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Yue Li, Shawn Gappy, Xiuli Liu, Therese Sassalos, Paul A Edwards, Hua Gao, Xiaoxi Qiao; Metformin reduces diabetes-related inflammatory molecules in human vitreous and retinal vascular endothelial cells. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6346.
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© ARVO (1962-2015); The Authors (2016-present)
Inflammation plays a prominent role in the pathogenesis of diabetic retinopathy (DR). We have reported that metformin treatment is associated with substantially reduced severity of DR in patients, and significant anti-inflammatory action in animal models. The purpose of this study was to examine whether metformin affects the levels of inflammatory cytokines and chemokines in the vitreous of DR patients, and whether metformin specifically affects the diabetes related inflammatory molecules in human retinal vascular endothelial cell cultures.
Patients with type 2 diabetes for more than 15 years with or without metformin treatment for at least 5 years prior to the onset of DR were included respectively as metformin treatment group or control group. Undiluted core vitreous biopsies were collected for analysis of a panel of inflammatory and immune molecules using a Human Cytokine Array. Primary cultured human retinal vascular endothelial cells (hRVECs) were challenged by high glucose with or without metformin co-treatment. The expression of ICAM-1 and phosphorylated NF-κB in hRVECs were measured by western blot. The production of TNFα and IL-8 by the cell were determined by ELISA.
Our data revealed that metformin treatment significantly reduced the levels of multiple key molecules crucial for the inflammatory and immune responses in the vitreous of DR patients, including ICAM-1, MCP-1, Serpin E1, CXCL12, CXCL10, MIF, IL-6, and C5/C5a. High glucose exposure remarkably elevated the expression of ICAM-1 (p〈 0.01) and pNF-κB (p〈 0.05) in hRVECs; as well as the production of TNFα (p〈 0.001) and IL-8 (p〈 0.05) by hRVECs. Metformin completely reversed the up-regulation of ICAM-1 and pNF-κB induced by high glucose to a level comparable to the normal control. Metformin also markedly reduced the levels of TNFα and IL-8 elevated by high glucose in hRVECs (both p〈 0.05). The effects of metformin on hRVECs were at least partially blocked by compound C, an inhibitor of AMP-activated protein kinase.
Our results confirm that metformin directly and effectively suppresses the inflammatory and immune responses in the pathogenesis of diabetic retinopathy. Such a strong anti-inflammatory action of metformin could be a major mechanism underlying its vascular protective effect.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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