ABSTRACT-We investigated therapeutic effects of a rapid-and short-acting non-sulfonylurea hypoglycemic agent, calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229), on streptozotocin (STZ)-induced non-insulin-dependent diabetes mellitus (NIDDM) rats. The effects exerted by KAD-1229 on the post-prandial plasma glucose rise in STZ-induced mild NIDDM (mNIDDM) rats were different from those of sulfonylureas. When KAD-1229 with liquid meal (10 kcal/kg) was given to the mNIDDM rats, the plasma glucose migration was similar to that of normal healthy rats. On the contrary, glibenclamide had little or no effect on the plasma glucose rise 0.5-1 hr after oral adminis tration, and its effect was only evident 2-5 hr after dosing. Tolbutamide showed similar hypoglycemia to that induced by glibenclamide at 2-5 hr with insufficient efficacy at 0.5 hr. Gliclazide sufficiently sup pressed the level of post-prandial plasma glucose. However, its complete inhibition of post-prandial plasma glucose was associated with the extra-hypoglycemia 1-5 hr after oral administration. We also tested the efficacy of KAD-1229 in more severe STZ-induced NIDDM (sNIDDM) rats to elucidate the effects of the drug on the long-term glycemic controls and diabetic complications. When the sNIDDM rats were treated with 10 mg/kg KAD-1229 twice a day for about 17 weeks, increases in fasting plasma glucose and hemoglobin A1c were inhibited. Furthermore, treatment with KAD-1229 suppressed the development of microalbuminuria and cortical cataract. We conclude that the rapid-and short-acting insulinotropic agent KAD-1229 is able to improve the deterioration in the glycemic controls and inhibit the development of dia betic complications in STZ-induced NIDDM rats.

We examined the cooperative effect of a newly synthesized oral hypoglycaemic agent, KAD‐1229 with glucose on insulin, glucagon and somatostatin secretion in the isolated perfused pancreas of the rat. KAD‐1229 stimulated concentration‐dependently the first phase of insulin secretion without the second phase in the presence of 2.8 mM glucose, while it stimulated both the first and the second phase of insulin release in the presence of 5.6 mM glucose. It was confirmed that the first phase of insulin release is depolarization‐induced release with no other additional signal transduction. KAD‐1229 also enhanced insulin release evoked by 16.7 mM glucose, a concentration known to inhibit the ATP‐sensitive K+ current completely. A low concentration (2.8 mM) of glucose stimulated somatostatin release transiently, while a higher concentration (16.7 mM) of glucose exerted a sustained stimulation. KAD‐1229 stimulated somatostatin secretion in a concentration‐dependent manner irrespective of glucose concentrations. When glucagon release was stimulated with 2.8 mM glucose, KAD‐1229 inhibited this hypoglycaemia‐induced glucagon secretion. When pancreata from rats pretreated with streptozotocin (STZ) 60 mg kg−1 were perfused, the basal secretion of glucagon was markedly elevated, and the glucagon response to the low glucose was abolished. Further, the insulin and somatostatin responses to KAD‐1229 were largely attenuated. KAD‐1229 showed transient enhancement followed by inhibition of the glucagon release from the STZ‐pretreated rat pancreas. We conclude that KAD‐1229 stimulates insulin and somatostatin release, while it inhibits glucagon release following transient stimulation.

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