Effects of L-citrulline Supplementation on Vascular Function in Metabolic Syndrome

Effects of L-Citrulline Supplementation on Vascular Function During Fasted and Acute Hyperglycemia in Middle-aged and Older Women With Metabolic Syndrome

The objective of this project is to provide evidence that L-Citrulline (CIT) supplementation can improve vascular function in the fasted and acute hyperglycemia conditions in middle-aged and older women with metabolic syndrome.

Study Overview

• Status: Recruiting
• Conditions: Metabolic Syndrome; Menopause
• Intervention / Treatment: Dietary supplement: L-Citrulline supplementation; Dietary supplement: Placebo

Detailed Description

Using a double-blind, randomized, placebo-controlled, and parallel design, middle-aged and older women with metabolic syndrome will be randomized into receiving either CIT supplementation (10g/day) or placebo (Microcrystalline Cellulose) for 4 weeks.

The first visit will be approximately 1hr and 30 minutes. The 2nd and 3rd visits will each be approximately 2hrs and 30 minutes, separated by 4 weeks in between each visit. During visits 2 and 3, vascular measurements will be assessed in the fasted state and 30, 60, and 90 minutes after acute glucose ingestion (75g).

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Arturo Figueroa, Ph.D,MD; Phone Number: 806-834-5587; Email: arturo.figueroa@ttu.edu

Study Locations

• United States
  • Texas
    • Lubbock, Texas, United States, 79409
      • Recruiting
      • TTU Kinesiology and Sport Management Building
      • Contact: Arturo Figueroa, M.D., Ph.D.; Phone Number: 806-834-5587

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Must present at least 3 of the following 5 cardiometabolic risk factors

• Waist circumference ≥88 cm
• Fasting glucose between 100-125 mg/dL or HbA1c between 5.7-6.4%.
• Blood pressure ≥130 mm Hg
• Triglyceride ≥ 150 mg/dL
• HDL <50 mg/dL

The following are also inclusion criteria's:

• Women aged 45-79 years old
• Body mass index ≤ 39.9 kg/m2
• Sedentary (defined as < 120 min/week of exercise)
• Abstain from any dietary supplements with vascular effects for one month prior to the beginning of the study and until participation in study has terminated.

Exclusion Criteria:

• < 45 and > 79 years of age
• Use of medications and/or any supplements that may affect outcome variables (such as arginine-containing supplements, nitroglycerin, statin drugs, biguanides, insulin, beta blockers, statins, verapamil)
• Systolic blood pressure ≥ 160 mmHg
• BMI > 40 kg/m2
• Recent changes in medication (3 months)
• Current smoking any tobacco use
• Cardiovascular disease, diabetes (Type 1 or 2), and other metabolic or chronic diseases
• More than 7 alcoholic drinks/week of consumption

