Vitreous metabolomics profiling of proliferative diabetic retinopathy

• Published in: Diabetologia Vol. 64; no. 1; pp. 70 - 82
• Main Authors: Tomita, Yohei, Cagnone, Gael, Fu, Zhongjie, Cakir, Bertan, Kotoda, Yumi, Asakage, Masaki, Wakabayashi, Yoshihiro, Hellström, Ann, Joyal, Jean-Sébastien, Talukdar, Saswata, Smith, Lois E. H., Usui, Yoshihiko
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2021; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Allantoin; Amino Acids - analysis; angiogenesis; Animals; anti-vegf; Chromatography, High Pressure Liquid; Creatine; Creatine - administration & dosage; Creatine - analysis; Diabetes; Diabetes mellitus; Diabetic retinopathy; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - physiopathology; Dietary supplements; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; High-performance liquid chromatography; Human Physiology; Humans; Internal Medicine; Lactic acid; Male; Mass Spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolites; Metabolomics; Mice; Mice, Inbred C57BL; Middle Aged; mouse; Oftalmologi; Ophthalmology; Oxygen-induced retinopathy; pdgf-cc; Proliferative; Proline; Pyruvic acid; quantification; Retina; Retinal neovascularisation; Retinal Neovascularization - metabolism; Retinopathy; reveals; Vitreous Body - chemistry; Vitreous Body - metabolism; Metabolomics; Creatine; Proliferative diabetic retinopathy; Oxygen-induced retinopathy; Retinal neovascularisation
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-020-05309-y

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. Graphical abstract