PMID- 35802672
OWN - NLM
STAT- MEDLINE
DCOM- 20220712
LR  - 20220722
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 17
IP  - 7
DP  - 2022
TI  - Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients 
      and human retinal vascular endothelium.
PG  - e0268451
LID - 10.1371/journal.pone.0268451 [doi]
LID - e0268451
AB  - 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-kappaB) 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-kappaB 
      p65, sICAM-1, and tumor necrosis factor-alpha (TNF-alpha). Metformin-induced suppression 
      of the inflammatory cytokines could also be mediated through its direct 
      inhibition of NF-kappaB, 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.
FAU - Li, Yue
AU  - Li Y
AUID- ORCID: 0000-0002-3015-7581
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Gappy, Shawn
AU  - Gappy S
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Liu, Xiuli
AU  - Liu X
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Sassalos, Therese
AU  - Sassalos T
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Zhou, Tongrong
AU  - Zhou T
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Hsu, Andrew
AU  - Hsu A
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Zhang, Alice
AU  - Zhang A
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Edwards, Paul A
AU  - Edwards PA
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Gao, Hua
AU  - Gao H
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
FAU - Qiao, Xiaoxi
AU  - Qiao X
AD  - Department of Ophthalmology, Henry Ford Hospital, Detroit, Michigan, United 
      States of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220708
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - *Cytokines/metabolism
MH  - *Diabetes Mellitus/metabolism
MH  - *Diabetic Retinopathy/drug therapy/metabolism
MH  - Endothelial Cells/metabolism
MH  - Endothelium, Vascular/metabolism
MH  - Glucose/metabolism
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - *Metformin/pharmacology/therapeutic use
MH  - NF-kappa B/metabolism
PMC - PMC9269956
COIS- The authors have declared that no competing interests exist.
EDAT- 2022/07/09 06:00
MHDA- 2022/07/14 06:00
PMCR- 2022/07/08
CRDT- 2022/07/08 14:03
PHST- 2021/12/08 00:00 [received]
PHST- 2022/05/01 00:00 [accepted]
PHST- 2022/07/08 14:03 [entrez]
PHST- 2022/07/09 06:00 [pubmed]
PHST- 2022/07/14 06:00 [medline]
PHST- 2022/07/08 00:00 [pmc-release]
AID - PONE-D-21-38866 [pii]
AID - 10.1371/journal.pone.0268451 [doi]
PST - epublish
SO  - PLoS One. 2022 Jul 8;17(7):e0268451. doi: 10.1371/journal.pone.0268451. 
      eCollection 2022.