Research progress of metabolomics in diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Qingbo ,  Shao Yan

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Shao Yan, Email: sytmueh@163.com

Keywords：

Diabetic retinopathy; Metabolomics; Metabolites; Review

DOI：

10.3760/cma.j.cn511434-20211124-00655

Video：

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Abstract Full text Figures/Tables Video References Cited by

Diabetic retinopathy (DR) is one of the microvascular complications of diabetes mellitus causing severe visual impairment, and it is the main cause of blindness in adults. Metabolic abnormalities play an important role in the occurrence and development of DR, including the abnormal levels of glucose metabolism, lipid metabolism, amino acid metabolism and purine metabolism, which indicate that there are disorders of phosphopentose pathway, arginine metabolism pathway, polyol pathway and ascorbic acid pathway in the progression of DR. Metabolomics has great advantages in exploring the pathogenesis and diagnosis of DR, helping to identify the characteristic metabolic changes of DR And discover potential biomarkers. However, the existing metabolomics studies on DR have some limitations, such as the potential biomarkers found in some studies are difficult to verify in other studies due to differences in race, age, gender and sample size. There are few studies on biomarkers at different stages of DR. Therefore, in the future, multi-center and large-scale clinical studies are needed to screen out biomarkers with practical clinical diagnostic value.

Citation： Li Qingbo, Shao Yan. Research progress of metabolomics in diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2023, 39(6): 510-514. doi: 10.3760/cma.j.cn511434-20211124-00655 Copy

