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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active Comparator (Naive to metformin) | Experimental | 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. |
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| Placebo Comparator (Naive to metformin) | Placebo Comparator | 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. |
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| Active Comparator (Taking metformin) | Experimental | 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. |
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| Placebo Comparator (Taking metformin) | Placebo Comparator | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dietary Supplement: Inorganic Nitrate (Beetroot juice) | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Vascular Endothelial Function (Pulse wave analysis and velocity [PWA/V]) | PWA/V- These measures will be calculated using the SphygmoCor XCEL system (AtCor Medical). This system will provide arterial stiffness, central, and peripheral pressure waveforms. | 3 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Vascular Endothelial Function (Flow-Mediated Dilation [FMD]) | FMD- Participants will be placed in a supine position with their left forearm slightly extended and supinated, and their legs straight. The arteries will be imaged using a high-resolution 7.5 MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 3 minutes post-occlusion. An EKG trigger will be used to capture images during the end-diastole of the cardiac cycle. | 3 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Skin microvascular function using post-occlusive reactive hyperemia (PORH) | Skin microvascular function will be measured using Moor Instruments' FLPI-2 laser speckle imaging system. PORH will also be measured during the FMD measurement. Baseline measures will be captured, and the cuff will be inflated for 5 minutes, with the post-occlusion reactive period being measured. The laser positioned above the forearm skin will measure skin blood flow at all these time points. | 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 | Skin microvascular function will be measured using Moor Instruments' FLPI-2 laser speckle imaging system. For LTH, ~2 mL of diH2O will be placed on a small disc on the forearm. The solution will be slowly heated to 44 °C. This will allow us to measure the endothelial function of the microcirculation in the skin. | 3 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Measure | Description | Time Frame |
|---|---|---|
| Oral Microbiome | In order to assess abundance and classification of nitrate-reducing bacteria, a sample of the oral microbiome will be obtained. The dorsal surface of the tongue will be swabbed using a 6" HydraFlock Sterile Large Flock Swab for 60 seconds (Puritan Medical Products, USA). Additionally, an unstimulated saliva sample (~5ml) will be collected through an unstimulated drool technique. Both swab and saliva samples will be sequenced to analyze bacteria present in the oral microbiome following supplement/placebo. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Money Ghimire, M.S | Contact | 4342438677 | eta8xd@uvahealth.org |
| Name | Affiliation | Role |
|---|---|---|
| Jason Allen, PhD | University of Virginia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Virginia | Recruiting | Charlottesville | Virginia | 22903 | United States |
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| Dietary supplement: Placebo (Nitrate-depleted beetroot juice) | 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). |
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| Skin microvascular function: Change in microvascular dilation in response to acetylcholine (ACh) | Skin microvascular function will be measured using Moor Instruments' FLPI-2 laser speckle imaging system. For skin ACh iontophoresis, ~2 ml of 2% ACh solution (0.1g of ACh in diH2O and filtered) and low current will be used to deliver small quantities of ACh to the skin. This will allow us to measure the endothelial function of the microcirculation in the skin. | 3 days following either active NO3 or placebo without nitrate (following 7-day washout) |
| Oral Glucose Tolerance Test (OGTT) | Participants will consume a 75g glucose beverage and then undergo a test to measure insulin, glucose, and C-peptide. A qualified team member will insert a catheter into the antecubital vein for the collection of blood. Blood will be collected at 5 timepoints to estimate insulin sensitivity: before drinking the 75g sugar beverage (0 minutes), and every 30 minutes until the end of the test (120 minutes). Participants will rest in a supine position for the duration of the test. | 3 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Plasma Nitrate/Nitrite | Plasma samples will be collected to assess changes in plasma nitrate and nitrite following either BRJ or placebo. | 4 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Cardiorespiratory fitness | Peak aerobic capacity (VO2peak) will be assessed on a cycle ergometer. An IV will be placed and lactate measured during rest and after the completion of every 3-minute stage to determine VO2 at lactate threshold and VO2peak. | 4 days following either active NO3 or placebo without nitrate (following 7 day washout). |
| Exercise time trial to exhaustion (TTE) | Participants will complete a time-to-exhaustion (TTE) test on a cycle ergometer. Participants will begin cycling for 4 minutes at 20 Watts as a warm-up. They will then cycle at a work rate equivalent to 75% of the difference between lactate threshold and VO2peak achieved prior. The TTE test will be terminated when pedal cadence falls ≥ 10 rpm for ≥ 5 sec. When participants reach exhaustion, they will complete a 3-minute unloaded recovery period on the cycle ergometer. | 4 days following either active NO3 or placebo without nitrate (following 7 day washout). |
| Tissue oxygenation during exercise (near-infrared spectropscopy [NIRS] | Tissue oxygenation will be captured noninvasively using near-infrared spectrometry (NIRS, PortaMon, Artinis Medical Systems B.V., The Netherlands) positioned on the gastrocnemius (calf) or vastus lateralis (quad) muscle during the VO2peak/lactate test. | 4 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Oral nitrate reducing capacity (ONRC) | To assess the oral microbiome's ability to reduce nitrate to nitrite, the participant will rinse their mouth with a solution of potassium nitrate and ultra-pure water for five minutes. The rinsed solution will be collected into a 50ml Falcon tube. The nitrite concentration will be measured to determine ONRC | 4 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| 4 days following either active NO3 or placebo without nitrate (following 7-day washout). |
| Biomarker Analyses: Concentration of Inflammatory markers in fasting blood plasma | The investigators plan to assess various markers of inflammation. A fasting blood sample will be collected to measure markers of inflammation. | 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 | The investigators plan to assess various markers of oxidative stress. A fasting blood sample will be collected to measure markers of oxidative stress. | Sample collected 4 days post active NO3 juice/placebo and will be analyzed post study completion. |
| ID | Term |
|---|---|
| D057185 | Sedentary Behavior |
| D011236 | Prediabetic State |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D001519 | Behavior |
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D006946 | Hyperinsulinism |
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