Normalization of impaired glucose tolerance by the short-acting hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus rats.

We have investigated the hypoglycemic effects of the newly synthesized short-acting nonsulphonylurea hypoglycemic agent calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)-propionate dihydrate (KAD-1229) in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM rats that were given a neonatal injection of 60 mg/kg streptozotocin showed a dose-dependent but attenuated response to oral administration of KAD-1229 and gliclazide, and their impaired glucose tolerance was improved but not normalized. We next produced, using a neonatal injection of 30 mg/kg streptozotocin, a mild type of NIDDM rat with less impaired glucose tolerance. These rats responded well to these insulinotropic hypoglycemic agents. Their impaired glucose and meal tolerance were completely normalized by oral administration of 3 mg/kg KAD-1229. The efficacy of KAD-1229 in this NIDDM rat model 1-3 h after oral glucose administration was comparable with similar doses of gliclazide, despite its shorter hypoglycemic action (compared with gliclazide), in fasting normal rats. In meal tolerance tests (20 kcal/kg; 1 cal = 4.2 J), KAD-1229 reduced abnormally enhanced plasma glucose levels 1-3 h after administration. This effect disappeared by 5 h. In contrast, gliclazide showed sustained hypoglycemic effects until 5 h after oral administration, with a lower postprandial (0.5-1 h) effect. These data indicated that the rapid- and short-acting efficacy of KAD-1229 would be beneficial and sufficient to control postprandial plasma glucose in NIDDM rats.