The Effect of 4 Weeks of L-Citrulline Supplementation on Macro- and Microvascular Function in Type 2 Diabetes

Sponsor

Texas Tech University (Other)

Overall Status

Recruiting

CT.gov ID

NCT06016478

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

2.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the effect of 4 weeks of Citrulline supplementation on macro- and microvascular function during acute hyperglycemia in middle-aged and older adults with type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Dietary Supplement: L-citrulline Dietary Supplement: Placebo	N/A

Detailed Description

Using a double-blind, randomized, placebo-controlled, and parallel design, middle-aged and older adults with type 2 diabetes will be randomized to receive either CIT supplementation (6g/day) or placebo (Microcrystalline Cellulose, 6g/day) for 4 weeks.

There will be a total of 3 laboratory visits. Visit 1 (screening visit) will take approximately 1 hour and 30 minutes, visit 2 will take approximately 2 hours and 30 minutes, and visit 3 will be approximately 3 hours each.

Visit 1 will measure blood pressure, blood glucose and lipid levels, anthropometry, body composition, and muscle strengths. Visits 2 and 3 will assess vascular function and glucose control during fasted and acute hyperglycemia conditions induced by 75g of glucose ingestion.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Double-blind (subject, investigator), randomized, parallel, placebo-controlledDouble-blind (subject, investigator), randomized, parallel, placebo-controlled

Masking:

Double (Participant, Investigator)

Masking Description:

Double-blind (subject, investigator), randomized, parallel, placebo-controlled

Primary Purpose:

Basic Science

Official Title:

The Effect of 4 Weeks of L-Citrulline Supplementation on Macro- and Microvascular Function in Type 2 Diabetes

Actual Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: L-citrulline 6 grams/day	Dietary Supplement: L-citrulline 4 weeks of L-citrulline (6 g/day) in 8 capsules. Supplementation will be ingested daily, half of the doses in the morning and half at night.
Placebo Comparator: Placebo Microcrystalline cellulose	Dietary Supplement: Placebo 4 weeks of microcrystalline cellulose in 8 capsules. Supplementation will be ingested daily, half of the doses in the morning and half at night.

Arm

Intervention/Treatment

Experimental: L-citrulline

6 grams/day

Dietary Supplement: L-citrulline

4 weeks of L-citrulline (6 g/day) in 8 capsules. Supplementation will be ingested daily, half of the doses in the morning and half at night.

Placebo Comparator: Placebo

Microcrystalline cellulose

Dietary Supplement: Placebo

4 weeks of microcrystalline cellulose in 8 capsules. Supplementation will be ingested daily, half of the doses in the morning and half at night.

