title: Complete metabolome and lipidome analysis reveals novel biomarkers in the human diabetic corneal stroma.
abstract: Prolonged hyperglycemia during diabetes mellitus can cause severe ophthalmic complications affecting both the anterior and posterior ocular segments leading to impaired vision or blindness. Diabetes-induced corneal pathologies are associated with decreased wound healing capacity, corneal edema, and altered epithelial basement membrane. The mechanism by which diabetes modulates structure and function within the corneal stroma are unknown. In our study, we characterized the effects of diabetes on extracellular matrix, lipid transport, and cellular metabolism by defining the entire metabolome and lipidome of Type 1 and Type 2 human diabetic corneal stroma. Significant increases in Collagen I and III were found in diabetic corneas suggesting that diabetes promotes defects in matrix structure leading to scarring. Furthermore, increased lipid content, including sphingosine-1-phosphate and dihydrosphingosine, in diabetic corneas compared to healthy controls were measured suggesting altered lipid retention. Metabolomics analysis identified elevated tryptophan metabolites, independent of glucose metabolism, which correlated with upregulation of the Kynurenine pathway in diabetic corneas. We also found significant upregulation of novel biomarkers aminoadipic acid, D,L-pipecolic acid, and dihydroorotate. Our study links aberrant tryptophan metabolism to end-stage pathologies associated with diabetes indicating the potential of the Kynurenine pathway as a therapeutic target for inhibiting diabetes-associated defects in the eye.
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Shrestha
authors.initials: S
authors.lastname: Priyadarsini
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Tina B
authors.initials: TB
authors.lastname: McKay
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Akhee
authors.initials: A
authors.lastname: Sarker-Nag
authors.affiliation: Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA, USA; Department of Biochemistry and Molecular Biology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; The VCU Johnson Center, Richmond, VA, USA; The VCU Massey Cancer Center, Richmond, VA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allegood
authors.affiliation: Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA, USA; Department of Biochemistry and Molecular Biology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; The VCU Johnson Center, Richmond, VA, USA; The VCU Massey Cancer Center, Richmond, VA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Chalfant
authors.affiliation: Department of Physiology Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.affiliation: Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. Electronic address: dimitrios-karamichos@ouhsc.edu.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Karamichos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism*; D024061:Collagen Type III / Q000378:metabolism; D003316:Corneal Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D003319:Corneal Stroma / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D006801:Humans; D008055:Lipids / Q000032:analysis*; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome / Q000502:physiology*; D008875:Middle Aged; D013110:Sphingosine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024061:Collagen Type III; D008055:Lipids; D013110:Sphingosine
keywords: Cellular metabolism; Corneal fibrosis; Diabetes mellitus; Kynurenine; Lipidomics