Review Article | Published:

The α-cell in diabetes mellitus

Nature Reviews Endocrinologyvolume 14pages694704 (2018) | Download Citation

Abstract

Findings from the past 10 years have placed the glucagon-secreting pancreatic α-cell centre stage in the development of diabetes mellitus, a disease affecting almost one in every ten adults worldwide. Glucagon secretion is reduced in patients with type 1 diabetes mellitus, increasing the risk of insulin-induced hypoglycaemia, but is enhanced in type 2 diabetes mellitus, exacerbating the effects of diminished insulin release and action on blood levels of glucose. A better understanding of the mechanisms underlying these changes is therefore an important goal. RNA sequencing reveals that, despite their opposing roles in the control of blood levels of glucose, α-cells and β-cells have remarkably similar patterns of gene expression. This similarity might explain the fairly facile interconversion between these cells and the ability of the α-cell compartment to serve as a source of new β-cells in models of extreme β-cell loss that mimic type 1 diabetes mellitus. Emerging data suggest that GABA might facilitate this interconversion, whereas the amino acid glutamine serves as a liver-derived factor to promote α-cell replication and maintenance of α-cell mass. Here, we survey these developments and their therapeutic implications for patients with diabetes mellitus.

Key points

  • The mechanisms involved in the control of glucagon secretion in pancreatic α-cells have now been identified.

  • The pancreatic α-cell has a role in the development of diabetes mellitus.

  • Physiological and pharmacological activators and inhibitors of glucagon secretion might provide therapeutic targets.

  • Single α-cell gene expression profiling in health and disease has resulted in new insights about the function of α-cells.

  • Advances in understanding α-cell to β-cell reprogramming could lead to new therapeutic strategies for diabetes mellitus.

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Acknowledgements

The authors thank Y. Xin and J. Kim for help with preparation of the manuscript and figures. G.A.R. was supported by MRC Programmes (MR/J0003042/1, MR/N00275X/1 and MR/L020149/1 (DIVA)), Wellcome Trust Senior Investigator Award (WT098424AIA), Diabetes UK (BDA11/0004210 and BDA/15/0005275) and Biotechnology and Biological Sciences Research Council (BB/J015873/1) project grants.

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  1. Regeneron Pharmaceuticals, Tarrytown, NY, USA

    • Jesper Gromada
  2. Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK

    • Pauline Chabosseau
    •  & Guy A. Rutter

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All authors contributed to all aspects of the manuscript.

Competing interests

J.G. is an employee and shareholder of Regeneron Pharmaceuticals, Inc. G.A.R. has received research funding from Les Laboratoires Servier. P.C. declares no competing interests.

Corresponding authors

Correspondence to Jesper Gromada or Guy A. Rutter.

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https://doi.org/10.1038/s41574-018-0097-y