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Author Notes:

Milam A. Brantley Jr, Vanderbilt Eye Institute, Vanderbilt University Medical Center, 2311 Pierce Avenue, Nashville, TN 37232- 8808, USA; milam.brantley@vumc.org.

The authors thank Vi Linh Tran for her technical assistance.

Authors reported no disclosures.


Research Funding:

Supported by National Institutes of Health (Bethesda, MD, USA) Grants R01 EY022618, P30 EY008126, P30 ES019776, U2C ES030163, and S10 OD018006; a grant from the International Retinal Research Foundation (Birmingham, AL, USA); and an unrestricted departmental grant to Vanderbilt University Medical Center from Research to Prevent Blindness (New York, NY, USA).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Ophthalmology
  • diabetic retinopathy
  • arginine
  • citrulline
  • carnitine
  • metabolomics
  • RISK

Arginine and Carnitine Metabolites Are Altered in Diabetic Retinopathy

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Journal Title:

Investigative Ophthalmology & Visual Science


Volume 60, Number 8


, Pages 3119-3126

Type of Work:

Article | Final Publisher PDF


Purpose: To determine plasma metabolite and metabolic pathway differences between patients with type 2 diabetes with diabetic retinopathy (DR) and without retinopathy (diabetic controls), and between patients with proliferative DR (PDR) and nonproliferative DR (NPDR). Methods: Using high-resolution mass spectrometry with liquid chromatography, untargeted metabolomics was performed on plasma samples from 83 DR patients and 90 diabetic controls. Discriminatory metabolic features were identified through partial least squares discriminant analysis, and linear regression was used to adjust for age, sex, diabetes duration, and hemoglobin A1c. Pathway analysis was performed using Mummichog 2.0. Results: In the adjusted analysis, 126 metabolic features differed significantly between DR patients and diabetic controls. Pathway analysis revealed alterations in the metabolism of amino acids, leukotrienes, niacin, pyrimidine, and purine. Arginine, citrulline, glutamic γ-semialdehyde, and dehydroxycarnitine were key contributors to these pathway differences. A total of 151 features distinguished PDR patients from NPDR patients, and pathway analysis revealed alterations in the β-oxidation of saturated fatty acids, fatty acid metabolism, and vitamin D3 metabolism. Carnitine was a major contributor to the pathway differences. Conclusions: This study demonstrates that arginine and citrulline-related pathways are dysregulated in DR, and fatty acid metabolism is altered in PDR patients compared with NPDR patients.

Copyright information:

Copyright 2019 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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