TY - JOUR
T1 - Complete metabolome and lipidome analysis reveals novel biomarkers in the human diabetic corneal stroma
AU - Priyadarsini, Shrestha
AU - McKay, Tina B.
AU - Sarker-Nag, Akhee
AU - Allegood, Jeremy
AU - Chalfant, Charles
AU - Ma, Jian Xing
AU - Karamichos, Dimitrios
N1 - Funding Information:
This work was supported by the National Institutes of Health Grants 5R01EY023568 (DK), 5R01EY020886 (DK) and T32EY023202 . We acknowledge the support of the NEI/DMEI Cellular Imaging Core Facility at OUHSC ( P30EY021725 ), an unrestricted grant (DMEI) from Research to Prevent Blindness (New York, NY USA). The authors thank Dr John M Asara Min Yuan and Susanne Breitkopf of Harvard Medical School for technical help with metabolomics experiments. We would also like to acknowledge the research grants from the Veteran's Administration (VA Merit Review I BX001792 (CEC) and a Research Career Scientist Award 13F-RCS-002 (CEC): from the National Institutes of Health via HL125353 (CEC), CA154314 (CEC). In support of the research project, all the services and products were generated by the VCU Massey Cancer Center Shared supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059 . The manuscript contents do not represents the views of the Department of Veterans Affairs or the United States Government.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - Cellular metabolism
KW - Corneal fibrosis
KW - Diabetes mellitus
KW - Kynurenine
KW - Lipidomics
UR - http://www.scopus.com/inward/record.url?scp=84992058732&partnerID=8YFLogxK
U2 - 10.1016/j.exer.2016.10.010
DO - 10.1016/j.exer.2016.10.010
M3 - Article
C2 - 27742548
AN - SCOPUS:84992058732
VL - 153
SP - 90
EP - 100
JO - Experimental Eye Research
JF - Experimental Eye Research
SN - 0014-4835
ER -