Interaction Between Inorganic Nitrate Supplementation and Metformin in Individuals With Prediabetes

NCT ID: NCT07131384

Last Updated: 2025-08-26

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-01
• Study Completion Date: 2026-12-01

Brief Summary

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.

Conditions

Males; Females; Sedentary; Metformin; Prediabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: QUADRUPLE

Study Groups

Active Comparator (Naive to metformin)

Participants will supplement with nitrate-rich beetroot juice (BRJ) for 4 days: 6.45 mmol of NO3 in the morning and 6.45 mmol in the evening for 3 days, and 12.9 mmol 2 hours before the lab visit. Supplement order based on randomization and crossover will happen after a minimum of a 7-day washout period.

Group Type: EXPERIMENTAL

Dietary Supplement: Inorganic Nitrate (Beetroot juice)

Intervention Type: DIETARY_SUPPLEMENT

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).

Placebo Comparator (Naive to metformin)

Participants will supplement with nitrate-depleted beetroot juice (BRJ) for 4 days: 6.45 mmol of NO3 in the morning and 6.45 mmol in the evening for 3 days, and 12.9 mmol 2 hours before the lab visit. Supplement order based on randomization and crossover will happen after a minimum of a 7-day washout period.

Group Type: PLACEBO_COMPARATOR

Dietary supplement: Placebo (Nitrate-depleted beetroot juice)

Intervention Type: DIETARY_SUPPLEMENT

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).

Active Comparator (Taking metformin)

Participants will supplement with nitrate-rich beetroot juice (BRJ) for 4 days: 6.45 mmol of NO3 in the morning and 6.45 mmol in the evening for 3 days, and 12.9 mmol 2 hours before the lab visit. Supplement order based on randomization and crossover will happen after a minimum of a 7-day washout period.

Group Type: EXPERIMENTAL

Dietary Supplement: Inorganic Nitrate (Beetroot juice)

Intervention Type: DIETARY_SUPPLEMENT

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).

Placebo Comparator (Taking metformin)

Participants will supplement with nitrate-depleted beetroot juice (BRJ) for 4 days: 6.45 mmol of NO3 in the morning and 6.45 mmol in the evening for 3 days, and 12.9 mmol 2 hours before the lab visit. Supplement order based on randomization and crossover will happen after a minimum of a 7-day washout period.

Group Type: PLACEBO_COMPARATOR

Dietary supplement: Placebo (Nitrate-depleted beetroot juice)

Intervention Type: DIETARY_SUPPLEMENT

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).

Interventions

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).

Intervention Type: 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).

Intervention Type: DIETARY_SUPPLEMENT

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Jason Allen

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Arthur Weltman, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Central Contacts

Money Ghimire, M.S

Role: CONTACT

eta8xd@virginia.edu

4342438677

Other Identifiers

302659

Identifier Type: -

Identifier Source: org_study_id