title: Metformin inhibits development of diabetic retinopathy through inducing alternative splicing of VEGF-A.
abstract: Previous studies have shown that metformin, an AMP-activated protein kinase activator widely prescribed for type 2 diabetes, is especially beneficial in cases of diabetic retinopathy (DR) with undetermined mechanisms. Here, we used a streptozotocin-induced diabetes model in mice to study the effects of metformin on the development of DR. We found that 10 weeks after STZ treatment, DR was induced in STZ-treated mice, regardless treatment of metformin. However, metformin alleviated the DR, seemingly through attenuating the retina neovascularization. The total vascular endothelial cell growth factor A (VEGF-A) in eyes was not altered by metformin, but the phosphorylation of the VEGF receptor 2 (VEGFR2) was decreased, which inhibited VEGF signaling. Further analysis showed that metformin may induce VEGF-A mRNA splicing to VEGF120 isoform to reduce its activation of the VEGFR2. These findings are critical for generating novel medicine for DR treatment.
authors.affiliation: Department of Ophthalmology, Ningbo Eye Hospital Ningbo 315040, China.
authors.forename: Quan-Yong
authors.initials: QY
authors.lastname: Yi
authors.affiliation: Ningbo Central Blood Center Ningbo 315040, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Ophthalmology, the Fourth Affiliated Hospital of Guangzhou Medical University Guangzhou 510000, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Ningbo Eye Hospital Ningbo 315040, China.
authors.forename: Zhi-Sha
authors.initials: ZS
authors.lastname: Bai
authors.affiliation: Department of Ophthalmology, Ningbo Eye Hospital Ningbo 315040, China.
authors.forename: Jian-Shu
authors.initials: JS
authors.lastname: Yuan
authors.affiliation: Department of Ophthalmology, Ningbo Eye Hospital Ningbo 315040, China.
authors.forename: Guo-Hai
authors.initials: GH
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology, Ningbo Eye Hospital Ningbo 315040, China.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Ningbo Eye Hospital Ningbo 315040, China.
authors.forename: Shan-Jun
authors.initials: SJ
authors.lastname: Wu
keywords: Diabetic retinopathy (DR); VEGF receptor 2 (VEGFR2); VEGF120; VEGF164; splicing; vascular endothelial cell growth factor A (VEGF-A)