# title
Impaired Arginine, Citrulline, and Glutamine Metabolism in Type 2 Diabetes (T2D)-Insights from a Stable Isotope Study

# abstract
Introduction and Objective: Arginine (ARG) is an important amino acid in T2D as a potent insulin secretagogue and precursor for nitric oxide (NO). Citrulline (CIT), the substrate for de novo ARG synthesis, is mostly produced from glutamine (GLN). Here, we aimed to investigate their metabolism in T2D using a novel stable isotope tracer approach. Methods: We studied 42 individuals (21 with T2D, 21 controls). After an overnight fast, we collected blood samples following pulse administration of ARG, CIT, and GLN stable amino acid tracers. Plasma concentrations and isotopic enrichments were measured by LC-MS/MS and lean soft tissue (LST) by DXA. Compartmental analysis was performed to calculate their WBP. Data are mean (SD) or [95% CI] (t-test and ANCOVA by JASP). Results: The cohort was 60% female, mean age 64.4 (7.5) years, and BMI 33.0 (4.3) kg/m2 (all p>0.05). After adjusting for sex and age, T2D group had lower plasma concentrations of ARG (57.7 [48.9, 66.4] vs. 75.8 [66.9, 84.5] M, p=0.005), CIT (23.4 [18.9, 27.9] vs. 34.4 [29.9, 38.9] M, p=0.001), and GLN (463.5 [421.1, 506] vs. 561.7 [519, 604.3] M, p=0.002). In T2D, WBP was lower for CIT (11.8 [10.1, 13.6] vs. 15.5 [13.8, 17.2] mol/min, p=0.004) but higher for GLN (537 [503, 571] vs. 481.9 [448.3, 515.5] mol/min, p=0.004) after controlling for age, sex and LST. T2D group also had lower CIT intracellular production (p=0.003), but higher GLN clearance (p=0.001) and intracellular pool size (p=0.007), and a trend towards higher ARG clearance (p=0.06). Conclusion: In T2D, significant dysregulation exists in ARG, CIT and GLN metabolism. We hypothesize that increased muscle GLN synthesis stimulates gluconeogenesis, increases GLN consumption, and contributes to T2D pathogenesis via blunted insulin secretion, sensitivity and incretin response by having less GLN available for CIT production that may affect ARG (and NO) metabolism. Interventions aiming to reduce GLN production but increase CIT availability may be useful in T2D.  Disclosure M. Tosur: None. R. Wierzchowska-McNew: None. M.P. Engelen: None. N.E. Deutz: None.   Funding National Institutes of Health (K23-DK129821)(MT)

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Texas A&M University Naresh K. Vashisht College of Medicine

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College of Education and Human Development

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Center for Translational Research in Aging and Longevity

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College of Education and Human Development

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Center for Translational Research in Aging and Longevity

# authorList[]
Tosur, M., Wierzchowska-McNew, R., Engelen, M. P., & Deutz, N. E.