog JPD, Mensink RP, Smeets ETHC, Ivanov D, Joris PJ. Acute inorganic nitrate intake increases regional insulin action in the brain: Results of a double-blind, randomized, controlled cross-over trial with abdominally obese men. Neuroimage Clin. 2022;35:103115. doi: 10.1016/j.nicl.2022.103115. Epub 2022 Jul 14.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 21, 2021
• Primary Completion (ACTUAL): May 5, 2021
• Study Completion (ACTUAL): May 5, 2021

Study Registration Dates

• First Submitted: January 6, 2021
• First Submitted That Met QC Criteria: January 6, 2021
• First Posted (ACTUAL): January 7, 2021

Study Record Updates

• Last Update Posted (ACTUAL): June 9, 2021
• Last Update Submitted That Met QC Criteria: June 8, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Insulin Resistance
• Other Study ID Numbers: METC 20-0.78

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No