MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic b-Cells Paul Richards, 1,2,3 Latif Rachdi, 1,2,3 Masaya Oshima, 1,2,3 Piero Marchetti, 4 Marco Bugliani, 4 Mathieu Armanet, 5 Catherine Postic, 1,2,3 Sandra Guilmeau, 1,2,3 and Raphael Scharfmann 1,2,3 Diabetes 2018;67:461–472 | https://doi.org/10.2337/db17-0595 Although the mechanisms by which glucose regulates insulin secretion from pancreatic b-cells are now well de- scribed, the way glucose modulates gene expression in such cells needs more understanding. Here, we demon- strate that MondoA, but not its paralog carbohydrate- responsive element–binding protein, is the predominant glucose-responsive transcription factor in human pan- creatic b-EndoC-bH1 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 b-cell dysfunction and diabe- tes. Importantly, increasing cAMP signaling in human b-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Further- more, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-bH1 cells. These re- sults highlight MondoA as a novel target in b-cells that coor- dinates transcriptional response to elevated glucose levels. In eukaryotic cells, glucose uptake and metabolism represent a major source of energy, but are also a strong regulator of gene expression and cellular function. Pancreatic b-cells represent a model system to dissect these processes, because they are responsible for orchestrating the response of the body to rising postprandial glucose levels by secreting insulin to avoid excessive hyperglycemia. Glucose enters b-cells via GLUTs and is first metabolized through the high-K m gluco- kinase (GK; hexokinase IV), which is considered to be “glu- cose sensor” of the b-cell (1). After this, insulin secretion occurs through a process of cellular depolarization via ATP- sensitive potassium channels, calcium entry, vesicle dock- ing, and exocytosis (2). The incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide further amplify insulin secretion. Both hormones act directly on b-cells to elevate intracellular cAMP levels and promote secretion downstream of glucose sensing. Both hormones also activate the transcription factor cAMP-responsive element–binding protein and thereby influence the b-cell transcriptome (3). Although the critical role of glucose on insulin secretion is now well described both in rodent and human b-cells (2), the effect of glucose on the b-cell transcriptome has been less explored. Long-term hyperglycemic conditions have been shown to be detrimental to b-cell function, leading to decreased insulin transcription, synthesis, and secretion giving rise to the concept of glucolipotoxicity (4). However, there is a limited understanding of the shorter-term effects of glucose on the b-cell transcriptome, particularly in human models. Carbohydrate-responsive transcription factors have emerged as major mediators of glucose action on gene expression. Adipocytes and hepatocytes express the carbohydrate- responsive element–binding protein (ChREBP), also named MondoB, whereas skeletal muscle cells express its paralog MondoA (5,6). Both transcription factors reside in the cy- toplasm in low-glucose conditions and undergo nuclear translocation in high-glucose conditions. They belong to the same family, with ChREBP encoded by the MLX inter- acting protein–like (MLXIPL) gene and MondoA encoded by the MLX interacting protein (MLXIP). ChREBP and MondoA are multidomain proteins with highly homologous N-terminal 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 Corresponding author: Raphael Scharfmann, raphael.scharfmann@inserm.fr. Received 22 May 2017 and accepted 15 December 2017. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0595/-/DC1. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Diabetes Volume 67, March 2018 461 ISLET STUDIES