# Investigation of Arginine Metabolism and Its Effects on Beta Cell Function in Children with Type 2 Diabetes

> **NIH NIH K23** · BAYLOR COLLEGE OF MEDICINE · 2024 · $185,908

## Abstract

Summary/Abstract
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
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 a subset of the T2D population, namely, those with
ketosis-prone diabetes (KPD), our group found that adults with KPD had a unique metabolomic signature with a
significant reduction in “intracellular” arginine availability during hyperglycemia. Moreover, their insulin secretory
responses were restored following arginine administration. In my preliminary data in children with T2D, I found
a similar metabolic signature in them to that of adults with KPD. Specifically, children with T2D had lower fasting
arginine, citrulline (arginine precursor), and glutamine (citrulline precursor) levels. In this proposal, I will seek
kinetic validation of these hypothesis-generating observations to investigate the role of arginine metabolism in
pediatric T2D. My 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 my
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. I am uniquely suited to conduct this study
given my previous clinical and research experience, as well as my access to a large patient population, a wealth
of resources, and strong mentorship team at Texas Children’s Hosp...

## Key facts

- **NIH application ID:** 10899693
- **Project number:** 5K23DK129821-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Mustafa Tosur
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,908
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899693

## Citation

> US National Institutes of Health, RePORTER application 10899693, Investigation of Arginine Metabolism and Its Effects on Beta Cell Function in Children with Type 2 Diabetes (5K23DK129821-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899693. Licensed CC0.

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