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KATP channels and islet hormone secretion: new insights and controversies

Nature Reviews Endocrinology volume 9, pages 660–669 (2013)Cite this article

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Abstract

ATP-sensitive potassium channels (KATP channels) link cell metabolism to electrical activity by controlling the cell membrane potential. They participate in many physiological processes but have a particularly important role in systemic glucose homeostasis by regulating hormone secretion from pancreatic islet cells. Glucose-induced closure of KATP channels is crucial for insulin secretion. Emerging data suggest that KATP channels also play a key part in glucagon secretion, although precisely how they do so remains controversial. This Review highlights the role of KATP channels in insulin and glucagon secretion. We discuss how KATP channels might contribute not only to the initiation of insulin release but also to the graded stimulation of insulin secretion that occurs with increasing glucose concentrations. The various hypotheses concerning the role of KATP channels in glucagon release are also reviewed. Furthermore, we illustrate how mutations in KATP channel genes can cause hyposecretion or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, and how defective metabolic regulation of the channel may underlie the hypoinsulinaemia and the hyperglucagonaemia that characterize type 2 diabetes mellitus. Finally, we outline how sulphonylureas, which inhibit KATP channels, stimulate insulin secretion in patients with neonatal diabetes mellitus or type 2 diabetes mellitus, and suggest their potential use to target the glucagon secretory defects found in diabetes mellitus.

Key Points

  • Closure of ATP-sensitive potassium channels (KATP channels) stimulates insulin secretion but inhibits glucagon release

  • The role of KATP channels in insulin secretion is well understood, but precisely how glucose inhibits glucagon release remains controversial

  • Activating mutations in KATP channel genes cause neonatal diabetes mellitus, whereas loss-of-function mutations cause congenital hyperinsulinism

  • Both insufficient insulin secretion and dysregulation of glucagon release contribute to impaired glucose homeostasis in type 2 diabetes mellitus (T2DM)

  • A common KATP channel haplotype predisposes to T2DM

  • An age-dependent decline in metabolism may also contribute to T2DM via mechanisms that are both dependent on, and independent of, KATP channels

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Figure 1: KATP channel modulation of β-cell electrical activity.
Figure 2: Patch clamping enables the activity of one or more ion channels to be recorded from single cells or isolated membrane patches with high precision.
Figure 3: KATP channel modulation of α-cell electrical activity.
Figure 4: Relationship between KATP channel activity and hormone release.

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Change history

  • 09 October 2013

    In the version of this article initially published online in Figure 3, part c was incorrectly labelled as part b. The error has been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

Work in the authors' laboratories is funded by the Wellcome Trust, the European Union, Diabetes UK, the Medical Research Council and the Royal Society. F. M. Ashcroft holds the Wolfson-Royal Society merit award.

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  1. Department of Physiology, Henry Wellcome Centre for Gene Function, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK

    Frances M. Ashcroft

  2. Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK

    Patrik Rorsman

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Ashcroft, F., Rorsman, P. KATP channels and islet hormone secretion: new insights and controversies. Nat Rev Endocrinol 9, 660–669 (2013). https://doi.org/10.1038/nrendo.2013.166

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