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

Abstract

Diabetic retinopathy (DR) is a universal microvascular complication of diabetes mellitus (DM), which is the main reason for global sight damage/loss in middle-aged and/or older people. Current clinical analyses, like hemoglobin A1c, possess some importance as prognostic indicators for DR severity, but no effective circulating biomarkers are used for DR in the clinic currently, and studies on the latent pathophysiology remain lacking. Recent developments in omics, especially metabolomics, continue to disclose novel potential biomarkers in several fields, including but not limited to DR. Therefore, based on the overview of metabolomics, we reviewed progress in analytical technology of metabolomics, the prominent roles and the current status of biomarkers in DR, and the update of potential biomarkers in various DR-related samples via metabolomics, including tear as well as vitreous humor, aqueous humor, retina, plasma, serum, cerebrospinal fluid, urine, and feces. In this review, we underscored the in-depth analysis and elucidation of the common biomarkers in different biological samples based on integrated results, namely, alanine, lactate, and glutamine. Alanine may participate in and regulate glucose metabolism through stimulating N-methyl-D-aspartate receptors and subsequently suppressing insulin secretion, which is the potential pathogenesis of DR. Abnormal lactate could cause extensive oxidative stress and neuroinflammation, eventually leading to retinal hypoxia and metabolic dysfunction; on the other hand, high-level lactate may damage the structure and function of the retinal endothelial cell barrier via the G protein-coupled receptor 81. Abnormal glutamine indicates a disturbance of glutamate recycling, which may affect the activation of Müller cells and proliferation via the PPP1CA-YAP-GS-Gln-mTORC1 pathway.

Keywords: alanine; biomarker; diabetic retinopathy; glutamine; lactate; metabolomics; pathogenesis.

Figure 1

Metabolomic workflow.

Figure 2

Comparison of targeted and untargeted metabolomics and the main applications of metabolomics. Metabolomics has been applied in a spectrum of fields.

Figure 3

Discovery, ideal feature, and utility of biomarkers for DR. (1) discovery of biomarkers with various technologies; (2) Ideal characteristics of the biomarkers for DR; (3) an example of the utility of biomarkers for DR.

Figure 4

The application of metabolomics in DR. (1) disease diagnosis and sample collection; (2) metabolomic workflow; (3) summary of the main roles of metabolomics in DR; arrows indicate the next step or promotion.

Figure 5

Annual publication trend of metabolomic studies in diabetic retinopathy. Eighty-seven relevant articles were obtained by searching the Web of Science and PubMed before 30 April 2022, with search terms: “diabetic retinopathy” AND (“metabolomics” or “metabonomics” or “metabolic profiling” or “metabolome”).

Figure 6

Representative of altered metabolites in various biological samples with DR. (1) representative of changed metabolites in retina, vitreous humor, and aqueous humor; (2) representative of altered metabolites in plasma and serum; (3) representative of altered metabolites in cerebrospinal fluid, urine, and feces.

Figure 7

Venn diagram of common biomarkers in various biological samples. Common biomarkers of DR in various biological samples, but retina that is not applicable in clinic, were analyzed by Venn diagram.

Figure 8

Schematic diagram depicting the metabolic alterations in early DR. Chronic hyperglycemia leads to a series of altered metabolism, the glucose metabolism most affected, causing abnormal levels of pyruvate and lactate, which results in extensive oxidative stress, and finally damaging the retina.

Figure 9

The mechanism diagram of glutamine in the Müller cell. In Müller cells, high glucose leads to an elevated level of glutamine through the PPP1CA–YAP–GS–Gln–mTORC1 pathway, subsequently activating cells and proliferating.

Figure 10

Venn diagram of common pathways in various biological samples. Common changed pathways of DR in various biological samples, but retina is excluded, were analyzed by Venn diagram.

Figure 11

Schematic diagram of the relationship between the arginine–proline metabolism pathway and DR. In the retina, arginine is metabolized through two distinct pathways. The diabetic status could cause increased proline to damage the retinal pigment epithelium (RPE) and induce cellular proliferation and fibrosis. Meanwhile, hyperglycemia may lead to a deficiency of NO and result in consequential endothelial cell dysfunction, impaired vasodilation, and an increased level of oxygen and nitrogen reactive species.