Control of insulin secretion by sulfonylureas, meglitinide and diazoxide in relation to their binding to the sulfonylurea receptor in pancreatic islets.
Sulfonylureas inhibit an ATP-dependent K+ channel in the B-cell plasma membrane and thereby initiate insulin release. Diazoxide opens this channel and inhibits insulin release. In mouse pancreatic islets, we have explored whether other targets for these drugs must be postulated to explain their hypo- or hyperglycaemic properties. At non-saturating drug concentrations the rates of increase in insulin secretion declined in the order tolbutamide = meglitinide greater than glipizide greater than glibenclamide. The same rank order was observed when comparing the rates of disappearance of insulin-releasing and K+ channel-blocking effects. The different kinetics of response depend on the lipid solubility of the drugs, which controls their penetration into the intracellular space. Allowing for the different kinetics, the same maximum secretory rates were caused by saturating concentrations of tolbutamide, meglitinide, glipizide and glibenclamide. A close correlation between insulin-releasing and K+ channel-blocking potencies of these drugs was observed. The relative potencies of tolbutamide, meglitinide, glipizide and glibenclamide corresponded well to their relative affinities for binding to islet-cell membranes, suggesting that the binding site represents the sulfonylurea receptor. The biphasic time-course of dissociation of glibenclamide binding indicates a complex receptor-drug interaction. For diazoxide there was no correlation between affinity of binding to the sulfonylurea receptor and potency of inhibition of insulin secretion. Thus, opening or closing of the ATP-dependent K+ channel by diazoxide or sulfonylureas, respectively, appears to be due to interaction with different binding sites in the B-cell plasma membrane. The free concentrations of tolbutamide, glipizide, glibenclamide and diazoxide which are effective on B-cells are in the range of therapeutic plasma concentrations of the free drugs. It is concluded that the hypo- and hyperglycaemic effects of these drugs result from changing the permeability of the ATP-dependent K+ channel in the B-cell plasma membrane.
Panten
U
U
Institute of Pharmacology and Toxicology, University of Göttingen, Federal Republic of Germany.
Burgfeld
J
J
Goerke
F
F
Rennicke
M
M
Schwanstecher
M
M
Wallasch
A
A
Zünkler
B J
BJ
Lenzen
S
S
D018528:ATP-Binding Cassette Transporters; D000418:Albumins / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003981:Diazoxide / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying; D011485:Protein Binding; D011955:Receptors, Drug / Q000378:metabolism*; D012995:Solubility; D013453:Sulfonylurea Compounds / Q000378:metabolism / Q000494:pharmacology; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D000418:Albumins; D001549:Benzamides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; C030516:meglitinide; D003981:Diazoxide