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

Abstract

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.

• PMID: 33264613
• DOI: 10.1016/j.celrep.2020.108466