Cell Rep.: co-auth.: B.Thorens

Cell Rep. 2020 Dec 1;33(9):108466. doi: 10.1016/j.celrep.2020.108466.

Persistent or Transient Human β Cell Dysfunction Induced by Metabolic Stress: Specific Signatures and Shared Gene Expression with Type 2 Diabetes

Lorella Marselli 1Anthony Piron 2Mara Suleiman 3Maikel L Colli 2Xiaoyan Yi 2Amna Khamis 4Gaelle R Carrat 5Guy A Rutter 6Marco Bugliani 3Laura Giusti 7Maurizio Ronci 8Mark Ibberson 9Jean-Valery Turatsinze 2Ugo Boggi 10Paolo De Simone 11Vincenzo De Tata 12Miguel Lopes 2Daniela Nasteska 2Carmela De Luca 3Marta Tesi 3Emanuele Bosi 3Pratibha Singh 2Daniela Campani 13Anke M Schulte 14Michele Solimena 15Peter Hecht 14Brian Rady 16Ivona Bakaj 16Alessandro Pocai 16Lisa Norquay 16Bernard Thorens 17Mickaël Canouil 4Philippe Froguel 18Decio L Eizirik 19Miriam Cnop 20Piero Marchetti 21Affiliations expand


Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.