ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Rev Endocrinol 2020 May 6. doi: 10.1038/s41574-020-0351-y. [Epub ahead of print]. PMID:32376986

ATP-sensitive potassium (K_ATP) channels are composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1). This channel has a hetero-octameric structure compromising of four SUR1 subunits and four Kir6.2 units. Metabolic signals generated in the beta-cells in the form of nucleotides (such as ADP and ATP) regulate the function of this channel. This regulation of the activity of the K_ATP channel by adenine nucleotides is central to its ability to control insulin secretion. Alterations in the levels of ATP and ADP close the channel and magnesium nucleotides (MgATP and MgADP) open the channel. Inactivating mutations in these channels lead to congenital hyperinsulinism (CHI) and activating mutations cause neonatal diabetes mellitus (NDM).

This ‘state of the art’ review provides an in-depth understanding of how mutations in the genes encoding these channels lead to NDM and the mechanisms of action of sulphonylurea therapy in patients with NDM. Novel techniques such as cryo-electron microscopy (similar to X-ray crystallography) have aided understanding of the atomic level organization of the K_ATP channel complex and identification of the binding sites for nucleotides and sulphonylurea drugs. This has informed understanding of how mutations cause NDM and their functional effects. Gain of function mutations that lead to NDM result in K_ATP channels with reduced sensitivity to inhibition by ATP and therefore remain in the open state despite hyperglycaemia. There is some correlation between the ability of a given mutation to reduce the ATP sensitivity of the channel and the clinical phenotype, with the more severe mutations leading to NDM and neurological features.

Analysis of cryo- electron microscopy structures has shown that sulfonylureas and glinides bind within the same pocket, which lies within the transmembrane domains of SUR1. Most NDM patients can be transferred onto oral sulphonylurea, but not every patient responds to sulphonylurea. Whether a patient responds to oral sulphonylurea is determined by their specific mutation and duration of diabetes (1). Some mutations in the channel genes can affect the efficacy of sulphonylurea. Understanding the structure and functional aspects of K_ATP channels has provided unique insights into beta-cell physiology and disease mechanism but more importantly improved patient care and management.

Reference:

1. Babiker T, Vedovato N, Patel K, et al.Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes mellitus is determined by the mutation and duration of diabetes. Diabetologia, 2016;59:1162–1166.