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New insights into KATP channel gene mutations and neonatal diabetes mellitus

Nature Reviews Endocrinology volume 16, pages 378–393 (2020)Cite this article

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Abstract

The ATP-sensitive potassium channel (KATP channel) couples blood levels of glucose to insulin secretion from pancreatic β-cells. KATP channel closure triggers a cascade of events that results in insulin release. Metabolically generated changes in the intracellular concentrations of adenosine nucleotides are integral to this regulation, with ATP and ADP closing the channel and MgATP and MgADP increasing channel activity. Activating mutations in the genes encoding either of the two types of KATP channel subunit (Kir6.2 and SUR1) result in neonatal diabetes mellitus, whereas loss-of-function mutations cause hyperinsulinaemic hypoglycaemia of infancy. Sulfonylurea and glinide drugs, which bind to SUR1, close the channel through a pathway independent of ATP and are now the primary therapy for neonatal diabetes mellitus caused by mutations in the genes encoding KATP channel subunits. Insight into the molecular details of drug and nucleotide regulation of channel activity has been illuminated by cryo-electron microscopy structures that reveal the atomic-level organization of the KATP channel complex. Here we review how these structures aid our understanding of how the various mutations in the genes encoding Kir6.2 (KCNJ11) and SUR1 (ABCC8) lead to a reduction in ATP inhibition and thereby neonatal diabetes mellitus. We also provide an update on known mutations and sulfonylurea therapy in neonatal diabetes mellitus.

Key points

  • ATP-sensitive potassium channels (KATP channels) regulate insulin secretion from pancreatic β-cells by closing in response to metabolically generated ATP.

  • Gain-of-function mutations in the genes encoding KATP channel subunits (Kir6.2 and SUR1) cause neonatal diabetes mellitus, whereas loss-of-function mutations cause hyperinsulinism of infancy.

  • Most patients (~90%) with neonatal diabetes mellitus can be treated with sulfonylurea drugs, which inhibit the hyperactivated KATP channels.

  • Atomic-resolution structures of the KATP channel complex have identified the binding sites for nucleotides and sulfonylurea drugs and shed light on how disease-causing mutations produce their functional effects.

  • Functional and clinical studies have elucidated why some patients can be transferred to sulfonylurea therapy and others cannot.

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Fig. 1: Structure of the KATP channel complex.
Fig. 2: The inhibitory ATP-binding site.
Fig. 3: Location of Kir6.2 residues altered in neonatal diabetes mellitus.
Fig. 4: The nucleotide-binding sites on SUR1.
Fig. 5: Location of SUR1 residues altered in neonatal diabetes mellitus.

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Acknowledgements

Work in the F.M.A. and P.J.S. laboratories is funded by the UK Biotechnology and Biological Sciences Research Council, the UK Medical Research Council and the Wellcome Trust. T.P. and S.U. hold Wellcome Trust OXION studentships. The authors thank M. Puljung (University of Oxford) for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Tanadet Pipatpolkai, Samuel Usher & Frances M. Ashcroft

  2. Department of Biochemistry, University of Oxford, Oxford, UK

    Tanadet Pipatpolkai & Phillip J. Stansfeld

  3. School of Life Sciences, University of Warwick, Coventry, UK

    Phillip J. Stansfeld

  4. Department of Chemistry, University of Warwick, Coventry, UK

    Phillip J. Stansfeld

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T.P., S.U., P.J.S. and F.M.A., researched data for the manuscript and substantially contributed to discussion of the content. F.M.A. wrote the manuscript and reviewed/edited the manuscript before submission.

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Glossary

DEND syndrome

A syndrome caused by KCNJ11 mutations that produce a severe reduction in channel sensitivity to ATP inhibition. It is characterized by permanent neonatal diabetes mellitus, epilepsy and motor and mental development delay, and can be accompanied by features such as attention deficit hyperactivity disorder.

Cryo-electron microscopy

An electron microscopy method in which samples are cooled to cryogenic temperatures and embedded in vitreous water. It is widely used as an alternative to X-ray crystallography for determining the atomic structure of molecules, including ion channels.

Channel open probability

A measure of the fraction of the total recording time that an ion channel spends in its open state. An open probability of 1 indicates the channel is permanently open, and an open probability of 0 indicates the channel is always closed.

Fluorescence resonance energy transfer

The distance-dependent transfer of excitation energy from a fluorescent donor to a fluorescent acceptor that can be used for real-time imaging of the binding of a fluorescent ligand to a protein containing a fluorescent amino acid positioned close to the ligand-binding site.

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Pipatpolkai, T., Usher, S., Stansfeld, P.J. et al. New insights into KATP channel gene mutations and neonatal diabetes mellitus. Nat Rev Endocrinol 16, 378–393 (2020). https://doi.org/10.1038/s41574-020-0351-y

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