The synergistic effect of metformin and anti-vascular endothelial growth factor in the treatment of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Zhe , Liu Zhuqing , Liu Juping , Dong Lijie , Zhu Yimeng , Huang Liangyu , Su Ruihong , Zhang Xiaomin , Zhang Xiaomin ,  Li Xiaorong

Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, Tianjin Medical University School of Optometry and Ophthalmology, Tianjin 300384, China;

Corresponding author：

Li Xiaorong, Email: iiitc1989@163.com

Keywords：

Diabetic retinopathy/drug therapy; Metformin/therapeutic use; Angiogenesis inhibitors/therapeutic use; In vitro

DOI：

10.3760/cma.j.issn.1005-1015.2018.05.008

Video：

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Objective To observe the synergistic effect of metformin and anti-vascular endothelial growth factor (VEGF) in the treatment of diabetic retinopathy. Methods This study was composed of clinical data review and in vitro cell experiment. Ten patients (12 eyes) with diabetic macular edema treated with anti-VEGF drugs were included in the study. Patients were randomly divided into the VEGF group (anti-VEGF drug therapy) and the combined treatment group (anti-VEGF drug combined with metformin). The changes of visual acuity and central retinal thickness (CRT) were compared between the two groups. As far as the in vitro experiment was concerned, vascular endothelial cells were divided into the control group (normal cells), the VEGF group (50 ng/ml VEGF), the anti-VEGF group (50 ng/ml VEGF+2.5 μg/ml of conbercept), and the combined group (50 ng/ml VEGF +2.5 μg/ml of conbercept +2.0 mmol/L of metformin). And then MTT cell viability assay, scratch assay and real-time quantitative polymerase chain reaction assay were performed to analyze the cell viability, cell migration and mRNA level of VEGFR2, protein kinase C (PKC)-α and PKC-β successively. ResultsReview of clinical trial shows that the CRT recovery rates in the combined treatment group were much higher than that in the VEGF group at 3 month after the operation, while the difference was statistically significant (t=−2.462, P＜0.05). In vitro cell experiment results showed that VEGF induction upregulated the viability and mobility of vascular endothelial cells obviously compared with control group, at the same time, the use of anti VEGF drugs can effectively reverse the trend, in contrast, combination of metformin and anti-VEGF showed a more superior effect to some extent (P＜0.05). In the VEGF group, the mRNA expression of VEGFR2, PKC-αand PKC-β were significantly increased compared with the control group (P＜0.01); while the mRNA expression of VEGFR2, PKC-αand PKC-β in the combination group decreased significantly compared with the VEGF group and the control group (P＜0.05). However, in the anti-VEGF group, the mRNA expression of VEGFR2, PKC-αand PKC-β were decreased, but has failed to reach the level of statistical learn the difference. ConclusionsThe combination of metformin and anti-VEGF drugs can reduce the CRT of diabetic retinopathy patients and inhibit the proliferation and migration of retinal vascular endothelial cells which induced by VEGF. The synergistic mechanism may be related to the inhibitory effect of metformin on the expression of VEGFR and PKC.

Citation： Zhang Zhe, Liu Zhuqing, Liu Juping, Dong Lijie, Zhu Yimeng, Huang Liangyu, Su Ruihong, Zhang Xiaomin, Zhang Xiaomin, Li Xiaorong. The synergistic effect of metformin and anti-vascular endothelial growth factor in the treatment of diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2018, 34(5): 453-457. doi: 10.3760/cma.j.issn.1005-1015.2018.05.008 Copy

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9.	PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial[J]. Arch Ophthalmol, 2007, 125(3): 318-324. DOI: 10.1001/archopht.125.3.318.
10.	Giacco F, Brownlee M. Oxidative stress and diabetic complications[J]. Circ Res, 2010, 107(9): 1058-1070. DOI: 10.1161/CIRCRESAHA.110.223545.
11.	Vinores SA, Van Niel E, Swerdloff JL, et al. Electron microscopic immunocytochemical evidence for the mechanism of blood-retinal barrier breakdown in galactosemic rats and its association with aldose reductase expression and inhibition[J]. Exp Eye Res, 1993, 57(6): 723-735. DOI: 10.1006/exer.1993.1180.
12.	Duh EJ, Yang HS, Haller JA, et al. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: implications for ocular angiogenesis[J]. Am J Ophthalmol, 2004, 137(4): 668-674. DOI: 10.1016/j.ajo.2003.11.015.
13.	Funatsu H, Yamashita H, Ikeda T, et al. Angiotensin Ⅱ and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders[J]. Am J Ophthalmol, 2002, 133(4): 537-543.
14.	Gallo A, Ceolotto G, Pinton P, et al. Metformin prevents glucose-induced protein kinase C-beta2 activation in human umbilical vein endothelial cells through an antioxidant mechanism[J]. Diabetes, 2005, 54(4):1123-1131.
15.	Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1[J]. J Biol Chem, 1999, 274(33): 23463-23467.
16.	Miller JW, Le Couter J, Strauss EC, et al. Vascular endothelial growth factor a in intraocular vascular disease[J]. Ophthalmology, 2013,120(1): 106-114. DOI: 10.1016/j.ophtha.2012.07.038.
17.	Batchuluun B, Inoguchi T, Sonoda N, et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells[J]. Atherosclerosis, 2014,232(1): 156-164. DOI: 10.1016/j.atherosclerosis.2013.10.025.

