Metformin reduces inflammation in diabetic human vitreous by activating AMPK and inhibiting NFκB signaling pathway
Li Y, Zhou T, Hsu A, Edwards PA, Gao H, and Qiao X. Metformin reduces inflammation in diabetic human vitreous by activating AMPK and inhibiting NFκB signaling pathway. Invest Ophthalmol Vis Sci 2019; 60(9).
Invest Ophthalmol Vis Sci
Purpose: Inflammation has been recognized as a key component in the pathogenesis of diabetic retinopathy (DR). We have previously reported substantially reduced severity of DR in metformin-treated type 2 diabetes patients, and a significant anti-inflammatory effect of metformin in the retinal vasculature. Metformin-treated proliferative diabetic retinopathy (PDR) patients had reduced levels of human intravitreal inflammatory cytokines than non-metformin-treated PDR patients. This study was to explore potential mechanisms of the anti-inflammatory effect of metformin. Methods: Undiluted core vitreous biopsies were collected for analysis of a panel of inflammatory and immune cytokines using a Human Cytokine Array. An Ingenuity Pathway Analysis (IPA) was used to generate cytokine signaling related network. The effects of metformin on IPA identified signaling pathways were examined in primary cultured human retinal vascular endothelial cells (hRVECs) using western blot or ELISA. Results: Among 36 inflammatory cytokines on the array, 24 were detected in the vitreous of PDR patients. The cytokines significantly elevated in non-metformin-treated PDR group versus non-diabetic control group include IL-1ra, IL-13, CXCL12, IL-6, C5/C5a, IL-8, CXCL-11, MIF, MCP-1, Serpin E1, ICAM-1, and CXCL10 (all have p < 0.05). The majority of cytokines, 22/24, was found to have a lower level in metformin-treated than non-metformin-treated PDR group. The most significant ones included IL-16, CXCL1, and CXCL11 (all have p < 0.05). IPA study of these cytokines identified AMPK and NF-κB as two most relevant signaling pathways responded to metformin treatment. In hRVECs, metformin significantly reversed the up-regulation of ICAM-1, pNF-κB, soluble ICAM-1, MCP-1, TNFα, and IL-8 by high glucose (p < 0.05). AMPK and NF-kB inhibitors blocked the effects of metformin on ICAM-1, MCP-1, and IL-8 expressions, but had minimal effects on soluble ICAM-1 and TNFα levels. Conclusions: Metformin suppresses the inflammation in the vitreous of PDR patients through activation of AMPK and inhibition of NF-κB signaling pathways. The antiin flammatory action of metformin may play a key role in its vascular protective effect. (Figure presented).