中华眼底病杂志

中华眼底病杂志

二甲双胍联合抗血管内皮生长因子药物治疗糖尿病视网膜病变的可能协同作用

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目的 观察二甲双胍联合抗血管内皮生长因子(VEGF)药物治疗糖尿病视网膜病变(DR)的可能协同作用。 方法 研究由临床资料回顾分析及体外细胞实验两部分构成。经玻璃体腔注射康柏西普治疗的糖尿病黄斑水肿患者10例12只眼纳入研究。将患者随机分为单纯治疗组(单纯康柏西普治疗)和联合治疗组(康柏西普+二甲双胍)。对比分析两组患者治疗后视力、黄斑区中心凹视网膜厚度(CRT)变化。体外培养视网膜血管内皮细胞,将其分为对照组(正常细胞)、VEGF组(50 ng/ml的VEGF)、单独组(50 ng/ml的VEGF+2.5 μg/ml的康柏西普)、联合组(50 ng/ml的VEGF+2.5 μg/ml的康柏西普+2.0 mmol/L的二甲双胍)。通过细胞生存力实验、划痕实验及实时定量聚合酶链反应对比分析各组的细胞增生、迁移及VEGF受体(VEGFR)2、蛋白激酶C(PKC)-α和PKC-β的mRNA表达。 结果 治疗后3个月,联合治疗组患眼CRT恢复率明显优于单纯治疗组,差异有统计学意义(t=−2.462,P<0.05)。体外细胞实验结果显示,VEGF组细胞生存力、迁移率均较对照组明显升高,单独组及联合组细胞生存力、迁移率较VEGF组明显降低,联合组细胞生存力、迁移率较单独组进一步降低,差异均有统计学意义(P<0.05)。VEGF组细胞VEGFR2、PKC-α、PKC-β mRNA 表达量较对照组明显升高,联合组细胞VEGFR2、PKC-α、PKC-β mRNA表达量较VEGF组、单独组明显降低,差异均有统计学意义(P<0.05);单独组细胞VEGFR2、PKC-α、PKC-β mRNA表达量较VEGF组降低,但差异无统计学意义(P>0.05)。 结论 联合应用二甲双胍与抗VEGF药物较单纯抗VEGF药物更能降低DR患眼CRT,更能抑制VEGF所诱导的的视网膜血管内皮细胞增生及迁移。其协同作用机制可能与二甲双胍抑制VEGFR及PKC的表达有关。

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.

关键词: 糖尿病视网膜病变/药物疗法; 二甲双胍/治疗应用; 血管生成抑制剂/治疗应用; 体外研究

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

引用本文: 张哲, 刘竹青, 刘巨平, 东莉洁, 朱依萌, 黄亮瑜, 苏睿虹, 赵今稚, 张晓敏, 李筱荣. 二甲双胍联合抗血管内皮生长因子药物治疗糖尿病视网膜病变的可能协同作用. 中华眼底病杂志, 2018, 34(5): 453-457. doi: 10.3760/cma.j.issn.1005-1015.2018.05.008 复制

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