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

Abstract

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.

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.

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Fig. 1: T2DM risk loci that are associated with defects in pancreatic islet function.
Fig. 2: Glucose-stimulated insulin secretion in human pancreatic β-cells.
Fig. 3: Generation of immortalized human β-cell lines.
Fig. 4: Differentiation protocol for hiPSC-derived β-like cells.

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Acknowledgements

A.L.G. is a Wellcome Trust Senior Fellow in Basic Biomedical Science. A.L.G. is funded by the Wellcome Trust (095101, 200837, 106130, 203141), Medical Research Council (MR/L020149/1), European Union Horizon 2020 Programme (T2D Systems) and NIH (U01-DK105535; U01-DK085545), and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health.

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Glossary

Posterior probability of association

The likelihood of a given variant being causal.

Credible set

The minimal group of disease or trait-associated variants that are the product of fine-mapping.

Promoter capture Hi-C

A genome-wide experimental technique used to detect interactions between promoters and other regulatory elements.

Maturity-onset diabetes of the young

(MODY). A rare, autosomal dominantly inherited form of diabetes caused by a mutation in a single gene which typically presents before the age of 25 years.

Isogenic cell line

A cell line genetically engineered to introduce specific mutations and derived from a parental cell line.

Recruit by genotype study

A research study where patients are selected based on their genotype.

Capacitance

A measure of β-cell exocytosis based on electrical current.

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Krentz, N.A.J., Gloyn, A.L. Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics. Nat Rev Endocrinol 16, 202–212 (2020). https://doi.org/10.1038/s41574-020-0325-0

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