0 76

Cited 1 times in

Biguanides Metformin and Phenformin Generate Therapeutic Effects via AMP-Activated Protein Kinase/Extracellular-Regulated Kinase Pathways in an in Vitro Model of Graves' Orbitopathy

 Ye Eon Han  ;  Sena Hwang  ;  Jin Hee Kim  ;  Jung Woo Byun  ;  Jin Sook Yoon  ;  Eun Jig Lee 
 Thyroid, Vol.28(4) : 528-536, 2018 
Journal Title
Issue Date
Graves' ; adipogenesis ; extracellular-regulated kinase (ERK) ; hyaluronan production ; orbitopathy, biguanides, AMP-activated protein kinase
BACKGROUND: It was hypothesized that the biguanides metformin and phenformin, which are anti-hyperglycemic drugs used for diabetes mellitus, would have therapeutic effects in an in vitro model of Graves' orbitopathy (GO). Because adipogenesis, hyaluronan production, and inflammation are considered important in the pathogenesis of GO, this study aimed to determine the therapeutic effects and underlying mechanisms of biguanides on these parameters. METHODS: In vitro experiments were performed using primary cultured orbital fibroblasts from patients with GO. Orbital preadipocyte fibroblasts were allowed to differentiate into adipocytes and were treated with various concentrations of metformin or phenformin. Oil Red O staining was performed to evaluate lipid accumulation within the cells. Western blot analysis was used to measure the expression of adipogenic transcription factors and the phosphorylation of AMP-activated protein kinase and mitogen-activated protein kinase signaling proteins. Hyaluronan production was measured using enzyme-linked immunosorbent assay, and mRNA levels of proinflammatory molecules were determined using real-time polymerase chain reaction after interleukin (IL)-1β stimulation with or without biguanide treatment. RESULTS: Lipid accumulation during adipogenesis in GO orbital fibroblasts was dose-dependently suppressed by both metformin and phenformin. Adipocyte differentiation was attenuated, and the adipogenic transcription factors peroxisome proliferator-activated receptor γ and CCAAT-enhancer-binding proteins-α/β were downregulated. Furthermore, metformin and phenformin increased the phosphorylation of AMP-activated protein kinase and suppressed extracellular-regulated kinase activation. The IL-1β-induced hyaluronan production and mRNA expression of IL-6, cyclooxygenase-2, and intercellular adhesion molecule-1 were also significantly suppressed after metformin or phenformin co-treatment. CONCLUSIONS: The present study indicates that the biguanides metformin and phenformin exert an anti-adipogenic and inhibitory effect on hyaluronan production and expression of pro-inflammatory molecules in GO orbital fibroblasts, suggesting that they could potentially be used for the treatment of GO.
Full Text
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
윤진숙(Yoon, Jin Sook) ORCID logo https://orcid.org/0000-0002-8751-9467
이은직(Lee, Eun Jig) ORCID logo https://orcid.org/0000-0002-9876-8370
RIS (EndNote)
XLS (Excel)
사서에게 알리기


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.