New insights into KATP channel gene mutations and neonatal diabetes mellitus

被引:0
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作者
Tanadet Pipatpolkai
Samuel Usher
Phillip J. Stansfeld
Frances M. Ashcroft
机构
[1] University of Oxford,Department of Physiology, Anatomy and Genetics
[2] University of Oxford,Department of Biochemistry
[3] University of Warwick,School of Life Sciences
[4] University of Warwick,Department of Chemistry
来源
Nature Reviews Endocrinology | 2020年 / 16卷
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摘要
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.
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页码:378 / 393
页数:15
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