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Yue Li, Tongrong Zhou, Paul A Edwards, Hua Gao, Xiaoxi Qiao; Anti-inflammatory effects and mechanisms of metformin on high-glucose challenged monocytes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):63.
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We previously reported a significantly reduced severity of diabetic retinopathy (DR) by metformin in long-term type 2 diabetic patients, and a remarkable correlation between metformin treatment and decreased levels of inflammatory cytokines in vitreous samples obtained from DR patients. This study is to determine the effects and mechanisms of metformin on the inflammatory responses of high glucose challenged human monocytes and the interactions between human monocytes and retinal vascular endothelial cells (RVECs).
Human monocytic cells (THP-1, ATCC® TIB202™) and primary human RVECs (ACBRI 181) were exposed to normal (5 mM) or high (30 mM) glucose media, then treated with metformin alone or in combination with Compound C (inhibitor of AMP activated protein kinase) for 72 hrs. The effect of metformin on adhesion of monocytes to hRVEC monolayers was evaluated with a quantitative cell attachment assay. The levels of inflammatory factors produced by monocytes including ICAM-1, NFκB, and MCP-1 were measured by Western blot and ELISA.
Adhesion of monocytes to hRVEC monolayers was markedly enhanced with high glucose exposure by nearly 50%. This enhancement was significantly blocked by 10 mM metformin. High glucose exposure increased the expression of ICAM-1 and NF-κB as well as secretion of soluble ICAM-1 and MCP-1 by monocytes. There was a trend that metformin suppressed high-glucose caused upregulation of ICAM-1 and NF-κB expression in monocytes. Metformin also reduced the levels of MCP-1 and soluble ICAM-1 in the media of monocyte cultures. Metformin’s inhibitory effects on the production of these inflammatory factors were partially reversed by co-treatment with AMP activated protein kinase inhibitor Compound C in monocyte culture.
Metformin suppressed high glucose induced inflammatory responses in human monocytes, which was partially mediated via AMP activated protein kinase dependent pathways. These results suggest that metformin has anti-inflammatory effects not only on RVECs as we reported before, but also on monocytes and on the interaction of these two major cell types by reducing multiple inflammatory cytokines. Our findings can at least partially explain the mechanisms of potent beneficial effects of metformin for diabetic retinopathy.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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