GLUCOSE MODULATION OF ATP-SENSITIVE K-CURRENTS IN WILD-TYPE, HOMOZYGOUS AND HETEROZYGOUS GLUCOKINASE KNOCK-OUT MICE

One type of maturity-onset diabetes of the young (MODY2) is caused by mutations in the glucokinase gene, a key glycolytic enzyme in the beta cell and liver. Glucose fails to stimulate insulin secretion in mice in which the glucokinase gene has been selectively knocked out in the beta cell. We tested the hypothesis that this effect results from defe ctive metabolic regulation of beta cell ATP-sensitive potassium (K-ATP ) channels. Glucose had little effect on K-ATP currents in homozygous (-/-) mice but inhibited K-ATP currents in wild-type (+/+) and heteroz ygous (+/-) mice with EC50 of 3.2 mM and 5.5 mM, respectively, in newb orn animals, and of 4.7 mM and 9.9 mM, respectively, in 1.5-year-old m ice. Glucose (20 mmol/l) did not affect the resting membrane potential of -/- beta cells but depolarised wild-type and +/- beta cells and in duced electrical activity In contrast, 20 mmol/l ketoisocaproic acid o r 0.5 mmol/l tolbutamide depolarised all three types of beta-cell. The se results support the idea that defective glycolytic metabolism, prod uced by a loss (-/- mice) or reduction (+/- mice) of glucokinase activ ity, leads to defective K-ATP channel regulation and thereby to the se lective loss, or reduction, of glucose-induced insulin secretion.