High-Coverage Serum Metabolomics Reveals Metabolic Pathway Dysregulation in Diabetic Retinopathy: A Propensity Score-Matched Study

Abstract

Background: Diabetic retinopathy (DR) is a major diabetes-related disease linked to metabolism. However, the cognition of metabolic pathway alterations in DR remains scarce. We aimed to corroborate alterations of metabolic pathways identified in prior studies and investigate novel metabolic dysregulations that may lead to new prevention and treatment strategies for DR.Methods: In this case-control study, we tested 613 serum metabolites in 69 pairs of type 2 diabetic patients (T2DM) with DR and propensity score-matched T2DM without DR via ultra-performance liquid chromatography-tandem mass spectrometry system. Metabolic pathway dysregulation in DR was thoroughly investigated by metabolic pathway analysis, chemical similarity enrichment analysis (ChemRICH), and integrated pathway analysis. The associations of ChemRICH-screened key metabolites with DR were further estimated with restricted cubic spline analyses.Results: A total of 89 differentially expressed metabolites were identified by paired univariate analysis and partial least squares discriminant analysis. We corroborated biosynthesis of unsaturated fatty acids, glycine, serine and threonine metabolism, glutamate and cysteine-related pathways, and nucleotide-related pathways were significantly perturbed in DR, which were identified in prior studies. We also found some novel metabolic alterations associated with DR, including the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives in DR.Conclusions: The results suggest that the metabolism disorder in DR can be better understood through integrating multiple biological knowledge databases. The progression of DR is associated with the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives.

Metabolomic comparison followed by cross-validation of enzyme-linked immunosorbent assay to reveal potential biomarkers of diabetic retinopathy in Chinese with type 2 diabetes

“…In 2022, Guo et al. observed that compared with T2DM samples, the serum level of IAA in DR samples was significantly higher ( 34 ), which was consistent with our results of targeted and untargeted metabolomics. Through targeted metabolomics, we found that serum IAA levels in both NPDR and DR groups were significantly higher than those in T2DM group (AUC = 0.867, Figure 6B and AUC = 0.767, Figure 6C ), and our previous untargeted metabolomics studies also observed higher serum IAA level in DR group than T2DM group.…”

Metabolomics of various samples advancing biomarker discovery and pathogenesis elucidation for diabetic retinopathy

“…According to the separate validation set, a panel of biomarkers consisting of phenylacetyl glutamine, nicotinuric acid, linoleic acid, and ornithine were developed to efficiently distinguish DR from T2DM. Recently, 613 serum metabolites (T2DM and DR), another similar case-control study conducted by Guo et al., were tested via UPLC-MS ( 87 ). They found a total of 89 featured metabolites by multiple statistical analyses, of which some new metabolic changes related to DR were identified, i.e., enhanced choline and indole derivatives, attenuated trehalose, etc.…”

Recent Advances and Perspectives in Relation to the Metabolomics-Based Study of Diabetic Retinopathy

“…This multidimensional network biomarkers system may present the most effective means for identifying DR [61]. New DR-related metabolic changes, such as thiamine metabolic disorders, reduced trehalose, and increased choline and indole derivatives, were also revealed in another similar case-control study [62]. In order to gain further insights into the metabolic changes from T2DM to DR, Wang et al conducted comparative analyses of metabolic profiles across various stages, including NPDR and T2DM patients, PDR and T2DM patients, as well as DR and non-DR patients.…”