TY - JOUR
T1 - Vitreous metabolomics profiling of proliferative diabetic retinopathy
AU - Tomita, Yohei
AU - Cagnone, Gael
AU - Fu, Zhongjie
AU - Cakir, Bertan
AU - Kotoda, Yumi
AU - Asakage, Masaki
AU - Wakabayashi, Yoshihiro
AU - Hellström, Ann
AU - Joyal, Jean Sébastien
AU - Talukdar, Saswata
AU - Smith, Lois E.H.
AU - Usui, Yoshihiko
N1 - Funding Information:
Thanks to the NYU Metabolomics Core Resource Laboratory, New York, NY, USA for metabolome analysis for mice. ST is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Kenilworth, NJ, USA, and a stockholder in Merck & Co., Kenilworth, NJ, USA. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
Funding Information:
The work was supported by grants from the Manpei Suzuki Diabetic Foundation and Alcon Research Institute (YT); the Vision Health Research Network for its contribution to the Montreal Single-Cell Academy (GC); Boston Children's Hospital Manton Center for Orphan Disease Research, OFD/BTREC/CTREC Faculty Career Development Grant, and Ophthalmology Foundation, Little Giraffe Foundation, Mass Lions Eye Foundation (ZF); the German Research Foundation (DFG; to BC [CA1940/1-1]); the Wallenberg Clinical Scholars (AH); the Burroughs Wellcome Fund Career Award for Medical Scientists; the Foundation Fighting Blindness; the Canadian Institute of Health Research (CIHR; 390615); the Fonds de Recherche du Québec–Santé (FRQS); the Canadian Child Health Clinician Scientist Program; a CIHR New Investigator Award; the Natural Sciences and Engineering Research Council of Canada (NSERC: RGPIN-2016-06743) (J-SJ); NIH R24EY024868, EY017017, R01EY01717-13S1 and EY030904-01; the BCH IDDRC (1U54HD090255); Massachusetts Lions Eye Foundation (LEHS); and Grants-in-Aid for Scientific Research (C) 16K11330 and 19K09959 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (YU). Acknowledgements Authors’ relationships and activities
Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/1
Y1 - 2021/1
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
KW - Creatine
KW - Metabolomics
KW - Oxygen-induced retinopathy
KW - Proliferative diabetic retinopathy
KW - Retinal neovascularisation
UR - http://www.scopus.com/inward/record.url?scp=85093674733&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85093674733&partnerID=8YFLogxK
U2 - 10.1007/s00125-020-05309-y
DO - 10.1007/s00125-020-05309-y
M3 - Article
C2 - 33099660
AN - SCOPUS:85093674733
SN - 0012-186X
VL - 64
SP - 70
EP - 82
JO - Diabetologia
JF - Diabetologia
IS - 1
ER -
