Arginine Metabolism in Youth With Type 2 Diabetes

Arginine Metabolism in Pediatric Type 2 Diabetes

Type 2 diabetes (T2D), once considered only "a disease of older ages," is now a significant public health concern in youth. 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 youth with 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 youth with T2D, potentially supporting the use of this safe, low-cost, and readily available nutrient to improve pediatric diabetes outcomes.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Other: Stable isotope infusion, oral glucose ingestion, intravenous arginine bolus

Detailed Description

In parallel with the youth obesity epidemic, type 2 diabetes (T2D) in youth 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. Youth 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 youth with T2D and the effect of exogenous arginine administration on β-cell function in them.

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 youth with T2D. Our central hypothesis is that youth 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 Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mustafa Tosur, MD; Phone Number: 832-822-3780; Email: mustafa.tosur@bcm.edu
• Study Contact Backup: Name: Lori Malone; Phone Number: 832-822-3784; Email: lmalone@bcm.edu

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital / Baylor College of Medicine
      • Contact: Mustafa Tosur, MD; Email: mustafa.tosur@bcm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Youth with type 2 diabetes and healthy controls who meet other inclusion criteria outlined below.
2. Age and pubertal stage criteria (12- to 20-year-old girls who are postmenarchal, and 14- to 20-year-old boys who are at Tanner stage 5 genitalia),
3. Additional criteria for youth 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)
2. Current use of exogenous insulin,
3. Poorly controlled diabetes defined as HbA1c >8%,
4. Abnormal liver, thyroid, gonadal or adrenal functions,
5. Renal insufficiency defined by eGFR (estimated glomerular filtration rate) <90 mL/min/1.73 m2,
6. Any glucose lowering medications except metformin,
7. Any medication use that will likely to interfere amino acid metabolism,
8. Any hormonal replacement therapy, and
9. Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: The study cohort consisting of youth 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The difference in arginine availability	Arginine availability will be assessed and compared between youth with type 2 diabetes and healthy controls.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The difference in insulin secretion and the effect of intravenous arginine bolus on insulin secretion	Insulin secretion will be assessed and compared between youth 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.	1 day
The difference in insulin sensitivity and the effect of intravenous arginine bolus on insulin sensitivity	Insulin sensitivity will be assessed and compared between youth 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.	1 day

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Mustafa Tosur, MD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: July 25, 2022
• First Submitted That Met QC Criteria: July 25, 2022
• First Posted (Actual): July 28, 2022

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Children; Youth; Arginine; Pediatric type 2 diabetes; Pediatric diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: H-51936

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