1. Do DV, Nguyen QD, Khwaja AA, et al. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment[J]. JAMA Ophthalmol, 2013, 131(2):139-145. DOI: 10.1001/2013.jamaophthalmol.91.
2. Ji HT, Chien LT, Lin YH, et al. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase[J]. Mol Cancer Ther, 2010,9:91. DOI: 10.1186/1476-4598-9-91.
3. 中华医学会眼科学分会眼底病学组. 我国糖尿病视网膜病变临床诊疗指南(2014年)[J]. 中华眼科杂志, 2014, 50(11):851-865. DOI:10.3760/cam.j.issn.0412-4081.2014.11.014.Chinese Ocular Fundus Diseases Society, Chinese Ophthalmological Society, Chinese Medical Association. Clinical practice guidelines of diabetic retinopathy in China (2014)[J]. Chin J Ophthalmol, 2014,50(11):851-865. DOI:10.3760/cam.j.issn.0412-4081.2014.11.014.
4. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1[J]. Arch Ophthalmol, 1985, 127(2):1796-1806.
5. Yan SF, Ramasamy R, Naka Y, et al. Glycation, Inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond[J]. Circ Res, 2003, 93(12):1159-1169. DOI: 10.1161/01.RES.0000103862.26506.3D.
6. Yang Z, Kahn BB, Shi H, et al. Macrophage α1 AMP-activated protein kinase (α1AMPK) antagonizes fatty acid-induced in ammation through SIRT1[J]. J Biol Chem, 2010, 285(25): 19051-19059. DOI: 10.1074/jbc.M110.123620.
7. Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals[J]. Bmc Cancer, 2011, 11(1):20. DOI: 10.1186/1471-2407-11-20.
8. Bowker SL, Majumdar SR, Veugelers P, et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin[J]. Diabetes Care, 2006, 29(29):254-258. DOI: 10.2337/dc06-0997.
9. PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial[J]. Arch Ophthalmol, 2007, 125(3): 318-324. DOI: 10.1001/archopht.125.3.318.
10. Giacco F, Brownlee M. Oxidative stress and diabetic complications[J]. Circ Res, 2010, 107(9): 1058-1070. DOI: 10.1161/CIRCRESAHA.110.223545.
11. Vinores SA, Van Niel E, Swerdloff JL, et al. Electron microscopic immunocytochemical evidence for the mechanism of blood-retinal barrier breakdown in galactosemic rats and its association with aldose reductase expression and inhibition[J]. Exp Eye Res, 1993, 57(6): 723-735. DOI: 10.1006/exer.1993.1180.
12. Duh EJ, Yang HS, Haller JA, et al. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: implications for ocular angiogenesis[J]. Am J Ophthalmol, 2004, 137(4): 668-674. DOI: 10.1016/j.ajo.2003.11.015.
13. Funatsu H, Yamashita H, Ikeda T, et al. Angiotensin Ⅱ and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders[J]. Am J Ophthalmol, 2002, 133(4): 537-543.
14. Gallo A, Ceolotto G, Pinton P, et al. Metformin prevents glucose-induced protein kinase C-beta2 activation in human umbilical vein endothelial cells through an antioxidant mechanism[J]. Diabetes, 2005, 54(4):1123-1131.
15. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1[J]. J Biol Chem, 1999, 274(33): 23463-23467.
16. Miller JW, Le Couter J, Strauss EC, et al. Vascular endothelial growth factor a in intraocular vascular disease[J]. Ophthalmology, 2013,120(1): 106-114. DOI: 10.1016/j.ophtha.2012.07.038.
17. Batchuluun B, Inoguchi T, Sonoda N, et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells[J]. Atherosclerosis, 2014,232(1): 156-164. DOI: 10.1016/j.atherosclerosis.2013.10.025.

Chinese Journal of Ocular Fundus Diseases

The synergistic effect of metformin and anti-vascular endothelial growth factor in the treatment of diabetic retinopathy

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