Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression – published online 12/01/2023

Katia K. Mattis, Nicole A. J. Krentz, Christoph Metzendorf, Fernando Abaitua, Aliya F. Spigelman, Han Sun, Jennifer M. Ikle, Swaraj Thaman, Antje K. Rottner, Austin Bautista, Eugenia Mazzaferro, Marta Perez-Alcantara, Jocelyn E. Manning Fox, Jason M. Torres, Agata Wesolowska-Andersen, Grace Z. Yu, Anubha Mahajan, Anders Larsson, Patrick E. MacDonald, Benjamin Davies, Marcel den Hoed, Anna L. Gloyn

Genome-wide association studies have identified multiple independent signals at the RREB1 locus associated with type 2 diabetes. However, how altered expression or function of the transcription factor Ras-responsive element binding protein 1 (RREB1) influences diabetes risk was previously unknown. In this issue, Mattis and Krentz et al (https://doi.org/10.1007/s00125-022-05856-6) describe how a combination of zebrafish and human cellular models was used to identify disease-causing mechanisms at the RREB1 locus. The authors show how RREB1 loss-of-function reduced insulin gene expression and insulin content in zebrafish as well as in human beta cell models. Transcriptomic analysis identified RREB1 as a regulator of several genes involved in beta cell development and function, including the RFX family of transcription factors. Consistent with these findings, the authors show how isolated islets from human carriers of RREB1 diabetes-risk alleles exhibited altered glucose-stimulated insulin secretion. The authors conclude that the genetic association of RREB1 with type 2 diabetes is mediated, in part, by a transcriptional role for RREB1 in normal beta cell development and function.

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