Genome-edited human stem cell-derived beta cells: A powerful tool for drilling down on type 2 diabetes GWAS biology.

Abstract

Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by acomplex aetiological mix of genetic, epigenetic, environmental, and lifestyle riskfactors. Whilst the last decade of T2D genetic research has identified morethan 100 loci showing strong statistical association with disease susceptibility,our inability to capitalise upon these signals reflects, in part, a lack ofappropriate human cell models for study. This review discusses the impact oftwo complementary, state-of-the-art technologies on T2D genetic research: thegeneration of stem cell-derived, endocrine pancreas-lineage cells and theediting of their genomes. Such models facilitate investigation ofdiabetes-associated genomic perturbations in a physiologically representativecell context and allow the role of both developmental and adult islet dysfunctionin T2D pathogenesis to be investigated. Accordingly, we interrogate the rolethat patient-derived induced pluripotent stem cell models are playing inunderstanding cellular dysfunction in monogenic diabetes, and howsite-specific nucleases such as the clustered regularly interspaced shortpalindromic repeats (CRISPR)-Cas9 system are helping to confirm genescrucial to human endocrine pancreas development. We also highlight the novelbiology gleaned in the absence of patient lines, including an ability to model thewhole phenotypic spectrum of diabetes phenotypes occurring both in utero andin adult cells, interrogating the non-coding 'islet regulome' for disease-causingperturbations, and understanding the role of other islet cell types in aberrantglycaemia. This article aims to reinforce the importance of investigating T2Dsignals in cell models reflecting appropriate species, genomic context,developmental time point, and tissue type.