Metformin suppresses retinal angiogenesis and inflammation in vitro and in vivo

Abstract

The oral anti-diabetic drug metformin has been found to reduce cardiovascular complications independent of glycemic control in diabetic patients. However, its role in diabetic retinal microvascular complications is not clear. This study is to investigate the effects of metformin on retinal vascular endothelium and its possible mechanisms, regarding two major pathogenic features of diabetic retinopathy: angiogenesis and inflammation. In human retinal vascular endothelial cell culture, metformin inhibited various steps of angiogenesis including endothelial cell proliferation, migration, and tube formation in a dose-dependent manner. Its anti-angiogenic activity was confirmed in vivo that metformin significantly reduced spontaneous intraretinal neovascularization in a very-low-density lipoprotein receptor knockout mutant mouse (p<0.05). Several inflammatory molecules upregulated by tumor necrosis factor-α in human retinal vascular endothelial cells were markedly reduced by metformin, including nuclear factor kappa B p65 (NFκB p65), intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8). Further, metformin significantly decreased retinal leukocyte adhesion (p<0.05) in streptozotocin-induced diabetic mice. Activation of AMP-activated protein kinase was found to play a partial role in the suppression of ICAM-1 and MCP-1 by metformin, but not in those of NFκB p65 and IL-8. Our findings support the notion that metformin has considerable anti-angiogenic and anti-inflammatory effects on retinal vasculature. Metformin could be potentially used for the purpose of treating diabetic retinopathy in addition to blood glucose control in diabetic patients.

Phenotyping Individuals With Newly-Diagnosed Type 2 Diabetes at Risk for All-Cause Mortality: A Single Centre Observational, Prospective Study

“…our observation, that need to be con rmed on larger numbers, seems to support the idea that an early use of metformin might protect the eye, likely because it does not induce hypoglycaemia, detrimental toward the retina [30], or -alternatively -by exerting endothelial protection [31].…”

Association of Metformin Treatment with Reduced Severity of Diabetic Retinopathy in Type 2 Diabetic Patients

“…Experiments in endothelial cells and STZ-induced diabetes mice by us and others also identified significant attenuation of ICAM-1 and MCP-1 levels, as well as inflammatory responses by metformin [28, 29]. The antiangiogenic activity of metformin was demonstrated in various endothelial cell lines as well as retinal neovascularization mouse models [29, 30]. …”

“…However, AMPK may not account for all actions of metformin, as demonstrated by the preserved metabolic effect of metformin in liver-specific AMPK-deficient mice [32]. The regulation on endothelial inflammatory and angiogenic responses by metformin also has been shown through both AMPK-dependent and AMPK-independent mechanisms [29, 33]. …”

Potential Protective Effects of Metformin on Ocular Complications in Patients with Type 2 Diabetes

“…Han et al [37] in their in vitro study found that metformin directly inhibits angiogenesis of human retinal vascular endothelial cells (hRVECs) and has prevented tumor necrosis factor alpha (TNFα)-induced upregulation of multiple inflammatory cytokines in hRVECs.…”

“…AMPK activation was suggested to be protective for the tissues that are undergoing metabolic stress. However, the regulation on endothelial inflammatory and angiogenic responses by metformin also has been shown through both AMPK-dependent and AMPK-independent mechanisms [37,40].…”