Insulinotropic action of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate I. Secretory and cationic aspects

1. 1. Sodium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate (KAD-1229) is a newly introduced non-sulphonylurea insulinotropic agent. 2. 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 μM and a close-to-maximal response recorded with 1.0 μM KAD-1229. Even at 16.7 mM D-glucose, KAD-1229 (10 μM) still augmented insulin output. 3. 3. At 6.0 mM D-glucose, KAD-1229 (0.1-1.0 μM) 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. 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. 5. These findings support the view that the mode of action of KAD-1229 displays analogy with that of hypoglycemic sulphonylurea. © 1995.SCOPUS: ar.j