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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. 2016;57(12):No Pagination Specified. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To determine plasma metabolite differences between Type 2 diabetics with retinopathy (T2DR) and Type 2 diabetics without retinopathy (T2DM).
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.
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).
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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