Effects of combination of mitiglinide with various oral antidiabetic drugs in streptozotocin-nicotinamide-induced type 2 diabetic rats and Zucker fatty rats.

We examined the effects of combining the rapid insulin secretagogue, mitiglinide, with various oral hypoglycaemic drugs including biguanides, pioglitazone, α-glucosidase inhibitors, and sodium-glucose co-transporter 2 inhibitors in a rat model of type 2 diabetes. The oral glucose tolerance test (OGTT) using glucose, sucrose, or a liquid meal was used to compare the effects of mitiglinide with those of the four oral hypoglycaemic drugs and examine their combined effects on blood glucose levels and insulin secretion in the rat model. The combination of mitiglinide with other oral hypoglycaemic drugs suppressed the plasma glucose levels more than either agent did alone. Furthermore, the combination of these agents decreased insulin secretion more than mitiglinide did alone. These results indicate that mitiglinide is suitable for use in combination with other hypoglycaemic drugs because it inhibits postprandial hyperglycaemia by rapidly stimulating insulin secretion.

Comparison of the Effects of Mitiglinide and Glibenclamide Administered in Combination with the Dipeptidyl Peptidase-IV Inhibitor Sitagliptin in Rats with Streptozotocin-Nicotinamide-Induced Type 2 Diabetes.

We compared the individual effects of mitiglinide and glibenclamide administered in combination with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin on plasma DPP-IV activity and blood glucose levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes (STZ-NA rats). We examined the inhibitory activity of mitiglinide and glibenclamide as well as their combination with sitagliptin on plasma DPP-IV activity in STZ-NA rats. The oral glucose tolerance test (OGTT) was used to compare effects of mitiglinide, glibenclamide, and their combination with sitagliptin on blood glucose levels in STZ-NA rats. Mitiglinide and glibenclamide did not inhibit rat DPP-IV and did not influence the inhibitory effect of sitagliptin on rat plasma DPP-IV activity. In STZ-NA rats, plasma glucose levels were stronger suppressed by a combination of mitiglinide and sitagliptin than by either drug used alone. However, no clear effect of the combination of glibenclamide and sitagliptin was observed. These results indicate that the combination of mitiglinide and sitagliptin has a lower risk of hypoglycemia in the rats with induced type 2 diabetes compared with the combination of glibenclamide and sitagliptin. The combination of mitiglinide and sitagliptin can be a promising combination for the treatment of diabetic patients.

Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats.

The low-affinity sodium glucose cotransporter (SGLT2) is responsible for most of the glucose reabsorption in the kidney and has been highlighted as a novel therapeutic target for the treatment of diabetes. We discovered sergliflozin etabonate, a novel selective SGLT2 inhibitor, and found that selective inhibition of SGLT2 increased urinary glucose excretion and consequently decreased plasma glucose levels. In this report, we examined the antihyperglycemic effects of sergliflozin etabonate in normal and diabetic rats in comparison with those of a sulfonylurea (gliclazide) and an alpha-glucosidase inhibitor (voglibose). Sergliflozin etabonate increased urinary glucose excretion in a dose-dependent manner, and inhibited the increase in plasma glucose after sucrose loading independently of insulin secretion in normal rats. Sergliflozin etabonate also improved postprandial hyperglycemia in neonatal streptozotocin-induced diabetic rats; whereas gliclazide did not improve it. In rats with mild or moderate streptozotocin-induced diabetes, the degree of the antihyperglycemic effects of sergliflozin etabonate correlated with the severity of the diabetic condition. Sergliflozin etabonate did not affect the plasma glucose level of normal rats as seen with gliclazide. Chronic treatment with sergliflozin etabonate reduced the levels of glycated hemoglobin and fasting plasma glucose, and improved the glycemic response after glucose loading in Zucker fatty rats. In addition, sergliflozin etabonate did not affect the body weight or food intake. These data indicate that sergliflozin etabonate could improve glycemic control without its use resulting in insulin secretion, hypoglycemia, and body weight gain, and may provide a unique approach to the treatment of diabetes.

Effects of mitiglinide and sulfonylureas in isolated canine coronary arteries and perfused rat hearts.

