Effects of tolbutamide and N-benzoyl-D-phenylalanine (NBDP) on the regulation of [Ca2+]i oscillations in mouse pancreatic islets.
The sulfonylurea derivative, tolbutamide, and the phenylalanine derivative, N-benzoyl-D-phenylalanine (NBDP), both of which stimulate insulin secretion through interaction with the sulfonylurea receptor (SUR1), were studied for their ability to increase the [Ca(2+)](i) and to interact with the glucose-induced slow large amplitude [Ca(2+)](i) oscillations in isolated mouse pancreatic islets. Tolbutamide as well as NBDP induced [Ca(2+)](i) oscillations of extremely slow frequency. Both compounds also lowered the threshold for the glucose-induced slow large amplitude [Ca(2+)](i) oscillations and significantly reduced their frequency in intact islets as well as in single pancreatic beta cells. These [Ca(2+)](i) oscillations apparently require a glucokinase-mediated glycolytic flux. This conclusion is supported by the observations that KIC, a mitochondrial fuel, cannot replace glucose in this synergism and that mannoheptulose, an inhibitor of glucokinase and glucose-induced insulin secretion, abolishes these slow [Ca(2+)](i) oscillations. In conclusion, these compounds potentiate the effect of glucose. This additive effect is the likely result of a synergistic closing action upon the ATP-sensitive K(+) (K(ATP)) channel, mediated in the case of glucose through an action upon the channel protein itself of ATP generated in glucose catabolism and in the case of tolbutamide and NBDP upon the sulfonylurea receptor (SUR1) associated with this channel.
Lenzen
S
S
Institute of Clinical Biochemistry, Hannover Medical School, D-30623, Hannover, Germany.
Peckmann
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019920:Photoaffinity Labels / Q000494:pharmacology; D015221:Potassium Channels; D014044:Tolbutamide / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D019920:Photoaffinity Labels; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D010649:Phenylalanine; D014044:Tolbutamide; C053764:benzoylphenylalanine; D005947:Glucose; D002118:Calcium