IN-VITRO INSULINOTROPIC ACTION OF A NEW NON-SULFONYLUREA HYPOGLYCEMIC AGENT, CALCIUM (2S)-2-BENZYL-3-(CIS-HEXAHYDRO-2-ISOINDOLINYL-CARBONYL) PROPIONATE DIHYDRATE (KAD-1229), IN RAT PANCREATIC B-CELLS

We examined the in vitro insulinotropic action of a novel non-sulfonylurea compound, calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate dihydrate (KAD-1229), which is a succinate derivative, using rat pancreatic islets and perfused pancreas. The sodium salt of KAD-1229 free acid (KAD-1229-Na) stimulated insulin secretion from isolated rat islets and perfused rat pancreas in a concentration-dependent manner at 0.1 to 10 mu M. It produced a predominant first phase and a less prominent second phase response in the presence of 5.55 mM glucose. An ATP-sensitive K+ (K-ATP(+)) channel activator, diazoxide, eliminated the insulinotropic effect of KAD-1229-Na. Glucose primed the B-cell in the perfused pancreas, but KAD-1229-Na did not. When the insulinotropic effects of 16.7 mM glucose on isolated rat islets were inhibited submaximally by 1 mu M norepinephrine, the addition of 1 mu M KAD-1229-Na reversed this inhibition. All of these insulinotropic effects of KAD-1229-Na were qualitatively indistinguishable from those of sulfonylurea compounds. We conclude that KAD-1229-Na acts on K-ATP(+) channels of pancreatic B-cells despite its non-sulfonylurea structure.