New Insight Into Metformin Action: Regulation of ChREBP and FOXO1 Activities in Endothelial Cells

Mol Endocrinol. 2015 Aug;29(8):1184-94. doi: 10.1210/ME.2015-1090. Epub 2015 Jul 6.


Metformin has been considered a potential adjunctive therapy in treating poorly controlled type 1 diabetes with obesity and insulin resistance, owing to its potent effects on improving insulin sensitivity. However, the underlying mechanism of metformin's vascular protective effects remains obscure. Thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox state induced by high-glucose concentration, decreases thioredoxin reductase activity and mediates apoptosis induced by oxidative stress. Here we report that high glucose-induced endothelial dysfunction is associated with induction of TXNIP expression in primary human aortic endothelial cells exposed to high-glucose conditions, whereas the metformin treatment suppresses high-glucose-induced TXNIP expression at mRNA and protein levels. We further show that metformin decreases the high-glucose-stimulated nuclear entry rate of two transcription factors, carbohydrate response element-binding protein (ChREBP) and forkhead box O1 (FOXO1), as well as their recruitment on the TXNIP promoter. An AMP-activated protein kinase inhibitor partially compromised these metformin effects. Our data suggest that endothelial dysfunction resulting from high-glucose concentrations is associated with TXNIP expression. Metformin down-regulates high-glucose-induced TXNIP transcription by inactivating ChREBP and FOXO1 in endothelial cells, partially through AMP-activated protein kinase activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Aorta / metabolism
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy
  • Endothelial Cells / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Inflammation
  • Male
  • Metformin / pharmacology*
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Thioredoxins / metabolism
  • Transcription Factors / metabolism


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carrier Proteins
  • Cell Cycle Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • MLXIPL protein, human
  • Mlxipl protein, mouse
  • Mlxipl protein, rat
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Reactive Oxygen Species
  • TXNIP protein, human
  • TXNIP protein, rat
  • Transcription Factors
  • Txnip protein, mouse
  • Foxo1 protein, rat
  • Thioredoxins
  • Metformin
  • Adenylate Kinase