September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Non-targeted plasma metabolomics of diabetic retinopathy demonstrates increased arginine and related metabolites
Author Affiliations & Notes
  • Milam A Brantley
    Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • David J. Herren
    Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Karan Uppal
    Department of Medicine, Emory University, Atlanta, Georgia, United States
  • L. Goodwin Burgess
    Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Isaac Chocron
    Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • M. Wade Calcutt
    Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, United States
  • David C. Samuels
    Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States
  • Dean P. Jones
    Department of Medicine, Emory University, Atlanta, Georgia, United States
  • Footnotes
    Commercial Relationships   Milam Brantley, None; David Herren, None; Karan Uppal, None; L. Burgess, None; Isaac Chocron, None; M. Calcutt, None; David Samuels, None; Dean Jones, None
  • Footnotes
    Support  NIH Grants EY022618, AG038746, ES023485, ES019776, OD018006, EY008126, the International Retina Research Foundation, and departmental funding from Research to Prevent Blindness
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Milam A Brantley, David J. Herren, Karan Uppal, L. Goodwin Burgess, Isaac Chocron, M. Wade Calcutt, David C. Samuels, Dean P. Jones; Non-targeted plasma metabolomics of diabetic retinopathy demonstrates increased arginine and related metabolites. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To determine plasma metabolite differences between Type 2 diabetics with retinopathy (T2DR) and Type 2 diabetics without retinopathy (T2DM).

Methods : We performed untargeted metabolomic analysis using ultra-high resolution mass spectrometry with C18 liquid chromatography on frozen plasma samples from 83 T2DR patients and 90 T2DM controls. Metabolic features were extracted using apLCMS with xMSanalyzer. LIMMA was used to isolate differentially expressed metabolites (DEM) after correcting for multiple testing. DEM were further analyzed using MetaboAnalyst to identify metabolic pathways altered in diabetic retinopathy (DR). Four specific metabolites were measured individually in targeted fashion using liquid chromatography-mass spectrometry (LC-MS). For these targeted measurements, t-tests and multivariate linear regressions were used to analyze differences between the groups.

Results : Of 11,763 mass/charge (m/z) features recovered, 78 differed significantly between T2DR cases and T2DM controls. Twenty-eight features possessed putative matches to the Metlin metabolomics database. Three of these matched to arginine-related metabolites, including arginine, asymmetric/symmetric dimethyl arginine (ADMA/SDMA), and citrulline. Pathway analysis also indicated arginine metabolism was altered in DR. Targeted LC-MS measurements of each arginine metabolite confirmed a significant difference between T2DM and T2DR patients (arginine, p=1.3x10-10; ADMA, p=1.8x10-5; SDMA, p=0.0098; citrulline, p=0.0084). After adjusting for age, sex, race, duration of diabetes, and hemoglobin A1c, each of the four metabolites remained significantly different between T2DM and T2DR (arginine, p=1.3x10-6; ADMA, p=7.0x10-5; SDMA, p=0.0042; citrulline, p=0.040). None of the four metabolites differed between nonproliferative DR (n=49) and proliferative DR (n=24) patients (arginine, p=0.96; ADMA, p=0.89; SDMA, p=0.43; citrulline, p=0.25).

Conclusions : Using non-targeted high-resolution metabolomics, we determined that plasma arginine metabolites were altered in our cohort of Type 2 diabetics with retinopathy. Targeted LC-MS measurements confirmed that four specific arginine-related metabolites were elevated in plasma in T2DR patients compared to T2DM controls. This suggests that arginine metabolites might be effective biomarkers for DR and that the arginine pathway might be a target for future DR therapy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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