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-citrulline; L-citrulline: 10 grams/day	Dietary supplement: L-Citrulline supplementation; 4 weeks of L-Citrulline supplementation (10 grams/day).
Experimental: Placebo; Microcrystalline Cellulose	Dietary supplement: Placebo; 4 weeks of microcrystalline Cellulose supplementation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrovascular Endothelial function in the fasted condition	Endothelial function will be measured via brachial artery flow mediated dilation (ultrasonography) during reactive hyperemia at baseline and after 4 weeks of supplementation.	4 weeks
Microvascular endothelial function in the fasted condition	Endothelial function will be measured using forearm muscle oxygenation (near-infrared spectroscopy) will assessed during reactive hyperemia at baseline and after 4 weeks of supplementation.	4 weeks
Microvascular digital endothelial function in the fasted condition	Endothelial function will be measured using peripheral (finger) arterial tonometry (EndoPAT device) during reactive hyperemia at baseline and after 4 weeks of supplementation.	4 weeks
Macrovascular Endothelial function during acute hyperglycemia	Endothelial function will be measured via brachial artery flow mediated dilation (ultrasonography) during reactive hyperemia at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.	4 weeks
Microvascular forearm endothelial function during acute hyperglycemia	Endothelial function will be measured using forearm muscle oxygenation (near-infrared spectroscopy) during reactive hyperemia at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.	4 weeks
Central and peripheral arterial stiffness in the fasted condition	Arterial stiffness will be measured using central (carotid-femoral) and peripheral (femoral-ankle) PWV at baseline and after 4 weeks of supplementation.	4 weeks
Central arterial stiffness during acute hyperglycemia	Arterial stiffness will be measured using central (carotid-femoral) PWV at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.	4 weeks
Blood pressure in the fasted condition	Brachial and aortic blood pressures will be assessed using an automated sphygmomanometry arm cuff (SphygmoCor XCEL). Beat-to-beat blood pressure will be measured using an automated photoplethysmography finger cuff (Fineometer). Blood pressure will be measured at baseline and after 4 weeks of supplementation.	4 weeks
Blood pressure during acute hyperglycemia	Brachial and aortic blood pressures (systolic and diastolic) will be assessed using an automated sphygmomanometry arm cuff (SphygmoCor XCEL). Beat-to-beat blood pressure will be measured using an automated photoplethysmography finger cuff (Fineometer). Blood pressure will be measured after an oral glucose ingestion at 30, 60, and 90 minutes at baseline and after 4 weeks of supplementation.	4 weeks
Total peripheral resistance in the fasted condition.	Total peripheral resistance will be measured using an automated photoplethysmography finger cuff (Finometer) at baseline and after 4 weeks of supplementation.	4 weeks
Total peripheral resistance during acute hyperglycemia	Total peripheral resistance will be measured using an automated photoplethysmography finger cuff (Finometer) at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.	4 weeks
Stroke volume in the fasted condition	Stroke volume will be measured using an automated photoplethysmography finger cuff (Finometer) at baseline and after 4 weeks of supplementation.	4 weeks
Stroke volume during acute hyperglycemia	Stroke volume will be measured using an automated photoplethysmography finger cuff (Finometer) at 30, 60, and 90 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.	4 weeks
24-hour ambulatory blood pressure monitoring	An ambulatory blood pressure cuff, measuring blood pressure for 24-hours will be obtained on two separate days at baseline and after 4 weeks of supplementation.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum glucose and insulin levels.	Serum glucose and insulin levels will be tested at baseline and after 4 weeks of supplementation.	4 weeks
Serum arginine levels	Serum L-Arginine levels will be tested at baseline and after 4 weeks of supplementation.	4 weeks
Serum arginase levels	Serum arginase levels will be tested at baseline and after 4 weeks of supplementation.	4 weeks
Serum Nitric Oxide levels	Serum nitric oxide levels will be tested at baseline and after 4 weeks of supplementation.	4 weeks
Serum Endothelin-1 levels	Serum endothelin-1 levels will be tested at baseline and after 4 weeks of supplementation.	4 weeks

Collaborators and Investigators

• Sponsor: Texas Tech University
• Investigators: Principal Investigator: Arturo Figueroa, Texas Tech University

Publications and helpful links

General Publications

• McDonald JD, Mah E, Chitchumroonchokchai C, Dey P, Labyk AN, Villamena FA, Volek JS, Bruno RS. Dairy milk proteins attenuate hyperglycemia-induced impairments in vascular endothelial function in adults with prediabetes by limiting increases in glycemia and oxidative stress that reduce nitric oxide bioavailability. J Nutr Biochem. 2019 Jan;63:165-176. doi: 10.1016/j.jnutbio.2018.09.018. Epub 2018 Sep 25.
• Maharaj A, Fischer SM, Dillon KN, Kang Y, Martinez MA, Figueroa A. Acute Citrulline Blunts Aortic Systolic Pressure during Exercise and Sympathoactivation in Hypertensive Postmenopausal Women. Med Sci Sports Exerc. 2022 May 1;54(5):761-768. doi: 10.1249/MSS.0000000000002848. Epub 2022 Jan 3.
• Figueroa A, Maharaj A, Kang Y, Dillon KN, Martinez MA, Morita M, Nogimura D, Fischer SM. Combined Citrulline and Glutathione Supplementation Improves Endothelial Function and Blood Pressure Reactivity in Postmenopausal Women. Nutrients. 2023 Mar 23;15(7):1557. doi: 10.3390/nu15071557.
• Figueroa A, Alvarez-Alvarado S, Ormsbee MJ, Madzima TA, Campbell JC, Wong A. Impact of L-citrulline supplementation and whole-body vibration training on arterial stiffness and leg muscle function in obese postmenopausal women with high blood pressure. Exp Gerontol. 2015 Mar;63:35-40. doi: 10.1016/j.exger.2015.01.046. Epub 2015 Jan 28.
• Maharaj A, Fischer SM, Dillon KN, Kang Y, Martinez MA, Figueroa A. Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women. Nutrients. 2022 Oct 20;14(20):4396. doi: 10.3390/nu14204396.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: July 27, 2023
• First Submitted That Met QC Criteria: August 29, 2023
• First Posted (Actual): September 6, 2023

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Obesity; Hypertension; Endothelial function; Blood pressure; Aortic Hemodynamics
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Insulin Resistance; Hyperinsulinism; Syndrome; Metabolic Syndrome
• Other Study ID Numbers: IRB2022-362

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