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.

Clinical Metabolomics and Glaucoma

“…Analyses have been performed on tear fluid [23,[29][30][31][32] , aqueous humor [24,25,33,34] , vitreous humor [20,26,27,35,36] , cornea [37][38][39] , conjunctiva [40] , and lens [41,42] samples.…”

Unravelling the stromal-nerve interactions in the human diabetic cornea

“…In our previous study we have already reported severe structural mitochondrial dysfunction in T1DM and T2DM constructs when compared to healthy controls(Priyadarsini et al, 2016a,b). In this study our goal was to further delineate the mitochondrial damage at the basal cellular level and assess the length at which the mitochondria gets affected when neurons are present.…”

“…(Schultz et al, 1981; Schultz et al, 1983; Priyadarsini et al, 2016a,b). Prevalence of DM has increased over the years and is expected to affect over 500 million people worldwide by 2030(Priyadarsini et al, 2016a,b). DM presents with a significantly high clinical burden with major ramifications on the quality of life.…”

“…Several complications associated with DM can lead to severe loss of visual acuity or even blindness. DM is also associated with several structural and functional alterations of the human cornea, such as corneal epithelial changes, morphological changes to the corneal nerves, decreased endothelial cell density, reduced corneal sensitivity and altered central corneal thickness (Schultz et al, 1981; Schultz et al, 1983; Herse, 1988; Rosenberg et al, 2000; Bardsley and Want, 2004; Rother, 2007; Skarbez et al, 2010; Priyadarsini et al, 2016a,b). …”

Examination of Kynurenine Toxicity on Corneal and Conjunctival Epithelium: In vitro and in vivo Studies

“…Anti-scarring properties of KYN were also demonstrated in a fibrotic rabbit skin ear wound model in vivo [36]. On the other hand, it was suggested that the upregulation of the KYN pathway, independent of glucose metabolism, may play an important role in the progression of diabetes-induced fibrosis in the corneal stroma and may contribute to corneal scarring and delayed wound healing [43]. …”