Cargando…

Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium

Metformin is a traditional anti-hyperglycemic medication that has recently been shown to benefit vascular complications of diabetes via an anti-inflammatory mechanism other than glycemic control. This study aims to test the hypothesis that metformin suppresses diabetic retinopathy (DR) associated in...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Yue, Gappy, Shawn, Liu, Xiuli, Sassalos, Therese, Zhou, Tongrong, Hsu, Andrew, Zhang, Alice, Edwards, Paul A., Gao, Hua, Qiao, Xiaoxi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9269956/
https://www.ncbi.nlm.nih.gov/pubmed/35802672
http://dx.doi.org/10.1371/journal.pone.0268451
_version_ 1784744348654501888
author Li, Yue
Gappy, Shawn
Liu, Xiuli
Sassalos, Therese
Zhou, Tongrong
Hsu, Andrew
Zhang, Alice
Edwards, Paul A.
Gao, Hua
Qiao, Xiaoxi
author_facet Li, Yue
Gappy, Shawn
Liu, Xiuli
Sassalos, Therese
Zhou, Tongrong
Hsu, Andrew
Zhang, Alice
Edwards, Paul A.
Gao, Hua
Qiao, Xiaoxi
author_sort Li, Yue
collection PubMed
description Metformin is a traditional anti-hyperglycemic medication that has recently been shown to benefit vascular complications of diabetes via an anti-inflammatory mechanism other than glycemic control. This study aims to test the hypothesis that metformin suppresses diabetic retinopathy (DR) associated intraocular inflammation. Human vitreous from control and proliferative diabetic retinopathy (PDR) patients with or without long-term metformin treatment (> 5 years) were collected for multiple inflammatory cytokines measurements with a cytokine array kit. The vast majority of the measurable cytokines in PDR vitreous has a lower level in metformin group than non-metformin group. Although the p values are not significant due to a relatively small sample size and large deviations, the 95% confidence interval (CI) for the mean difference between the two groups shows some difference in the true values should not be neglected. Using quantitative ELISA, soluble intercellular adhesion molecule -1 (ICAM-1) and monocyte chemoattractant protein -1 (MCP-1) presented with significantly lower concentrations in metformin group versus non-metformin group. Metformin group also has significantly less up-regulated cytokines and diminished positive correlations among the cytokines when compared to non-metformin group. Possible role of AMP-activated protein kinase (AMPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in metformin’s anti-inflammatory effects were studied in human retinal vascular endothelial cells (hRVECs) cultured in normal glucose (NG) and high glucose (HG) conditions. Metformin inhibited HG-induced ICAM-1, IL-8, and MCP-1 via AMPK activation, whereas pharmacological AMPK inhibition had no effect on its inhibition of NF-κB p65, sICAM-1, and tumor necrosis factor-α (TNF-α). Metformin-induced suppression of the inflammatory cytokines could also be mediated through its direct inhibition of NF-κB, independent of AMPK pathway. This is a proof-of-concept study that found metformin treatment was associated with reduced inflammatory responses in vitreous of diabetes patients and retinal vascular endothelial cells, supporting the rationale for using metformin to treat DR at an early stage.
format Online
Article
Text
id pubmed-9269956
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-92699562022-07-09 Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium Li, Yue Gappy, Shawn Liu, Xiuli Sassalos, Therese Zhou, Tongrong Hsu, Andrew Zhang, Alice Edwards, Paul A. Gao, Hua Qiao, Xiaoxi PLoS One Research Article Metformin is a traditional anti-hyperglycemic medication that has recently been shown to benefit vascular complications of diabetes via an anti-inflammatory mechanism other than glycemic control. This study aims to test the hypothesis that metformin suppresses diabetic retinopathy (DR) associated intraocular inflammation. Human vitreous from control and proliferative diabetic retinopathy (PDR) patients with or without long-term metformin treatment (> 5 years) were collected for multiple inflammatory cytokines measurements with a cytokine array kit. The vast majority of the measurable cytokines in PDR vitreous has a lower level in metformin group than non-metformin group. Although the p values are not significant due to a relatively small sample size and large deviations, the 95% confidence interval (CI) for the mean difference between the two groups shows some difference in the true values should not be neglected. Using quantitative ELISA, soluble intercellular adhesion molecule -1 (ICAM-1) and monocyte chemoattractant protein -1 (MCP-1) presented with significantly lower concentrations in metformin group versus non-metformin group. Metformin group also has significantly less up-regulated cytokines and diminished positive correlations among the cytokines when compared to non-metformin group. Possible role of AMP-activated protein kinase (AMPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in metformin’s anti-inflammatory effects were studied in human retinal vascular endothelial cells (hRVECs) cultured in normal glucose (NG) and high glucose (HG) conditions. Metformin inhibited HG-induced ICAM-1, IL-8, and MCP-1 via AMPK activation, whereas pharmacological AMPK inhibition had no effect on its inhibition of NF-κB p65, sICAM-1, and tumor necrosis factor-α (TNF-α). Metformin-induced suppression of the inflammatory cytokines could also be mediated through its direct inhibition of NF-κB, independent of AMPK pathway. This is a proof-of-concept study that found metformin treatment was associated with reduced inflammatory responses in vitreous of diabetes patients and retinal vascular endothelial cells, supporting the rationale for using metformin to treat DR at an early stage. Public Library of Science 2022-07-08 /pmc/articles/PMC9269956/ /pubmed/35802672 http://dx.doi.org/10.1371/journal.pone.0268451 Text en © 2022 Li et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Li, Yue
Gappy, Shawn
Liu, Xiuli
Sassalos, Therese
Zhou, Tongrong
Hsu, Andrew
Zhang, Alice
Edwards, Paul A.
Gao, Hua
Qiao, Xiaoxi
Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
title Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
title_full Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
title_fullStr Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
title_full_unstemmed Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
title_short Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
title_sort metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9269956/
https://www.ncbi.nlm.nih.gov/pubmed/35802672
http://dx.doi.org/10.1371/journal.pone.0268451
work_keys_str_mv AT liyue metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT gappyshawn metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT liuxiuli metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT sassalostherese metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT zhoutongrong metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT hsuandrew metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT zhangalice metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT edwardspaula metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT gaohua metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium
AT qiaoxiaoxi metforminsuppressesproinflammatorycytokinesinvitreousofdiabetespatientsandhumanretinalvascularendothelium