From Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes
2020
Mattis, Katia K. | Gloyn, Anna L.
Genome-wide association studies (GWAS) have identified over 400 signals robustly associated with risk for type 2 diabetes (T2D). At the vast majority of these loci, the lead single nucleotide polymorphisms (SNPs) reside in noncoding regions of the genome, which hampers biological inference and translation of genetic discoveries into disease mechanisms. The study of these T2D risk variants in normoglycemic individuals has revealed that a significant proportion are exerting their disease risk through islet-cell dysfunction. The central role of the islet is also demonstrated by numerous studies, which have shown an enrichment of these signals in islet-specific epigenomic annotations. In recent years the emergence of authentic human beta-cell lines, and advances in genome-editing technologies coupled with improved protocols differentiating human pluripotent stem cells into beta-like cells has opened up new opportunities for T2D disease modeling.Here we review the current understanding on the genetic basis of T2D focusing on approaches, which have facilitated the identification of causal variants and their effector transcripts in human islets. We will present examples of functional studies based on animal and conventional cellular systems and highlight the potential of novel stem cell-based T2D disease models.
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