Study of Arginine and Nitric Oxide in Patients With Diabetes

Arginine and Nitric Oxide Synthesis in the Pathogenesis of Ketosis-prone Diabetes

This study will test the effect of citrulline versus placebo supplementation in ketosis-prone diabetes (KPD) patients on arginine and nitric oxide production and on glucose- and arginine-stimulated insulin secretion and arterial flow-mediated dilation.

Study Overview

• Status: Completed
• Conditions: Ketosis Prone Diabetes
• Intervention / Treatment: Dietary supplement: Citrulline; Dietary supplement: Alanine

Detailed Description

Both arginine and its derivative nitric oxide (NO) have been implicated in the regulation of glucose homeostasis. Arginine is a β cell secretagogue, potentiating glucose stimulated insulin secretion. Further, it has been shown that glucose can stimulate NO production in primary β cells, and NO then enhances insulin secretion.

On the other hand, because the only known fate of citrulline is its conversion to arginine, citrulline supplementation could be a more efficient and safe way to increase intracellular arginine. Compared to enteral arginine, citrulline administration to healthy humans elicited a greater increase in plasma arginine and NO products, suggesting a greater increase in cellular arginine availability for NO synthesis. Therefore dietary citrulline supplementation will result in greater arginine availability and NO synthesis than arginine supplementation per se in KPD patients. In addition, because the consequences of diminished NO production in usual type 2 diabetes includes vascular dysfunction, an overall increase in NO production in response to citrulline supplementation will result in an improvement in vascular function assessed by arterial flow-mediated dilation

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor St Lukes Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• New onset (defined as receiving a diagnosis within the past 1 year) diagnosis of unprovoked" A-β+ ketosis-prone diabetes
• Aged 20-65 years
• In good health except for diabetes without clinical evidence of micro- or macrovascular complications by history, physical exam and blood chemistries

Exclusion Criteria:

• Chronic or acute illness
• History of myocardial infarction or coronary artery disease or stroke,
• Renal insufficiency (eGFR <90mL/min/1.73m2; <30 mg albumin / g creatinine in urine)
• Abnormal liver, thyroid, gonadal or adrenal functions
• On medications other than metformin,
• On any hormonal replacement therapy
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Citrulline; In this arm, 10 ketosis prone diabetes patients will be randomly assigned to receive 34.2 mmol/d of dietary citrulline for 20 days. Citrulline will be in the form of 2.85 mmol capsules and patients will be instructed to consume 4 capsules with each of their 3 main meals. The citrulline will be provided in a double-blind fashion by a designated unblinded investigator who will not come in direct contact with the subjects.	Dietary supplement: Citrulline; Ketosis prone diabetes patients (n=10) will be randomly assigned to receive either dietary supplement of citrulline or alanine as placebo. They will then cross over to the other supplement.
Placebo Comparator: alanine; In this arm, 10 ketosis prone diabetes patients will be randomly assigned to receive 34.2 mmol/d of dietary alanine for 20 days. Alanine will be in the form of 2.85 mmol capsules and patients will be instructed to consume 4 capsules with each of their 3 main meals. The alanine will be provided in a double-blind fashion by a designated unblinded investigator who will not come in direct contact with the subjects.	Dietary supplement: Alanine; Ketosis prone diabetes patients (n=10) will be randomly assigned to receive either dietary supplement of citrulline or alanine as placebo. They will then cross over to the other supplement.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Arginine production	The change in the amount of arginine produced from baseline in response to supplements of citrulline versus alanine (placebo) will be assessed by stable isotope tracers after 3 weeks of supplementation.	Three weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Nitric Oxide Synthesis	The change in the amount of nitric oxide produced produced from baseline in response to supplements of citrulline versus alanine (placebo) will be assessed by stable isotope tracers after 3 weeks of supplementation.	Three weeks
Change in Arterial function	The change in in arterial function (assessed by endopat) from baseline in response to supplements of citrulline versus alanine placebo will be assessed after 3 weeks of supplementation.	Three weeks
Change in Insulin secretion	The change in glucose stimulated insulin secretion from baseline in response to supplements of citrulline versus alanine placebo will be assessed after 3 weeks of supplementation.	Three weeks

Collaborators and Investigators

• Sponsor: Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): June 30, 2022

Study Registration Dates

• First Submitted: May 31, 2018
• First Submitted That Met QC Criteria: June 12, 2018
• First Posted (Actual): June 25, 2018

Study Record Updates

• Last Update Posted (Actual): July 29, 2022
• Last Update Submitted That Met QC Criteria: July 27, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Acid-Base Imbalance; Acidosis; Diabetes Mellitus; Ketosis
• Other Study ID Numbers: DK101411

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
• product manufactured in and exported from the U.S.: No