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2.	Wong TY, Cheung CM, Larsen M, et al. Diabetic retinopathy[J]. Nat Rev Dis Primers, 2016, 2: 16012. DOI: 10.1038/nrdp.2016.12.
3.	Funatsu H, Yamashita H, Noma H, et al. Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients[J]. Graefe’s Arch Clin Exp Ophthalmol, 2005, 243(1): 3-8. DOI: 10.1007/s00417-004-0950-7.
4.	Liew G, Lei Z, Tan G, et al. Metabolomics of diabetic retinopathy[J]. Curr Diab Rep, 2017, 17(11): 102. DOI: 10.1007/s11892-017-0939-3.
5.	Lu J, Lam SM, Wan Q, et al. High-coverage targeted lipidomics reveals novel serum lipid predictors and lipid pathway dysregulation antecedent to type 2 diabetes onset in normoglycemic chinese adults[J]. Diabetes Care, 2019, 42(11): 2117-2126. DOI: 10.2337/dc19-0100.
6.	Razquin C, Toledo E, Clish CB, et al. Plasma lipidomic profiling and risk of type 2 diabetes in the predimed trial[J]. Diabetes Care, 2018, 41(12): 2617-2624. DOI: 10.2337/dc18-0840.
7.	Niewczas MA, Mathew AV, Croall S, et al. Circulating modified metabolites and a risk of ESRD in patients with type 1 diabetes and chronic kidney disease[J]. Diabetes Care, 2017, 40(3): 383-390. DOI: 10.2337/dc16-0173.
8.	Tamhane M, Cabrera-Ghayouri S, Abelian G, et al. Review of biomarkers in ocular matrices: challenges and opportunities[J]. Pharm Res, 2019, 36(3): 40. DOI: 10.1007/s11095-019-2569-8.
9.	Dunn WB, Broadhurst DI, Atherton HJ, et al. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy[J]. Chem Soc Rev, 2011, 40(1): 387-426. DOI: 10.1039/b906712b.
10.	Filla LA, Edwards JL. Metabolomics in diabetic complications[J]. Mol Biosyst, 2016, 12(4): 1090-1105. DOI: 10.1039/c6mb00014b.
11.	Wishart DS, Feunang YD, Marcu A, et al. HMDB 4.0: the human metabolome database for 2018[J]. Nucleic Acids Res, 2018, 46(D1): D608-D617. DOI: 10.1093/nar/gkx1089.
12.	Xuan Q, Ouyang Y, Wang Y, et al. Multiplatform metabolomics reveals novel serum metabolite biomarkers in diabetic retinopathy subjects [J/OL]. Adv Sci (Weinh), 2020, 7(22): 2001714[2020-10-01]. https://europepmc.org/article/MED/33240754. DOI: 10.1002/advs.202001714.
13.	Chen L, Cheng CY, Choi H, et al. Plasma metabonomic profiling of diabetic retinopathy[J]. Diabetes, 2016, 65(4): 1099-1108. DOI: 10.2337/db15-0661.
14.	Barba I, Garcia-Ramírez M, Hernández C, et al. Metabolic fingerprints of proliferative diabetic retinopathy: an 1H-NMR-based metabonomic approach using vitreous humor[J]. Invest Ophthalmol Vis Sci, 2010, 51(9): 4416-4421. DOI: 10.1167/iovs.10-5348.
15.	Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy[J]. Faseb J, 2004, 18(12): 1450-1452. DOI: 10.1096/fj.03-1476fje.
16.	Lorenzi M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient [J/OL]. Exp Diabetes Res, 2007, 2007: 61038[2007-01-01]. https://europepmc.org/article/MED/18224243. DOI: 10.1155/2007/61038.
17.	Jin H, Zhu B, Liu X, et al. Metabolic characterization of diabetic retinopathy: an (1)H-NMR-based metabolomic approach using human aqueous humor[J]. J Pharm Biomed Anal, 2019, 174: 414-421. DOI: 10.1016/j.jpba.2019.06.013.
18.	Gladden LB. Lactate metabolism: a new paradigm for the third millennium [J]. J Physiol, 2004, 558(Pt 1): 5-30. DOI: 10.1113/jphysiol.2003.058701.
19.	Trudeau K, Molina AJ, Roy S. High glucose induces mitochondrial morphology and metabolic changes in retinal pericytes[J]. Invest Ophthalmol Vis Sci, 2011, 52(12): 8657-8664. DOI: 10.1167/iovs.11-7934.
20.	Matsumoto M, Suzuma K, Maki T, et al. Succinate increases in the vitreous fluid of patients with active proliferative diabetic retinopathy[J]. Am J Ophthalmol, 2012, 153(5): 896-902. DOI: 10.1016/j.ajo.2011.10.006.
21.	Yun JH, Kim JM, Jeon HJ, et al. Metabolomics profiles associated with diabetic retinopathy in type 2 diabetes patients [J/OL]. PLoS One, 2020, 15(10): e0241365[2020-10-29]. https://europepmc.org/article/MED/33119699. DOI: 10.1371/journal.pone.0241365.
22.	Curovic VR, Suvitaival T, Mattila I, et al. Circulating metabolites and lipids are associated to diabetic retinopathy in individuals with type 1 diabetes[J]. Diabetes, 2020, 69(10): 2217-2226. DOI: 10.2337/db20-0104.
23.	Mitchell SL, Uppal K, Williamson SM, et al. The carnitine shuttle pathway is altered in patients with neovascular age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2018, 59(12): 4978-4985. DOI: 10.1167/iovs.18-25137.
24.	Sumarriva K, Uppal K, Ma C, et al. Arginine and carnitine metabolites are altered in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2019, 60(8): 3119-3126. DOI: 10.1167/iovs.19-27321.
25.	Poorabbas A, Fallah F, Bagdadchi J, et al. Determination of free L-carnitine levels in type Ⅱ diabetic women with and without complications[J]. Eur J Clin Nutr, 2007, 61(7): 892-895. DOI: 10.1038/sj.ejcn.1602594.
