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 defective 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 heterozygous (+/-) mice with EC50 of 3.2 mM and 5.5 mM, respectively, in newborn animals, and of 4.7 mM and 9.9 mM, respectively, in 1.5-year-old mice. Glucose (20 mmol/l) did not affect the resting membrane potential of -/- beta cells but depolarised wild-type and + /- beta cells and induced electrical activity. In contrast, 20 mmol/l ketoisocaproic acid or 0.5 mmol/ l tolbutamide depolarised all three types of beta-cell. These results support the idea that defective glycolytic metabolism, produced by a loss (-/- mice) or reduction (+/- mice) of glucokinase activity, leads to defective K(ATP) channel regulation and thereby to the selective loss, or reduction, of glucose-induced insulin secretion.
Sakura
H
H
University Laboratory of Physiology, Oxford, UK.
Ashcroft
S J
SJ
Terauchi
Y
Y
Kadowaki
T
T
Ashcroft
F M
FM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D005057:Eukaryotic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005941:Glucokinase / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D007651:Keto Acids / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D014044:Tolbutamide / Q000494:pharmacology
D007004:Hypoglycemic Agents; D007651:Keto Acids; D015221:Potassium Channels; C013082:alpha-ketoisocaproic acid; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005941:Glucokinase; D005947:Glucose