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The α-cell in diabetes mellitus

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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Fig. 1: The localization and number of α-cells differ between mouse and human pancreatic islets.
Fig. 2: Intracellular and intercellular mechanisms implicated in the suppression of glucagon secretion by glucose.
Fig. 3: Physiological and pharmacological activators and inhibitors of α-cell function and glucagon secretion.
Fig. 4: RNA sequencing of single human islet cells reveals a few genes that are enriched in α-cells and β-cells among a large number of detected genes.
Fig. 5: The liver–α-cell axis.
Fig. 6: α-Cell development and its possible modulation as a therapy in type 1 diabetes mellitus.
Fig. 7: Differentially regulated genes in single α-cells from donors with type 2 diabetes mellitus.
Fig. 8: Potential role of α-cell–α-cell connectivity in the control of glucagon secretion.

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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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Correspondence to Jesper Gromada or Guy A. Rutter.

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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.

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Gromada, J., Chabosseau, P. & Rutter, G.A. The α-cell in diabetes mellitus. Nat Rev Endocrinol 14, 694–704 (2018). https://doi.org/10.1038/s41574-018-0097-y

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