26.	Tamamoğullari N, Siliğ Y, Içağasioğlu S, et al. Carnitine deficiency in diabetes mellitus complications[J]. J Diabetes Complications, 1999, 13(5-6): 251-253. DOI: 10.1016/s1056-8727(99)00052-5.
27.	Liepinsh E, Skapare E, Vavers E, et al. High L-carnitine concentrations do not prevent late diabetic complications in type 1 and 2 diabetic patients[J]. Nutr Res, 2012, 32(5): 320-327. DOI: 10.1016/j.nutres.2012.03.010.
28.	Paris LP, Johnson CH, Aguilar E, et al. Global metabolomics reveals metabolic dysregulation in ischemic retinopathy[J]. Metabolomics, 2016, 12: 15. DOI: 10.1007/s11306-015-0877-5.
29.	Sas KM, Lin J, Rajendiran TM, et al. Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model[J]. J Lipid Res, 2018, 59(2): 173-183. DOI: 10.1194/jlr.M077222.
30.	Tikhonenko M, Lydic TA, Wang Y, et al. Remodeling of retinal fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4[J]. Diabetes, 2010, 59(1): 219-227. DOI: 10.2337/db09-0728.
31.	Peters KS, Rivera E, Warden C, et al. Plasma arginine and citrulline are elevated in diabetic retinopathy[J]. Am J Ophthalmol, 2021, 235: 154-162. DOI: 10.1016/j.ajo.2021.09.021.
32.	Lin HT, Cheng ML, Lo CJ, et al. ¹H nuclear magnetic resonance (NMR)-based cerebrospinal fluid and plasma metabolomic analysis in type 2 diabetic patients and risk prediction for diabetic microangiopathy[J]. J Clin Med, 2019, 8(6): 874. DOI: 10.3390/jcm8060874.
33.	Narayanan SP, Rojas M, Suwanpradid J, et al. Arginase in retinopathy[J]. Prog Retin Eye Res, 2013, 36: 260-280. DOI: 10.1016/j.preteyeres.2013.06.002.
34.	Haines NR, Manoharan N, Olson JL, et al. Metabolomics analysis of human vitreous in diabetic retinopathy and rhegmatogenous retinal detachment[J]. J Proteome Res, 2018, 17(7): 2421-2427. DOI: 10.1021/acs.jproteome.8b00169.
35.	Nyengaard JR, Ido Y, Kilo C, et al. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy[J]. Diabetes, 2004, 53(11): 2931-2938. DOI: 10.2337/diabetes.53.11.2931.
36.	Zhu SS, Ren Y, Zhang M, et al. Wld(S) protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice[J]. Diabetologia, 2011, 54(9): 2440-2450. DOI: 10.1007/s00125-011-2226-1.
37.	Böger RH, Bode-Böger SM. Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases[J]. Semin Thromb Hemost, 2000, 26(5): 539-545. DOI: 10.1055/s-2000-13210.
38.	Sydow K, Münzel T. ADMA and oxidative stress[J]. Atheroscler Suppl, 2003, 4(4): 41-51. DOI: 10.1016/s1567-5688(03)00033-3.
39.	Landaas S. The formation of 2-hydroxybutyric acid in experimental animals[J]. Clin Chim Acta, 1975, 58(1): 23-32. DOI: 10.1016/0009-8981(75)90481-7.
40.	Ola MS, Alhomida AS, LaNoue KF. Gabapentin attenuates oxidative stress and apoptosis in the diabetic rat retina[J]. Neurotox Res, 2019, 36(1): 81-90. DOI: 10.1007/s12640-019-00018-w.
41.	Kowluru RA, Engerman RL, Case GL, et al. Retinal glutamate in diabetes and effect of antioxidants[J]. Neurochem Int, 2001, 38(5): 385-390. DOI: 10.1016/s0197-0186(00)00112-1.
42.	Patel C, Rojas M, Narayanan SP, et al. Arginase as a mediator of diabetic retinopathy[J]. Front Immunol, 2013, 4: 173. DOI: 10.3389/fimmu.2013.00173.
43.	May JM. Ascorbic acid repletion: a possible therapy for diabetic macular edema?[J]. Free Radic Biol Med, 2016, 94: 47-54. DOI: 10.1016/j.freeradbiomed.2016.02.019.
44.	Dunn WB, Broadhurst D, Begley P, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry[J]. Nat Protoc, 2011, 6(7): 1060-1083. DOI: 10.1038/nprot.2011.335.
45.	Brownlee M. The pathobiology of diabetic complications: a unifying mechanism[J]. Diabetes, 2005, 54(6): 1615-1625. DOI: 10.2337/diabetes.54.6.1615.
46.	Lauwen S, de Jong EK, Lefeber DJ, et al. Omics biomarkers in ophthalmology[J]. Invest Ophthalmol Vis Sci, 2017, 58(6): Bio88-Bio98. DOI: 10.1167/iovs.17-21809.
47.	Cabral T, Lima LH, Polido J, et al. Aqueous vascular endothelial growth factor and clinical outcomes correlation after single intravitreal injection of bevacizumab in patients with neovascular age-related macular degeneration[J]. Int J Retina Vitreous, 2017, 3: 6. DOI: 10.1186/s40942-017-0066-y.
48.	Maurice DM. Flow of water between aqueous and vitreous compartments in the rabbit eye [J]. Am J Physiol, 1987, 252(1 Pt 2): F104-108. DOI: 10.1152/ajprenal.1987.252.1.F104.
49.	Trivedi D, Denniston AK, Murray PI. Safety profile of anterior chamber paracentesis performed at the slit lamp[J]. Clin Exp Ophthalmol, 2011, 39(8): 725-728. DOI: 10.1111/j.1442-9071.2011.02565.x.
50.	Lam DS, Chua JK, Tham CC, et al. Efficacy and safety of immediate anterior chamber paracentesis in the treatment of acute primary angle-closure glaucoma: a pilot study[J]. Ophthalmology, 2002, 109(1): 64-70. DOI: 10.1016/s0161-6420(01)00857-0.

