LAUSR

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. Gain-of-function mutations in the genes encoding ATP-sensitive potassium channel (KATP channel) subunits cause neonatal diabetes mellitus. This Review discusses the mechanism of action of mutations that lead to neonatal diabetes mellitus and briefly reviews work on the management of this disease. 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. 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.