Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent multifactorial disease that has both genetic and environmental risk factors, resulting in impaired glucose homeostasis. Genome-wide association studies (GWAS) have identified over 400 genetic signals that are associated with altered risk of T2DM. Human physiology and epigenomic data support a central role for the pancreatic islet in the pathogenesis of T2DM. This Review focuses on the promises and challenges of moving from genetic associations to molecular mechanisms and highlights efforts to identify the causal variant and effector transcripts at T2DM GWAS susceptibility loci. In addition, we examine current human models that are used to study both β-cell development and function, including EndoC-β cell lines and human induced pluripotent stem cell-derived β-like cells. We use examples of four T2DM susceptibility loci ( CDKAL1 , MTNR1B , SLC30A8 and PAM ) to emphasize how a holistic approach involving genetics, physiology, and cellular and developmental biology can disentangle disease mechanisms at T2DM GWAS signals. Type 2 diabetes mellitus (T2DM) has genetic and environmental risk factors that result in impaired glucose homeostasis. This Review discusses efforts to identify molecular mechanisms associated with T2DM susceptibility loci and highlights the current human models that are used to study β-cell development and function. Key points Genome-wide association studies (GWAS) have identified >400 signals associated with the risk of type 2 diabetes mellitus (T2DM). The pancreatic islet has been identified as a key tissue involved in mediating GWAS signals in T2DM risk. Integrating genetic, epigenomic and cellular data can unlock the biology behind GWAS signals. Improvements in human β-cell models coupled with genome-editing technologies offer new possibilities for modelling the pathogenesis of T2DM.