A novel enhancer of insulinotrophic action by high glucose (JTT-608) stimulates insulin secretion from pancreatic beta-cells via a new cellular mechanism
N. Itabashi et al., A novel enhancer of insulinotrophic action by high glucose (JTT-608) stimulates insulin secretion from pancreatic beta-cells via a new cellular mechanism, J PHARM EXP, 297(3), 2001, pp. 953-960
Citations number
44
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Insulin secretion from MIN6 cells (a pancreatic beta -cell line) induced by
high glucose (greater than 16.8 mM) was potentiated by a novel hypoglycemi
c agent [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid (JTT-608)] (but not
glibenclamide, a sulfonylurea). The extracellular Ca2+-free condition, a L
-type Ca2+ channel blocker (nifedipine) and an ATP-sensitive Ki channel ope
ner, diazoxide, completely inhibited increases in cytosolic free Ca2+ ([Ca2
+](i)) and insulin secretion evoked by JTT-608 in the presence of extracell
ular Ca2+. An electrophysiological study using single-barreled microelectro
de techniques demonstrated that membrane potential (V-m) and input resistan
ce of the cell membrane (R-i) are depolarized acid increased by JTT-608, re
spectively. The apparent transference number for Kt 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 JT
T-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 [H-3]glibenclamide to the sulfonylurea recep
tor. These findings suggest that JTT-608 mainly inhibits ATP-sensitive K+ c
hannel activity via a binding site distinct from the sulfonylurea receptor
and then depolarizes V-m to open voltage-dependent L-type Ca2+ channels. Su
bsequently, these events stimulate Ca2+ entry to increase [Ca2+](i) and ind
uce insulin secretion from MIN6 cells. Therefore, JTT-608 is a unique hypog
lycemic agent that enhances high glucose-induced insulin secretion. The pre
sent findings indicate that JTT-608 is a more useful new class of therapeut
ic drug for patients with non-insulin-dependent diabetes mellitus, compared
with sulfonylurea derivatives.