1. Arneth B, Arneth R, Shams M. Metabolomics of type 1 and type 2 diabetes[J]. Int J Mol Sci, 2019, 20(10): 2467. DOI: 10.3390/ijms20102467.
2. Wong TY, Cheung CM, Larsen M, et al. Diabetic retinopathy[J]. Nat Rev Dis Primers, 2016, 2: 16012. DOI: 10.1038/nrdp.2016.12.
3. Funatsu H, Yamashita H, Noma H, et al. Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients[J]. Graefe’s Arch Clin Exp Ophthalmol, 2005, 243(1): 3-8. DOI: 10.1007/s00417-004-0950-7.
4. Liew G, Lei Z, Tan G, et al. Metabolomics of diabetic retinopathy[J]. Curr Diab Rep, 2017, 17(11): 102. DOI: 10.1007/s11892-017-0939-3.
5. Lu J, Lam SM, Wan Q, et al. High-coverage targeted lipidomics reveals novel serum lipid predictors and lipid pathway dysregulation antecedent to type 2 diabetes onset in normoglycemic chinese adults[J]. Diabetes Care, 2019, 42(11): 2117-2126. DOI: 10.2337/dc19-0100.
6. Razquin C, Toledo E, Clish CB, et al. Plasma lipidomic profiling and risk of type 2 diabetes in the predimed trial[J]. Diabetes Care, 2018, 41(12): 2617-2624. DOI: 10.2337/dc18-0840.
7. Niewczas MA, Mathew AV, Croall S, et al. Circulating modified metabolites and a risk of ESRD in patients with type 1 diabetes and chronic kidney disease[J]. Diabetes Care, 2017, 40(3): 383-390. DOI: 10.2337/dc16-0173.
8. Tamhane M, Cabrera-Ghayouri S, Abelian G, et al. Review of biomarkers in ocular matrices: challenges and opportunities[J]. Pharm Res, 2019, 36(3): 40. DOI: 10.1007/s11095-019-2569-8.
9. Dunn WB, Broadhurst DI, Atherton HJ, et al. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy[J]. Chem Soc Rev, 2011, 40(1): 387-426. DOI: 10.1039/b906712b.
10. Filla LA, Edwards JL. Metabolomics in diabetic complications[J]. Mol Biosyst, 2016, 12(4): 1090-1105. DOI: 10.1039/c6mb00014b.
11. Wishart DS, Feunang YD, Marcu A, et al. HMDB 4.0: the human metabolome database for 2018[J]. Nucleic Acids Res, 2018, 46(D1): D608-D617. DOI: 10.1093/nar/gkx1089.
12. Xuan Q, Ouyang Y, Wang Y, et al. Multiplatform metabolomics reveals novel serum metabolite biomarkers in diabetic retinopathy subjects [J/OL]. Adv Sci (Weinh), 2020, 7(22): 2001714[2020-10-01]. https://europepmc.org/article/MED/33240754. DOI: 10.1002/advs.202001714.
13. Chen L, Cheng CY, Choi H, et al. Plasma metabonomic profiling of diabetic retinopathy[J]. Diabetes, 2016, 65(4): 1099-1108. DOI: 10.2337/db15-0661.
14. Barba I, Garcia-Ramírez M, Hernández C, et al. Metabolic fingerprints of proliferative diabetic retinopathy: an 1H-NMR-based metabonomic approach using vitreous humor[J]. Invest Ophthalmol Vis Sci, 2010, 51(9): 4416-4421. DOI: 10.1167/iovs.10-5348.
15. Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy[J]. Faseb J, 2004, 18(12): 1450-1452. DOI: 10.1096/fj.03-1476fje.
16. Lorenzi M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient [J/OL]. Exp Diabetes Res, 2007, 2007: 61038[2007-01-01]. https://europepmc.org/article/MED/18224243. DOI: 10.1155/2007/61038.
17. Jin H, Zhu B, Liu X, et al. Metabolic characterization of diabetic retinopathy: an (1)H-NMR-based metabolomic approach using human aqueous humor[J]. J Pharm Biomed Anal, 2019, 174: 414-421. DOI: 10.1016/j.jpba.2019.06.013.