Outcome Measures

Primary Outcome Measures

Change in macrovascular endothelial function in the fasted condition [4 weeks]
Macrovascular endothelial function will be measured using brachial artery flow mediated dilation (ultrasonography) during reactive hyperemia at baseline and after 4 weeks of supplementation.
Change in macrovascular endothelial function during acute hyperglycemia [4 weeks]
Macrovascular endothelial function will be measured using brachial artery flow mediated dilation (ultrasonography) during reactive hyperemia at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
Change in microvascular endothelial function in the fasted condition [4 weeks]
Microvascular endothelial function will be assessed using peripheral arterial tonometry (EndoPAT device) during reactive hyperemia at baseline and after 4 weeks of supplementation.
Change in microvascular endothelial function in the fasted condition [4 weeks]
Microvascular endothelial function will be assessed using forearm muscle oxygenation (near-infrared spectroscopy) during reactive hyperemia at baseline and after 4 weeks of supplementation.
Change in microvascular endothelial function during acute hyperglycemia [4 weeks]
Microvascular endothelial function will be assessed using forearm muscle oxygenation (near-infrared spectroscopy) during reactive hyperemia at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
Change in blood glucose levels in the fasted condition [4 weeks]
Blood glucose levels will be measured by finger prick at baseline and after 4 weeks of supplementation.
Change in blood glucose levels during acute hyperglycemia [4 weeks]
Blood glucose levels will be measured by finger prick at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
Change in central and peripheral arterial stiffness in the fasted condition [4 weeks]
Arterial stiffness will be assessed using the central (carotid-femoral) and peripheral (femoral-ankle) pulse wave velocity at baseline and after 4 weeks of supplementation.
Change in central and peripheral arterial stiffness during acute hyperglycemia [4 weeks]
Arterial stiffness will be assessed using the central (carotid-femoral) and peripheral (femoral-ankle) pulse wave velocity at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
Change in blood pressure in the fasted condition [4 weeks]
Brachial and aortic blood pressure will be measured using an automated sphygmomanometry arm cuff (SphygmoCor XCEL). Beat-to-beat blood pressure will be measured using an automated photoplethysmography finger cuff (Finometer). Blood pressure will be measured at baseline and after 4 weeks of supplementation.
Change in blood pressure during acute hyperglycemia [4 weeks]
Brachial and aortic blood pressure will be measured using an automated sphygmomanometry arm cuff (SphygmoCor XCEL). Beat-to-beat blood pressure will be measured using an automated photoplethysmography finger cuff (Finometer). Blood pressure will be measured at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
Change in stroke volume in the fasted condition [4 weeks]
Stroke volume will be measured using impedance cardiography (PhysioFlow) at baseline and after 4 weeks of supplementation.
Change in stroke volume during acute hyperglycemia [4 weeks]
Stroke volume will be measured using impedance cardiography (PhysioFlow) at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.
Change in total peripheral resistance in the fasted condition [4 weeks]
Total peripheral resistance will be measured using impedance cardiography (PhysioFlow) at baseline and after 4 weeks of supplementation.
Change in total peripheral resistance during acute hyperglycemia [4 weeks]
Total peripheral resistance will be measured using impedance cardiography (PhysioFlow) at 60 minutes after oral glucose ingestion at baseline and after 4 weeks of supplementation.

Secondary Outcome Measures

Change in body composition [4 weeks]
Body composition (fat and lean mass) will be measured at baseline and after 4 weeks of supplementation.
Change in muscle strength [4 weeks]
Maximal handgrip strength will be measured using handgrip dynamometer. Leg extension and plantar flexion strength will be measured using the 10RM test at baseline and after 4 weeks of supplementation.
Change in insulin levels [4 weeks]
Serum insulin levels will be tested at baseline and after 4 weeks of supplementation.
Change in serum arginine levels [4 weeks]
Serum arginine levels will tested at baseline and after 4 weeks of supplementation.
Change in serum arginase activity levels [4 weeks]
Serum arginase activity levels will tested at baseline and after 4 weeks of supplementation.
Change in 24-hour ambulatory blood pressure monitoring [4 weeks]
Ambulatory blood pressure will be obtained using a monitor during daytime and nighttime on two separate days at baseline and after 4 weeks of supplementation.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Middle-aged and older women and men between 40-75 years old
A physician diagnosed type 2 diabetes at least 3 months ago
Treated with an oral hypoglycemic medication
Body mass index < 40 kg/m2
Systolic blood pressure < 160 mmHg
Sedentary (defined as < 120 min/week of exercise)
Not currently participating in exercise or dietary interventions for at least 2 months prior the present study and willing to abstain from participating in those strategies during the duration of this study.

Exclusion Criteria:

< 40 years of age and > 65 years of age
Use of medications and/or any supplements that may affect outcome variables (such as arginine- or citrulline-containing supplements, nitrates, and nitroglycerin)
Body mass index ≥ 40 kg/m2
Systolic blood pressure ≥ 160 mmHg
Recent changes in medications within 3 months
Current smoking any tobacco use
Type 1 diabetes, severe cardiovascular/renal/pulmonary diseases
More than 7 alcoholic drinks/week of consumption
Premenopausal women with an irregular menstrual cycle (oligomenorrhea) or pregnancy