ATP-sensitive potassium (KATO channels play a central role in glucose-stimulated insulin secretion (GSIS) by pancreatic beta-cells. Activity of these channels is determined by their open probability (P.) and the number of channels present in a cell. Glucose is known to reduce P-o, but whether it also affects the channel density is unknown. Using INS-I model beta-cell line, we show that the expression of K-ATP channel subunits, Kir6.2 and SUR1, is high at low glucose, but declines sharply when the ambient glucose concentration exceeds 5 mM. In response to glucose deprivation, channel synthesis increases rapidly by up-regulating translation of existing mRNAs. The effects of glucose deprivation could be mimicked by pharmacological activation of 5'-AMP-activated protein kinase with 5-aminoimidazole-4-carboxamide ribonucleotide and metformin. Pancreatic beta-cells which have lost their ability for GSIS do not show such changes implicating a possible (patho-) physiological link between glucose-regulated KATP channel expression and the capacity for normal GSIS. (c) 2006 Elsevier Inc. All rights reserved.