Nutritional Supplementation and Insulin Sensitivity

Study Overview
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Brief Summary
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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.

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

Conditions
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Nitric Oxide, Insulin Sensitivity, Vascular Function, L-arginine, Nitrate / Nitrite

Intervention / Treatment
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* Dietary Supplement: L-arginine + Nitrate / Nitrite
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Experimental: L-arginine + Nitrate/Nitrite<br>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<br>* Longer-term supplementation (8 weeks)<br>|
| Placebo Comparator: Placebo<br>Subjects will receive 1 cellulose tablet per day and drink 35 mL of nitrate/nitrite depleted beetroot juice for 8 weeks. | Dietary Supplement: Placebo<br>* Longer-term supplementation (8 weeks)<br>|

What is the study measuring?
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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 |