Sulphonylurea action revisited: the post-cloning era

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Abstract
Hypoglycaemic agents such as sulphonylureas and the newer group of "glinides" stimulate insulin secretion by closing ATP-sensitive potassium (KATP) channels in pancreatic beta cells, but have varying cross-reactivity with related channels in extrapancreatic tissues such as heart, vascular smooth and skeletal muscle. Experiments on the structure-function relationships of recombinant KATP channels and the phenotypes of mice deficient in different KATP channel subunits have provided important insights into the mechanisms underlying sulphonylurea selectivity, and the potential consequences of KATP channel blockade outside the pancreatic beta cell. The different pharmacological properties of KATP channels from beta cells compared with those from cardiac, smooth and skeletal muscle, are accounted for by the expression of alternative types of sulphonylurea receptor, with non-identical drug binding sites. The sulphonylureas and glinides are found to fall into two groups: one exhibiting selectivity for beta cell sulphonylurea receptors (SUR1), and the other blocking cardiovascular and skeletal muscle sulphonylurea receptors (SUR2) with potencies similar to their action on SUR1. In seeking potential side effects of KATP channel inhibitors in humans, it is essential to take these drug differences into account, along with the probability (suggested by the studies on KATP channel knockout mice) that the effects of extrapancreatic KATP channel inhibition might be either subtle or rare. Further studies are still required before a final decision can be made on whether non-selective agents are appropriate for the therapy of Type 2 diabetes.