Sulphonylurea action revisited: the post-cloning era.
Hypoglycaemic agents such as sulphonylureas and the newer group of "glinides" stimulate insulin secretion by closing ATP-sensitive potassium (K(ATP)) 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 K(ATP) channels and the phenotypes of mice deficient in different K(ATP) channel subunits have provided important insights into the mechanisms underlying sulphonylurea selectivity, and the potential consequences of K(ATP) channel blockade outside the pancreatic beta cell. The different pharmacological properties of K(ATP) 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 K(ATP) channel inhibitors in humans, it is essential to take these drug differences into account, along with the probability (suggested by the studies on K(ATP) channel knockout mice) that the effects of extrapancreatic K(ATP) 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.
Gribble
F M
FM
Department of Clinical Biochemistry, Addenbrooke's Hospital, Hills Road, Box 232, Cambridge CB2 2QR, UK. fmg23@cam.ac.uk
Reimann
F
F
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015221:Potassium Channels; D012106:Research / Q000639:trends; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; C117780:mitochondrial K(ATP) channel