Study of the insulinotropic effect of the novel antihyperglycemic agent KAD-1229 using HIT T15 cells, a hamster's insulinoma cell line.
The insulinotropic effect of (+)-monocalcium bis [(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl)propionate] dihydrate (CAS 145375-43-5, KAD-1229) was assessed by comparing it with those of glibenclamide (CAS 10238-21-8), nateglinide (CAS 105816-04-4), and repaglinide (CAS 135062-02-1) using HIT T15 cells, a hamster insulinoma cell line. Although their potencies were different, KAD-1229, glibenclamide, nateglinide, and repaglinide all concentration-dependently and significantly induced insulin release from these cells. Further, each agent displaced the binding of 3H-glibenclamide to the cell membrane and inhibited 86Rb+ efflux from the cells. These results indicate that KAD-1229, glibenclamide, nateglinide, and repaglinide each exert their insulinotropic effect by binding to the glibenclamide binding sites (sulfonylurea receptors) on pancreatic beta-cells and closing K+ channels. Diazoxide, a K+ channel opener, and nitrendipine, a Ca2+ blocker, suppressed the insulin release induced by KAD-1229 or glibenclamide. These results demonstrate that the insulinotropic actions of KAD-1229 and glibenclamide involve similar underlying pathways.
Ichikawa
Kiyoshi
K
Pharmacology Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Minamiazumi, Nagano, 399-8304, Japan. kiyoshi_ichikawa@pharm.kissei.co.jp
Yamato
Tokuhisa
T
Tsuji
Atsutoshi
A
Ojima
Kazuma
K
Kusama
Hiroshi
H
Kojima
Masami
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000096:biosynthesis*; D007340:Insulinoma / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054833:Isoindoles; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D015221:Potassium Channels / Q000819:agonists; D012414:Rubidium Radioisotopes / Q000378:metabolism
D002121:Calcium Channel Blockers; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D054833:Isoindoles; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; C087255:mitiglinide; D005947:Glucose; D005905:Glyburide