A novel enhancer of insulinotrophic action by high glucose (JTT-608) stimulates insulin secretion from pancreatic beta-cells via a new cellular mechanism.
Insulin secretion from MIN6 cells (a pancreatic beta-cell line) induced by high glucose (greater than 16.8 mM) was potentiated by a novel hypoglycemic agent [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid (JTT-608)] (but not glibenclamide, a sulfonylurea). The extracellular Ca(2+)-free condition, a L-type Ca(2+) channel blocker (nifedipine) and an ATP-sensitive K(+) channel opener, diazoxide, completely inhibited increases in cytosolic free Ca(2+) ([Ca(2+)]i) and insulin secretion evoked by JTT-608 in the presence of extracellular Ca(2+). An electrophysiological study using single-barreled microelectrode techniques demonstrated that membrane potential (V(m)) and input resistance of the cell membrane (R(i)) are depolarized and increased by JTT-608, respectively. The apparent transference number for K(+) was also significantly decreased after the addition of JTT-608. These effects immediately occurred after addition of JTT-608 and very rapidly disappeared after removal of JTT-608, which has not been observed in sulfonylureas. Also, these effects of JTT-608 were diminished, but not completely by diazoxide. JTT-608 did not affect the specific binding of [(3)H]glibenclamide to the sulfonylurea receptor. These findings suggest that JTT-608 mainly inhibits ATP-sensitive K(+) channel activity via a binding site distinct from the sulfonylurea receptor and then depolarizes V(m) to open voltage-dependent L-type Ca(2+) channels. Subsequently, these events stimulate Ca(2+) entry to increase [Ca(2+)]i and induce insulin secretion from MIN6 cells. Therefore, JTT-608 is a unique hypoglycemic agent that enhances high glucose-induced insulin secretion. The present findings indicate that JTT-608 is a more useful new class of therapeutic drug for patients with non-insulin-dependent diabetes mellitus, compared with sulfonylurea derivatives.
Itabashi
N
N
Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Minamikawachi Tochigi, Japan.
Okada
K
K
Muto
S
S
Fujita
N
N
Ohta
T
T
Miyazaki Ji
Asano
Y
Y
Saito
T
T
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003510:Cyclohexanes / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005905:Glyburide / Q000493:pharmacokinetics / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D007424:Intracellular Fluid / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008839:Microelectrodes; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D002087:Butyrates; D002121:Calcium Channel Blockers; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D005947:Glucose; D003981:Diazoxide; D011188:Potassium; D005905:Glyburide; D002118:Calcium; C116719:4-(4-methylcyclohexyl)-4-oxobutyric acid