Vitreous metabolomics profiling of proliferative diabetic retinopathy

Abstract

Aims/hypothesis Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR. Methods We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration. Results We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024). Conclusions/interpretation These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR.

Investigation the effects of vitreous humor on proliferation and dedifferentiation of differentiated NTERA2 cells

“…The dimethylarginine dimethylaminohydrolase (DDAH), gamma-enolase, cytosolic acyl coenzyme A thioester hydrolase and malate dehydrogenase are cellular enzymes, and their levels are all changes in the vitreous of condition, also DDAH is an extremely oxidant-sensitive enzyme. The different expression levels of cytosolic acyl coenzyme A thioester hydrolase and malate dehydrogenase in the VH could reflect the alterations in glucose and lipid metabolism (Tomita et al, 2021). Our data here are also in line with these reports, where treatment of the normal NT2 cells showed an obvious increase in the rate of proliferation.…”

Updates on the Current Treatments for Diabetic Retinopathy and Possibility of Future Oral Therapy

“…Haines et al demonstrated that the purine-related pathways were activated, and pyruvate levels increased in PDR patients [62]. Furthermore, our group showed that glycine levels increased, and creatine levels decreased in the vitreous humor of PDR patients [63]. Although research from new angles is underway, the pathophysiology of PDR has not yet been elucidated.…”

Identification of Metabolic Pathway Dysregulation in Diabetic Retinopathy: A Propensity Score-Matched Metabolomic Study

“…According to Rajala et al (30), serine and glycine residues can stabilize the Warburg-like effect by enriching the photoreceptor protein rhodopsin, which is closely associated with the phosphorylation of pyruvate kinase M2. The decrease in creatine is also reported to be linked to vascular proliferation, and supplementing creatine may be helpful to suppress retinal neovascularization in DR (11). Furthermore, the levels of L-cysteine and glutamate (glutamic acid) are also evidently increased in DR patients.…”