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Arginine Metabolism in Pediatric Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT05477134
Recruitment Status : Recruiting
First Posted : July 28, 2022
Last Update Posted : February 8, 2023
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Mustafa Tosur, Baylor College of Medicine

Study Description
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Brief Summary:
Type 2 diabetes (T2D), once considered only "a disease of older ages," is now a significant public health concern in children. Although it is characterized by insulin resistance and impaired insulin secretion, its precise etiology and pathogenesis are not yet fully understood. This study aims to (1) explore arginine metabolism in pediatric T2D via safe, minimally invasive kinetic experiments using stable isotope tracers and targeted metabolomics, and (2) determine the effect of exogenous arginine administration on β-cell function in children with T2D, potentially supporting the use of this safe, low-cost, and readily available nutrient to improve pediatric diabetes outcomes.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Other: Stable isotope infusion, oral glucose ingestion, intravenous arginine bolus Not Applicable

Detailed Description:

In parallel with the childhood obesity epidemic, type 2 diabetes (T2D) in children is becoming a significant public health concern. The incidence of pediatric T2D increased by 50% during the past decade, and recent data show that T2D accounts for one in four newly-diagnosed diabetes cases in children. Children with T2D have an aggressive disease course and a rapid decline in β-cell function, and many also have multiple cardiovascular disease risk factors at an early age. The disease is characterized by insulin resistance and impaired insulin secretion, but the molecular underpinnings of T2D are not yet fully elucidated. This study aims to uncover the role of arginine metabolism in the pathogenesis of pediatric T2D and the effect of exogenous arginine administration on β-cell function in children with T2D.

Arginine is a known stimulant of insulin secretion in pancreatic β-cells. Nitric oxide (NO) is synthesized from arginine by NO synthase, and arginine stimulates insulin secretion in both NO-mediated and NO-independent mechanisms by stimulating guanylate cyclase, membrane depolarization, and metabolic by-products. The effects of arginine in pancreatic β-cells are dependent on the cells' available arginine concentration. Kinetic techniques using isotope tracer infusions and targeted metabolomics provide a unique opportunity to determine "intracellular" arginine availability and its relative contribution of various pathways to this pool. Such studies in adults with T2D have shown that arginine and NO play roles in the pathogenesis of T2D by affecting insulin secretion and insulin sensitivity. In the preliminary data on children with T2D, the investigators found that children with T2D had lower fasting arginine, citrulline (arginine precursor), and glutamine (citrulline precursor) levels. In this proposal, the investigators will seek kinetic validation of these hypothesis-generating observations to investigate the role of arginine metabolism in pediatric T2D. Our central hypothesis is that children with T2D have inadequate arginine availability (Aim 1), leading to suboptimal β-cell function, which can be restored by exogenous arginine administration (Aim 2). If our hypotheses are proven, arginine supplementation will play a clinically vital role in improving diabetes outcomes in this population as a safe, low-cost, and readily available nutrient.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Arginine Metabolism in Pediatric Type 2 Diabetes
Actual Study Start Date : February 6, 2023
Estimated Primary Completion Date : June 2027
Estimated Study Completion Date : August 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: The study cohort consisting of children with type 2 diabetes and healthy controls

In Study Day 1, participants will be given a primed dose of stable isotopes followed by continuous intravenous infusions for 5 hours. The investigators will use the following isotopes: U-13C6-Arg, 5,5-2H2-Cit, 15N2-Orn, 2H5-Phe, Na13CO3, and 13C5-Orn.

On Study Day 2, participants will drink a 75-gram glucose solution prior to an oral glucose tolerance test.

On Study Day 3, participants will drink a 75-gram glucose solution and will be injected 5-gram arginine into their veins.

 Other: Stable isotope infusion, oral glucose ingestion, intravenous arginine bolus
On separate study days, each participant will have a stable isotope infusion, ingest oral glucose, and be given an intravenous arginine bolus.


Outcome Measures
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Primary Outcome Measures :
  1. The difference in arginine availability [ Time Frame: 1 day ]
    Arginine availability will be assessed and compared between children with type 2 diabetes and healthy controls.


Secondary Outcome Measures :
  1. The difference in insulin secretion and the effect of intravenous arginine bolus on insulin secretion [ Time Frame: 1 day ]
    Insulin secretion will be assessed and compared between children with type 2 diabetes and healthy controls using oral glucose tolerance tests and modified oral glucose tolerance tests including intravenous arginine administration. The effect of arginine bolus on insulin secretion will be compared between the groups.

  2. The difference in insulin sensitivity and the effect of intravenous arginine bolus on insulin sensitivity [ Time Frame: 1 day ]
    Insulin sensitivity will be assessed and compared between children with type 2 diabetes and healthy controls using oral glucose tolerance tests and modified oral glucose tolerance tests including intravenous arginine administration. The effect of arginine bolus on insulin sensitivity will be compared between the groups.


Eligibility Criteria
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Ages Eligible for Study:   12 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Children with type 2 diabetes and healthy controls who meet other inclusion criteria outlined below.
  2. Age and pubertal stage criteria (12- to 17-year-old girls who are postmenarchal, and 14- to 17-year-old boys who are at Tanner stage 5 pubic hair),
  3. Additional criteria for children with diabetes: i. diagnosis of T2D, and ii. diabetes duration between 3 months and 10 years.

Exclusion Criteria:

  1. Previous history of diabetic ketoacidosis (DKA) or ketosis (defined as β-hydroxybutyrate level ≤ 0.3 mmol/L at diabetes diagnosis or any time after).
  2. Current use of exogenous insulin,
  3. Poorly controlled diabetes defined as HbA1c >8%,
  4. Other chronic or acute illness,
  5. Abnormal liver, thyroid, gonadal or adrenal functions,
  6. Renal insufficiency defined by eGFR (estimated glomerular filtration rate) <90 mL/min/1.73 m2,
  7. Medications other than metformin,
  8. Any hormonal replacement therapy, and
  9. Pregnancy.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05477134


Contacts
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Contact: Mustafa Tosur, MD 832-822-3780 mustafa.tosur@bcm.edu
Contact: Lori Malone 832-822-3784 lmalone@bcm.edu

Locations
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United States, Texas
Texas Children's Hospital / Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Mustafa Tosur, MD       mustafa.tosur@bcm.edu   
Sponsors and Collaborators
Baylor College of Medicine
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Mustafa Tosur, MD Baylor College of Medicine
More Information
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Responsible Party: Mustafa Tosur, Assistant Professor of Pediatrics, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT05477134    
Other Study ID Numbers: H-51936
First Posted: July 28, 2022    Key Record Dates
Last Update Posted: February 8, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mustafa Tosur, Baylor College of Medicine:
Children
Pediatric type 2 diabetes
Pediatric diabetes
Arginine
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases