May 8, 2020

New insights into KATP channel gene mutations and neonatal diabetes mellitus

Nature Reviews. Endocrinology
Tanadet PipatpolkaiFrances M Ashcroft

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 (A...Continue Reading

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Mentioned in this Paper

Insulin/Insulin Receptor Signaling Pathway
Channel
Physiologic Organization
Insulin Secretion
Glinide [EPC]
First-Line Therapy
Gene Mutation
ABCC8 protein, human
KATP Channels
Adenosine Triphosphate

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