Interaction Between Inorganic Nitrate Supplementation and Metformin in Individuals With Prediabetes

Official title

The Interaction Between Inorganic Nitrate Supplementation and Metformin on Exercise Capacity, Vascular Function, and Insulin Sensitivity in Individuals With Pre-Diabetes

Overview

This study is examining whether short-term supplementation with inorganic nitrate, in the form of beetroot juice, can enhance blood vessel health, insulin sensitivity, and exercise capacity in individuals with prediabetes. We will be comparing the responses in individuals who are taking metformin to those who are naive to metformin. The results from this study may help identify non-pharmacological interventions in prediabetes.

Detailed description

One in 10 Americans have diabetes, with \~ 95% having type 2 diabetes (T2D). Another 1 in 3 have prediabetes, with 70% developing T2D during their lifetimes. Exercise is the standard of care for T2D. However, responses to exercise are blunted in T2D, in part due to the widespread use of metformin, which may inhibit mitochondrial function. Alternative therapies, such as inorganic nitrate supplementation, may provide benefits without attenuating exercise responses.

Purpose: To examine inorganic nitrate supplementation on exercise tolerance, vascular function, and insulin sensitivity in subjects with PD (an ideal time to prevent progression to T2D) who are either taking or naïve to metformin pharmacotherapy.

This study willl recruit twenty-four individuals with PD (12 on, 12 metformin naïve) will participate in a double-blind cross-over design after either oral nitrate or placebo supplementation, including: 1) tests of vascular function (pulse wave velocity, flow mediated dilation, microvascular function with post-occlusive reactive hyperemia, local thermal heating, and skin ACh iontophoresis); 2) exercise testing to determine VO2peak and lactate threshold; 3) an oral glucose tolerance test; and 4) an exercise time trial to exhaustion.

Interventions

• Dietary supplement Dietary Supplement: Inorganic Nitrate (Beetroot juice)
  Participants will be supplemented with inorganic nitrate in the form of beetroot juice for 4 days (12.9 mmol of NO3/day), and their vascular health, insulin sensitivity, and exercise capacity will be measured post-supplementation. This is a randomized crossover design with 2 parallel groups (Group 1: Currently taking metformin, Group 2: Naive to metformin).
• Dietary supplement Dietary supplement: Placebo (Nitrate-depleted beetroot juice)
  Participants will be supplemented with nitrate-depleted beetroot juice for 4 days (\<0.01 mmol NO3/day), and their vascular health, insulin sensitivity, and exercise capacity will be measured post-supplementation. This is a randomized crossover design with 2 parallel groups (Group 1: Currently taking metformin, Group 2: Naive to metformin).

Primary outcome measures

• Vascular Endothelial Function (Pulse wave analysis and velocity [PWA/V]) [Time frame: 3 days following either active NO3 or placebo without nitrate (following 7-day washout).]
• Vascular Endothelial Function (Flow-Mediated Dilation [FMD]) [Time frame: 3 days following either active NO3 or placebo without nitrate (following 7-day washout).]
• Skin microvascular function using post-occlusive reactive hyperemia (PORH) [Time frame: 3 days following either active NO3 or placebo without nitrate (following 7-day washout)]
• Skin microvascular function: Change in Skin Microvascular Dilation in Response to Local Thermal Heating [Time frame: 3 days following either active NO3 or placebo without nitrate (following 7-day washout).]
• Skin microvascular function: Change in microvascular dilation in response to acetylcholine (ACh) [Time frame: 3 days following either active NO3 or placebo without nitrate (following 7-day washout)]
• Oral Glucose Tolerance Test (OGTT) [Time frame: 3 days following either active NO3 or placebo without nitrate (following 7-day washout).]
• Plasma Nitrate/Nitrite [Time frame: 4 days following either active NO3 or placebo without nitrate (following 7-day washout).]
• Cardiorespiratory fitness [Time frame: 4 days following either active NO3 or placebo without nitrate (following 7 day washout).]
• Exercise time trial to exhaustion (TTE) [Time frame: 4 days following either active NO3 or placebo without nitrate (following 7 day washout).]
• Tissue oxygenation during exercise (near-infrared spectropscopy [NIRS] [Time frame: 4 days following either active NO3 or placebo without nitrate (following 7-day washout).]

Secondary outcome measures (3)

• Oral Microbiome [Time frame: 4 days following either active NO3 or placebo without nitrate (following 7-day washout).]
• Biomarker Analyses: Concentration of Inflammatory markers in fasting blood plasma [Time frame: Sample collected 4 days post active NO3 juice/placebo and will be analyzed post study completion.]
• Biomarker Analyses: Concentration of Oxidative stress markers in fasting blood plasma [Time frame: Sample collected 4 days post active NO3 juice/placebo and will be analyzed post study completion.]

Eligibility criteria

Inclusion criteria

• Individuals who can communicate meaningfully with the investigator and can provide written consent.
• Confirmed prediabetic individuals (ages 18-60 years old) (2-hour glucose of 140-199 mg/dL following OGTT test or HbA1c between 5.7-6.4% tested on two occasions within 6 months).
• Taking metformin (stable dose for at least a week) or naïve to metformin
• Sedentary (<1 day/week of structured exercise)
• Be able to perform exercise on a cycle ergometer without assistance
• Stable medication regimen for the last 6 months
• If female, have a normal menstrual cycle

Exclusion criteria

• Estimated Glomerular filtration rate (GFR) ≤ 45
• Body mass index ≥ 40 Kg/m2
• HbA1c > 6.4%
• Smokers within the last 5 years
• Has experienced significant weight loss \~3 kg in the last three months or is taking any weight loss drugs
• Current medical condition that prohibits exercising at high intensities
• Currently on hormone replacement of any kind
• History of myocardial infarction, cerebrovascular event, acute or unstable disease other than pre-diabetes or obesity
• Currently taking any of the following medications (calcium channel blockers, statins, ACE or renin inhibitors, angiotensin receptor blockers, organic nitrates (e.g., nitroglycerine) or recent regular use of inorganic nitrates, alpha- or beta-blockers, diuretics, proton pump inhibitors, PDE-5 inhibitors (e.g.,: Cialis, Viagra), or xanthine oxidase inhibitors (e.g.,: Allopurinol))
• Oral antibiotic use within the previous four weeks, including over-the-counter antibacterial mouthwash or a mouthwash containing chlorhexidine and unwilling to discontinue use
• Oral cancer/severe oral disease
• Uncontrolled hypertension (>140/90)
• Had hysterectomy or oophorectomy
• Fetuses, neonates, children, prisoners, cognitively impaired, non-English speaking participants

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Other

Study locations

United States · 1 center

• University of Virginia — Charlottesville

Identifiers

NCT: NCT07131384 · 302659

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