A Rapid- and Short-Acting Hypoglycemic Agent KAD-1229 Improves Post-Prandial Hyperglycemia and Diabetic Complications in Streptozotocin-Induced Non-Insulin-Dependent Diabetes Mellitus Rats

Abstract

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.

Effect of mitiglinide on Streptozotocin-induced experimental type 2 diabetic rats: A urinary metabonomics study based on ultra-performance liquid chromatography–tandem mass spectrometry

“…It is thought to stimulate insulin secretion by closing the ATP-sensitive K + (K ATP ) channels in pancreatic beta-cells. Its early insulin release and short duration of action could be effective in improving postprandial hyperglycemia [31]. However, as a newly developed drug, the exact mechanism of mitiglinide is not clear yet.…”

Perturbation of mitiglinide metabolism by chronic unpredicted mild stress in rats

“…MGN is thought to stimulate insulin secretion by closing the ATP-sensitive K + (K ATP ) channels in pancreatic beta cells18. Its early insulin release and short duration of action is effective to improve postprandial hyperglycemia19. Currently MGN is an ideal drug to treat type 2 diabetes and is widely used in clinical practice.…”

Effect of KAD-1229, a Nonsulfonylurea Hypoglycemic Agent, on Plasma Glucose and Insulin in Streptozotocin-Induced Diabetic Dogs

“…Our previous studies in normal animals (rats, rabbits and dogs) and our in vitro experiments have demonstrated that the hypoglycemic effect of KAD-1229 (i) has a rapid onset and persists for only a short time and (ii) is derived from its biphasic insulinreleasing action on pancreatic ß-cells after binding to SU receptors [9][10][11]. In addition, KAD-1229 was also found to be effective at lowering postprandial plasma glucose in type 2 diabetes model rats [12,13]. However, changes in plasma glucose and insulin levels were not evaluated simultaneously in one and the same animal, because the rat is too small for a sufficient volume of blood to be withdrawn at a given time.…”