Plasma Arginine and Citrulline are Elevated in Diabetic Retinopathy

Katherine S Peters; Emilio Rivera; Cassandra Warden; Paula A Harlow; Sabrina L Mitchell; M Wade Calcutt; David C Samuels; Milam A Brantley Jr

doi:10.1016/j.ajo.2021.09.021

Plasma Arginine and Citrulline are Elevated in Diabetic Retinopathy

Am J Ophthalmol. 2022 Mar:235:154-162. doi: 10.1016/j.ajo.2021.09.021. Epub 2021 Sep 26.

Authors

Katherine S Peters¹, Emilio Rivera², Cassandra Warden¹, Paula A Harlow¹, Sabrina L Mitchell¹, M Wade Calcutt², David C Samuels³, Milam A Brantley Jr⁴

Affiliations

¹ From Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA (K.S.P, C.W, P.A.H, S.L.M, M.A.B Jr).
² Department of Biochemistry, Vanderbilt University, Nashville, TN, USA (E.R, M.W.C); Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN, USA (E.R, M.W.C).
³ Vanderbilt Genetics Institute and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
⁴ From Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA (K.S.P, C.W, P.A.H, S.L.M, M.A.B Jr). Electronic address: milam.brantley@vumc.org.

PMID: 34587493
DOI: 10.1016/j.ajo.2021.09.021

Abstract

Purpose: To determine if plasma levels of six arginine-related and citrulline-related metabolites (arginine, citrulline, asymmetric dimethylarginine [ADMA], ornithine, proline, and argininosuccinate) differ between patients with type 2 diabetes and diabetic retinopathy (DR) and type 2 diabetic controls or between patients with proliferative DR (PDR) and non-proliferative DR (NPDR).

Design: Cross-sectional study.

Methods: Adults with type 2 diabetes were recruited from the Vanderbilt Eye Institute. Exclusion criteria included non-diabetic retinal disease. Plasma metabolite levels were quantified in 159 diabetic controls and 156 DR patients (92 NPDR, 64 PDR) using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Metabolite levels were compared using Wilcoxon Rank Sum test and logistic regressions adjusting for age, sex, hemoglobin A1c, diabetes duration, statin use, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. A secondary analysis that included creatinine in the regression model was performed for the subset of patients with available creatinine values (135 diabetic controls, 100 DR patients [58 NPDR, 42 PDR]).

Results: Multivariable logistic regression analyses determined that arginine (OR = 1.20, [1.06-1.38], P = .0067) and citrulline (OR = 1.53, [1.20-1.98], P = .0025) were significantly elevated in DR patients compared to diabetic controls. While ADMA differed between NPDR and PDR patients in the primary analysis (OR = 1.56, [1.15-2.16], P = .0051), it was not significantly different when adjusting for creatinine (OR = 1.30, [0.90-1.91], P = .15).

Conclusions: Plasma arginine and citrulline were significantly elevated in type 2 diabetic patients with DR compared to diabetic controls. None of the tested metabolites significantly differed between NPDR and PDR patients in the adjusted analysis.

Keywords: ADMA; Arginine; asymmetric dimethylarginine; citrulline; diabetic retinopathy; liquid chromatography mass spectrometry; metabolomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Arginine
Chromatography, Liquid
Citrulline
Cross-Sectional Studies
Diabetes Mellitus, Type 2* / complications
Diabetic Retinopathy* / complications
Humans
Tandem Mass Spectrometry

Substances

Citrulline
Arginine

Grants and funding

P30 EY008126/EY/NEI NIH HHS/United States