MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

Diabetes. 2018 Mar;67(3):461-472. doi: 10.2337/db17-0595. Epub 2017 Dec 27.


Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Cyclic AMP / metabolism
  • Exenatide
  • Gene Expression Regulation* / drug effects
  • Glucose / metabolism*
  • Humans
  • Incretins / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Peptides / pharmacology
  • RNA Interference
  • Second Messenger Systems* / drug effects
  • Thioredoxins / genetics
  • Thioredoxins / metabolism
  • Tissue Culture Techniques
  • Venoms / pharmacology


  • Arrdc4 protein, mouse
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carrier Proteins
  • Incretins
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • MLXIP protein, human
  • MondoA protein, mouse
  • Peptides
  • TXNIP protein, human
  • Txnip protein, mouse
  • Venoms
  • Thioredoxins
  • Exenatide
  • Cyclic AMP
  • Glucose