Our aim was to compare the cardiovascular effects of mitiglinide ((+)-monocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate] dehydrate), a novel hypoglycemic drug, with those of glibenclamide and glimepiride, two sulfonylurea drugs. In isolated canine coronary arteries (organ-bath method), mitiglinide, glibenclamide, and glimepiride competitively antagonized the cromakalim-induced relaxation (pA2 values, 5.29, 7.36, and 7.49, respectively). In isolated perfused rat hearts (Langendorff method) subjected to a 12-min global ischemia followed by a 30-min reperfusion, mitiglinide (3 x 10(-6) mol/l) altered neither the change in coronary perfusion flow nor the alterations in cardiac functions associated with reperfusion. In contrast, both glibenclamide (3 x 10(-8) mol/l) and glimepiride (1 x 10(-7) mol/l) significantly reduced coronary perfusion flow after reperfusion. Moreover, at 30 min of reperfusion: (1) glibenclamide induced a significant increase in left ventricular end-diastolic pressure and significant decreases in left ventricular systolic pressure, left ventricular developed pressure, and the maximum first derivative of left ventricular pressure, while (2) glimepiride induced significant decreases in left ventricular developed pressure and the maximum first derivative of left ventricular pressure. Thus, the cardiovascular effects of mitiglinide (at least, in these rat and dog preparations) may be weaker than those of glibenclamide and glimepiride.

[Pharmacological and clinical profile of mitiglinide calcium hydrate (Glufast), a new insulinotropic agent with rapid onset].

Mitiglinide calcium hydrate (mitiglinide, Glufast) is a new insulinotropic agent of the glinide class with rapid onset. Mitiglinide is thought to stimulate insulin secretion by closing the ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells, and its early insulin release and short duration of action would be effective in improving postprandial hyperglycemia. In studies of various cloned K(ATP) channels, mitiglinide shows a higher selectivity for the beta-cell type of SUR1/Kir6.2 than the cardiac and smooth muscle types of K(ATP) channels in comparison with glibenclamide and glimepiride. In vitro and in vivo studies demonstrated the insulinotropic effect of mitiglinide is more potent than that of nateglinide, and mitiglinide surpassed in controlling postprandial hyperglycemia in normal and diabetic animals. In clinical trials, treatment with mitiglinide provided lasting improvement of postprandial hyperglycemia in Type 2 diabetic patients and decreased the fasting plasma glucose levels and HbA(1C) values. The incidence of adverse events related to mitiglinide were nearly equivalent to placebo; in particular there was no difference with the frequency of hypoglycemia. The results from these studies indicated that mitiglinide could be expected to possess good therapeutic features of being effective in reducing postprandial glucose excursions in the early stage of Type 2 diabetes and less incidence of events suggestive of hypoglycemia.

Study of the insulinotropic effect of the novel antihyperglycemic agent KAD-1229 using HIT T15 cells, a hamster's insulinoma cell line.

The insulinotropic effect of (+)-monocalcium bis [(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl)propionate] dihydrate (CAS 145375-43-5, KAD-1229) was assessed by comparing it with those of glibenclamide (CAS 10238-21-8), nateglinide (CAS 105816-04-4), and repaglinide (CAS 135062-02-1) using HIT T15 cells, a hamster insulinoma cell line. Although their potencies were different, KAD-1229, glibenclamide, nateglinide, and repaglinide all concentration-dependently and significantly induced insulin release from these cells. Further, each agent displaced the binding of 3H-glibenclamide to the cell membrane and inhibited 86Rb+ efflux from the cells. These results indicate that KAD-1229, glibenclamide, nateglinide, and repaglinide each exert their insulinotropic effect by binding to the glibenclamide binding sites (sulfonylurea receptors) on pancreatic beta-cells and closing K+ channels. Diazoxide, a K+ channel opener, and nitrendipine, a Ca2+ blocker, suppressed the insulin release induced by KAD-1229 or glibenclamide. These results demonstrate that the insulinotropic actions of KAD-1229 and glibenclamide involve similar underlying pathways.

Effect of KAD-1229, a novel hypoglycaemic agent, on plasma glucose levels after meal load in type 2 diabetic rats.

1. The effects of KAD-1229 (a novel non-sulphonylurea agent), voglibose (an alpha-glucosidase inhibitor) and nateglinide (a non-sulphonylurea antihyperglycaemic agent) on hyperglycaemia induced by a meal load were assessed in diabetic rats. 2. KAD-1229 suppressed the increase in plasma glucose levels seen after a meal load and the area under the curve for plasma glucose levels (AUCglucose) up to 5 h after the meal load. 3. Voglibose also suppressed the increase in plasma glucose levels; however, a significant decrease in AUCglucose following voglibose was not observed. 4. Nateglinide suppressed the increase in plasma glucose levels at 30 min and 1 h after the meal load; however, plasma glucose levels was above control thereafter and the AUCglucose was not decreased. 5. The results indicate that KAD-1229 has an antihyperglycaemic effect and KAD-1229 is suggested to be a suitable agent for controlling post-prandial hyperglycaemia.