Insulinotropic action of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate. I. Secretory and cationic aspects.
1. Sodium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate (KAD-1229) is a newly introduced non-sulphonylurea insulinotropic agent. 2. It failed to affect insulin release by rat islets incubated in the absence of D-glucose, slightly increased insulin output at 2.8 mM D-glucose and markedly enhanced secretion at 6.0 and 11.1 mM D-glucose. At the latter hexose concentration, the threshold concentration for the insulinotropic action of KAD-1229 was below 0.1 microM and a close-to-maximal response recorded with 1.0 microM KAD-1229. Even at 16.7 mM D-glucose, KAD-1229 (10 microM) still augmented insulin output. 3. At 6.0 mM D-glucose, KAD-1229 (0.1-1.0 microM) caused a concentration-related increase in 45Ca uptake. This coincided, in prelabelled islets, with a rapid and dual change in 86Rb outflow and dramatic increase in 45Ca outflow. 4. KAD-1229 also increased insulin release evoked by 2-ketoisocaproate (10 mM), albeit to a lesser extent than observed at a D-glucose concentration of comparable insulinotropic efficiency. 14C-labelled KAD-1229 was poorly oxidized by the islets. 5. These findings support the view that the mode of action of KAD-1229 displays analogy with that of hypoglycemic sulphonylurea.
Malaisse
W J
WJ
Laboratory of Experimental Medicine, Erasmus School of Medicine, Brussels Free University, Belgium.
Sato
F
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D054833:Isoindoles; D010194:Pancreatin / Q000187:drug effects; D051381:Rats; D012413:Rubidium / Q000378:metabolism; D013997:Time Factors
D002412:Cations; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D054833:Isoindoles; D010194:Pancreatin; C087255:mitiglinide; D012413:Rubidium; D002118:Calcium