18. Gladden LB. Lactate metabolism: a new paradigm for the third millennium [J]. J Physiol, 2004, 558(Pt 1): 5-30. DOI: 10.1113/jphysiol.2003.058701.
19. Trudeau K, Molina AJ, Roy S. High glucose induces mitochondrial morphology and metabolic changes in retinal pericytes[J]. Invest Ophthalmol Vis Sci, 2011, 52(12): 8657-8664. DOI: 10.1167/iovs.11-7934.
20. Matsumoto M, Suzuma K, Maki T, et al. Succinate increases in the vitreous fluid of patients with active proliferative diabetic retinopathy[J]. Am J Ophthalmol, 2012, 153(5): 896-902. DOI: 10.1016/j.ajo.2011.10.006.
21. Yun JH, Kim JM, Jeon HJ, et al. Metabolomics profiles associated with diabetic retinopathy in type 2 diabetes patients [J/OL]. PLoS One, 2020, 15(10): e0241365[2020-10-29]. https://europepmc.org/article/MED/33119699. DOI: 10.1371/journal.pone.0241365.
22. Curovic VR, Suvitaival T, Mattila I, et al. Circulating metabolites and lipids are associated to diabetic retinopathy in individuals with type 1 diabetes[J]. Diabetes, 2020, 69(10): 2217-2226. DOI: 10.2337/db20-0104.
23. Mitchell SL, Uppal K, Williamson SM, et al. The carnitine shuttle pathway is altered in patients with neovascular age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2018, 59(12): 4978-4985. DOI: 10.1167/iovs.18-25137.
24. Sumarriva K, Uppal K, Ma C, et al. Arginine and carnitine metabolites are altered in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2019, 60(8): 3119-3126. DOI: 10.1167/iovs.19-27321.
25. Poorabbas A, Fallah F, Bagdadchi J, et al. Determination of free L-carnitine levels in type Ⅱ diabetic women with and without complications[J]. Eur J Clin Nutr, 2007, 61(7): 892-895. DOI: 10.1038/sj.ejcn.1602594.
26. Tamamoğullari N, Siliğ Y, Içağasioğlu S, et al. Carnitine deficiency in diabetes mellitus complications[J]. J Diabetes Complications, 1999, 13(5-6): 251-253. DOI: 10.1016/s1056-8727(99)00052-5.
27. Liepinsh E, Skapare E, Vavers E, et al. High L-carnitine concentrations do not prevent late diabetic complications in type 1 and 2 diabetic patients[J]. Nutr Res, 2012, 32(5): 320-327. DOI: 10.1016/j.nutres.2012.03.010.
28. Paris LP, Johnson CH, Aguilar E, et al. Global metabolomics reveals metabolic dysregulation in ischemic retinopathy[J]. Metabolomics, 2016, 12: 15. DOI: 10.1007/s11306-015-0877-5.
29. Sas KM, Lin J, Rajendiran TM, et al. Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model[J]. J Lipid Res, 2018, 59(2): 173-183. DOI: 10.1194/jlr.M077222.
30. Tikhonenko M, Lydic TA, Wang Y, et al. Remodeling of retinal fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4[J]. Diabetes, 2010, 59(1): 219-227. DOI: 10.2337/db09-0728.
31. Peters KS, Rivera E, Warden C, et al. Plasma arginine and citrulline are elevated in diabetic retinopathy[J]. Am J Ophthalmol, 2021, 235: 154-162. DOI: 10.1016/j.ajo.2021.09.021.
32. Lin HT, Cheng ML, Lo CJ, et al. ¹H nuclear magnetic resonance (NMR)-based cerebrospinal fluid and plasma metabolomic analysis in type 2 diabetic patients and risk prediction for diabetic microangiopathy[J]. J Clin Med, 2019, 8(6): 874. DOI: 10.3390/jcm8060874.
33. Narayanan SP, Rojas M, Suwanpradid J, et al. Arginase in retinopathy[J]. Prog Retin Eye Res, 2013, 36: 260-280. DOI: 10.1016/j.preteyeres.2013.06.002.
