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

Paul Richards; Latif Rachdi; Masaya Oshima; Piero Marchetti; Marco Bugliani; Mathieu Armanet; Catherine Postic; Sandra Guilmeau; Raphael Scharfmann

doi:10.2337/db17-0595

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.

Authors

Paul Richards^{1

2

3}, Latif Rachdi^{1

2

3}, Masaya Oshima^{1

2

3}, Piero Marchetti⁴, Marco Bugliani⁴, Mathieu Armanet⁵, Catherine Postic^{1

2

3}, Sandra Guilmeau^{1

2

3}, Raphael Scharfmann^{6

2

3}

Affiliations

¹ INSERM U1016, Cochin Institute, Paris, France.
² CNRS UMR 8104, Paris, France.
³ University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
⁴ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁵ Cell Therapy Unit Hospital Saint-Louis and University Paris-Diderot, Paris, France.
⁶ INSERM U1016, Cochin Institute, Paris, France raphael.scharfmann@inserm.fr.

PMID: 29282201
DOI: 10.2337/db17-0595

Abstract

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

Substances

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