Review
Potassium Channels, Sulphonylurea Receptors and Control of Insulin Release

https://doi.org/10.1016/S1043-2760(98)00135-0Get rights and content

Abstract

Clinical profiles of the glucose regulation disorders persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) and diabetes mellitus are diametrically opposed: unregulated insulin secretion versus insulin insufficiency. Yet, despite this, recent studies of PHHI and other rare neonatal conditions have revealed common pathways of cellular dysfunction relevant to our understanding of diabetes. Such work has been based upon integration of the genetics of these diseases with the cellular and molecular biology of a potassium channel known to play a major role in the ‘glucose-sensing apparatus’ of the pancreatic β cell – the ATP-sensitive K+ (KATP) channel. The structure of this protein complex is unique among ion channel families, because it is composed partly of a K+ channel and partly of an ATP-binding cassette protein that has an extraordinarily high affinity for sulphonylurea compounds. Here, we describe how defects in KATP channel genes give rise to insulin hypersecretion, and may also predispose to the onset of Type 2 diabetes, and how acquired losses of function of these channels have been implicated in maturity onset diabetes of the young and reactive hyperinsulinaemia-induced hypoglycaemia.

Section snippets

K+ Channels and Sulphonylurea Receptors

Insulin-secreting cells express a KATP channel complex formed by the interaction of subunits belonging to at least two distinct families of proteins (for a review see Ref. 2) (Fig. 2). The K+-selective pore or tunnel is formed by the Kir6.2 subunit, a member of the inward rectifier K+ channel family. Kir6.2 shares ∼70% homology with Kir6.1, consists of 390 amino acids, and has a predicted membrane topology with two α-helical transmembrane domains linked by a highly conserved sequence of amino

K+ Channels and Unregulated Insulin Secretion

Hypoglycaemia is a relatively common childhood metabolic abnormality and when persistent or recurrent is most frequently a consequence of hyperinsulinism; neonatal hyperinsulinism (OMIM: 256450) (for a recent review see Ref. 18). Until recently, the pathophysiology of this group of conditions was not understood, although a defect in β-cell function was first suggested in 1981, when it was shown that glucose failed to promote a concentration-dependent release of insulin in tissue isolated from a

Future Directions

Progress in the areas covered in this review has been impressive over the past few years, yet many key questions remain. Are there additional KATP channel subunits to be discovered? How do nucleotides bring about opening and closure of channels after interactions with the subunits? How are the subunits associated and targeted to the cell membrane? The genetics of PHHI are still far from resolved; autosomal recessive and dominant inheritance have been described, as well as loss of maternal

Acknowledgements

Work in our laboratories is supported by the British Diabetic Association (MJD), the Medical Research Council (MJD) and the Economic Union (MJD, CÄ); and by Stiftelsen Clas Groschinskys minnesfond, Tore Nilssons Stiftelse, Åke Wibergs Stiftelse, Wilhelm och Martina Lundgrens vetenskapsfond, Swedish Medical Research Council (CÄ). KEC was supported by a Medical Research Council Studentship.

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