34. Haines NR, Manoharan N, Olson JL, et al. Metabolomics analysis of human vitreous in diabetic retinopathy and rhegmatogenous retinal detachment[J]. J Proteome Res, 2018, 17(7): 2421-2427. DOI: 10.1021/acs.jproteome.8b00169.
35. Nyengaard JR, Ido Y, Kilo C, et al. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy[J]. Diabetes, 2004, 53(11): 2931-2938. DOI: 10.2337/diabetes.53.11.2931.
36. Zhu SS, Ren Y, Zhang M, et al. Wld(S) protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice[J]. Diabetologia, 2011, 54(9): 2440-2450. DOI: 10.1007/s00125-011-2226-1.
37. Böger RH, Bode-Böger SM. Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases[J]. Semin Thromb Hemost, 2000, 26(5): 539-545. DOI: 10.1055/s-2000-13210.
38. Sydow K, Münzel T. ADMA and oxidative stress[J]. Atheroscler Suppl, 2003, 4(4): 41-51. DOI: 10.1016/s1567-5688(03)00033-3.
39. Landaas S. The formation of 2-hydroxybutyric acid in experimental animals[J]. Clin Chim Acta, 1975, 58(1): 23-32. DOI: 10.1016/0009-8981(75)90481-7.
40. Ola MS, Alhomida AS, LaNoue KF. Gabapentin attenuates oxidative stress and apoptosis in the diabetic rat retina[J]. Neurotox Res, 2019, 36(1): 81-90. DOI: 10.1007/s12640-019-00018-w.
41. Kowluru RA, Engerman RL, Case GL, et al. Retinal glutamate in diabetes and effect of antioxidants[J]. Neurochem Int, 2001, 38(5): 385-390. DOI: 10.1016/s0197-0186(00)00112-1.
42. Patel C, Rojas M, Narayanan SP, et al. Arginase as a mediator of diabetic retinopathy[J]. Front Immunol, 2013, 4: 173. DOI: 10.3389/fimmu.2013.00173.
43. May JM. Ascorbic acid repletion: a possible therapy for diabetic macular edema?[J]. Free Radic Biol Med, 2016, 94: 47-54. DOI: 10.1016/j.freeradbiomed.2016.02.019.
44. Dunn WB, Broadhurst D, Begley P, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry[J]. Nat Protoc, 2011, 6(7): 1060-1083. DOI: 10.1038/nprot.2011.335.
45. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism[J]. Diabetes, 2005, 54(6): 1615-1625. DOI: 10.2337/diabetes.54.6.1615.
46. Lauwen S, de Jong EK, Lefeber DJ, et al. Omics biomarkers in ophthalmology[J]. Invest Ophthalmol Vis Sci, 2017, 58(6): Bio88-Bio98. DOI: 10.1167/iovs.17-21809.
47. Cabral T, Lima LH, Polido J, et al. Aqueous vascular endothelial growth factor and clinical outcomes correlation after single intravitreal injection of bevacizumab in patients with neovascular age-related macular degeneration[J]. Int J Retina Vitreous, 2017, 3: 6. DOI: 10.1186/s40942-017-0066-y.
48. Maurice DM. Flow of water between aqueous and vitreous compartments in the rabbit eye [J]. Am J Physiol, 1987, 252(1 Pt 2): F104-108. DOI: 10.1152/ajprenal.1987.252.1.F104.
49. Trivedi D, Denniston AK, Murray PI. Safety profile of anterior chamber paracentesis performed at the slit lamp[J]. Clin Exp Ophthalmol, 2011, 39(8): 725-728. DOI: 10.1111/j.1442-9071.2011.02565.x.
50. Lam DS, Chua JK, Tham CC, et al. Efficacy and safety of immediate anterior chamber paracentesis in the treatment of acute primary angle-closure glaucoma: a pilot study[J]. Ophthalmology, 2002, 109(1): 64-70. DOI: 10.1016/s0161-6420(01)00857-0.

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