IAPP-induced beta cell stress recapitulates the islet transcriptome in type 2 diabetes

• DOI: 10.1007/s00125-021-05569-2
• Publication Date: 2021-09-24T00:59:01Z
• Authors: Montgomery Blencowe; Allison Furterer; Qing Wang; Fuying Gao; Madeline Rosenberger; Lina Pei; Hiroshi Nomoto; Alex M. Mawla; Mark O. Huising; Giovanni Coppola; Xia Yang; Peter C. Butler; Tatyana Gurlo
• Keywords: Amylin

Abstract Aims/hypothesis Type 2 diabetes is characterised by islet amyloid and toxic oligomers of polypeptide (IAPP). We posed the questions, (1) does IAPP toxicity induce an response comparable to that in humans with type diabetes, if so, (2) what are key transcriptional drivers this response? Methods The transcriptome was evaluated five groups mice: beta cell specific transgenic for human IAPP, rodent (3) calpastatin, (4) calpastatin (5) wild-type mice. RNA sequencing data analysed differential expression analysis gene co-expression network establish adaptation increased workload soluble oligomeric extent which latter rescued suppression calpain hyperactivation calpastatin. Rank-rank hypergeometric overlap used compare islets from or mice vs prediabetes diabetes. Results transcriptomes remarkably similar. Beta overexpression oligomer-prone induced changes present including decreased genes confer identity. Increased but not inflammation humans. Key mediators injury responses those individuals include STAT3, NF-κB, ESR1 CTNNB1 transcription factor COL3A1, NID1 ZNF800 regulatory analysis. Conclusions/interpretation mediated a plausible mechanism contribute dedifferentiation Inhibition potential therapeutic target Graphical abstract