Nutritional Supplementation and Insulin Sensitivity

Longer-term Effects of a Novel Nutritional Combination on Muscle Insulin Sensitivity and Mitochondrial Function, and Vascular Function in Abdominally Obese Subjects

Type 2 diabetes mellitus (T2DM) is a progressive disease and early intervention and prevention strategies are therefore very important. An important early hallmark in the development of T2DM is insulin resistance. Since the majority of postprandial glucose disposal occurs in skeletal muscle, improving muscle insulin sensitivity will thus have a major impact on disease prevention. Abdominally obese men and women have an increased risk to develop T2DM, and are also characterized by an impaired vascular function. This may hamper proper delivery of insulin, glucose and oxygen to muscles, thereby contributing to - and possibly causing - muscle insulin resistance. Earlier it has been shown that supplementation with L- arginine improves vascular function by improving nitric oxide (NO) bioavailability. These NO- mediated beneficial effects on vascular function may improve delivery of insulin, glucose and oxygen to the muscle tissue, thereby improving muscle insulin sensitivity and mitochondrial function. However, the doses needed of this amino acid cannot be provided by regular diets or supplements, also due to the bitter taste of L-arginine. Alternatively, smaller amounts of L- arginine with a specific combination of other nutritional components (i.e. nitrate and nitrite), which are already part of the regular diet and support alternative pathways to improve NO- mediated vascular function, may also induce beneficial effects. The investigators now hypothesize that in abdominally obese adults with impaired fasting glucose concentrations L-arginine combined with nitrate/nitrite increases muscle insulin sensitivity.

Study Overview

• Status: Terminated
• Conditions: Vascular Function; Nitric Oxide; Insulin Sensitivity; L-arginine; Nitrate / Nitrite
• Intervention / Treatment: Dietary supplement: L-arginine + Nitrate / Nitrite; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1
• 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: 50 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged between 50-70 years
• Men and postmenopausal (two or more years after last menstruation) women
• Waist circumference for men 3 102 cm and for women 3 88 cm (abdominally obese)
• Impaired fasting glucose concentrations (between 5.6 - 7.0 mmol/L in accordance with the American Diabetes Association guidelines for prediabetes) at two screening visits
• Fasting serum total cholesterol < 8.0 mmol/L
• 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
• No difficult venipuncture as evidenced during the screening visit
• Willingness to give up the use of antibacterial mouth wash or antibacterial toothpaste, chewing-gum and tongue-scraping during the study

Exclusion Criteria:

• Current smoker, or smoking cessation < 12 months
• Diabetic patients
• Familial hypercholesterolemia
• Abuse of drugs
• More than 3 alcoholic consumptions per day
• Use of dietary supplements known to interfere with the main study outcomes as judged by the principal investigators
• Use of anticoagulant drugs or drugs to treat blood pressure, lipid/glucose metabolism
• Use of an investigational product within another biomedical intervention trial within the previous 1-month
• Intolerance or allergy to the ingredients of the intervention products
• Severe medical conditions that might interfere with the study, such as epilepsy, asthma, kidney failure or renal insufficiency, chronic obstructive pulmonary disease (COPD), 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-arginine + Nitrate/Nitrite; Subjects will receive 1 L-arginine tablet per day and drink 35 mL of beetroot juice for 8 weeks.	Dietary supplement: L-arginine + Nitrate / Nitrite; Longer-term supplementation (8 weeks)
Placebo Comparator: Placebo; Subjects will receive 1 cellulose tablet per day and drink 35 mL of nitrate/nitrite depleted beetroot juice for 8 weeks.	Dietary supplement: Placebo; Longer-term supplementation (8 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity	Muscle insulin sensitivity	Change between 8-week placebo and 8-week intervention period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in muscle metabolism	Mitochondrial activity in muscle tissue	Change between 8-week placebo and 8-week intervention period
Change in physical functioning (1)	6 meter walking test	Change between 8-week placebo and 8-week intervention period
Change in physical functioning (2)	Timed up and go test	Change between 8-week placebo and 8-week intervention period
Change in physical functioning (3)	Handgrip strength test	Change between 8-week placebo and 8-week intervention period
Change in physical functioning (4)	Isokinetic muscle strength (BIODEX measurement)	Change between 8-week placebo and 8-week intervention period
Change in vascular function (1)	Flow-mediated vasodilation of the brachial artery	Change between 8-week placebo and 8-week intervention period
Change in vascular function (2)	Pulse wave analysis	Change between 8-week placebo and 8-week intervention period
Change in vascular function (3)	Pulse wave velocity	Change between 8-week placebo and 8-week intervention period
Change in vascular function (4)	Retinal microvascular calibers (Artery-to-Vein ratio)	Change between 8-week placebo and 8-week intervention period
Change in cardiometabolic risk markers (1)	Plasma markers for low-grade systemic inflammation (CRP)	Change between 8-week placebo and 8-week intervention period
Change in cardiometabolic risk markers (2)	Plasma markers for endothelial dysfunction (NOx)	Change between 8-week placebo and 8-week intervention period
Change in cardiometabolic risk markers (3)	24-h Systolic and Diastolic blood pressure	Change between 8-week placebo and 8-week intervention period
Change in continuous insulin sensitivity	36-h plasma glucose values	Change between 8-week placebo and 8-week intervention period

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Nutricia Research

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): October 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: December 20, 2019
• First Submitted That Met QC Criteria: January 20, 2020
• First Posted (Actual): January 27, 2020

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 8, 2021
• Last Verified: September 1, 2020

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 19-085

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