Arginine Metabolism in Pediatric Type 2 Diabetes
Study Details
Study Description
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 |
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N/A |
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
Arms and Interventions
Arm | Intervention/Treatment |
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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.
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Outcome Measures
Primary Outcome Measures
- The difference in arginine availability [1 day]
Arginine availability will be assessed and compared between children with type 2 diabetes and healthy controls.
Secondary Outcome Measures
- The difference in insulin secretion and the effect of intravenous arginine bolus on insulin secretion [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.
- The difference in insulin sensitivity and the effect of intravenous arginine bolus on insulin sensitivity [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
Criteria
Inclusion Criteria:
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Children with type 2 diabetes and healthy controls who meet other inclusion criteria outlined below.
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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),
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Additional criteria for children with diabetes: i. diagnosis of T2D, and ii. diabetes duration between 3 months and 10 years.
Exclusion Criteria:
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Previous history of diabetic ketoacidosis (DKA) or ketosis (defined as β-hydroxybutyrate level ≤ 0.3 mmol/L at diabetes diagnosis or any time after).
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Current use of exogenous insulin,
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Poorly controlled diabetes defined as HbA1c >8%,
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Other chronic or acute illness,
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Abnormal liver, thyroid, gonadal or adrenal functions,
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Renal insufficiency defined by eGFR (estimated glomerular filtration rate) <90 mL/min/1.73 m2,
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Medications other than metformin,
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Any hormonal replacement therapy, and
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Pregnancy.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Texas Children's Hospital / Baylor College of Medicine | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Baylor College of Medicine
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Mustafa Tosur, MD, Baylor College of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H-51936