Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (−)‐N‐(trans‐4‐isopropylcyclohexane‐carbonyl)‐d‐phenylalanine (A‐4166)

Abstract

Japan 1 (7)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166), a novel oral hypoglycaemic agent is a non-sulphonylurea insulin secretagogue. 2 We investigated the insulin-releasing action and hypoglycaemic e ect of A-4166 compared to sulphonylureas in vitro and in vivo. 3 A-4166 stimulated insulin secretion from rat freshly isolated pancreatic islets at concentrations from 3610 -6 M to 3610 -4 M in the presence of 2.8 mM glucose. There was no obvious di erence in glucose dependency between the insulinotropic e ect of A-4166 and that of glibenclamide, and no additive or synergistic e ect was observed between these two drugs. 4 A-4166 displaced [ 3 H]-glibenclamide bound to intact HIT-T15 cells in a concentration-dependent manner. The K i value was 4.34+0.04610 77 M, and the displacement potency of A-4166 was between that of glibenclamide and tolbutamide, being similar to that of gliclazide. 5 In fasted beagle dogs, A-4166 showed a dose-dependent hypoglycaemic e ect after oral administration over the range 1 to 10 mg kg 71 . The hypoglycaemic action of A-4166 showed an earlier onset and a shorter duration than that of sulphonylureas. 6 Simultaneous measurement of plasma insulin levels revealed that the hypoglycaemic e ect of A-4166 was caused by a rapid-onset and brief burst of insulin secretion. 7 The pharmacokinetic pro®le of A-4166 was consistent with the changes of the blood glucose and plasma insulin levels. 8 Although the in vitro insulin-releasing e ect of A-4166 was similar to that of sulphonylureas, its hypoglycaemic e ect was more rapid and shorter-lasting, associated with rapid absorption and clearance. Thus, A-4166 may be useful in suppressing postprandial hyperglycaemia in patients with non-insulindependent diabetes mellitus.

Nateglinide Suppresses Postprandial Hypertriglyceridemia in Zucker Fatty Rats and Goto-Kakizaki Rats: Comparison with Voglibose and Glibenclamide.

“…In addition, it has been pointed out that the optimum insulin secretagogue would be rapidly acting and has a short duration of effect, since the chronic hyperinsulinemia is undesirable. 9) Nateglinide is a recently approved oral hypoglycemic agent of a new class, which stimulates the early phase of insulin secretion by pancreatic b-cells, 10,11) and consequently suppresses postprandial hyperglycemia in both animals and patients with type 2 diabetes. 12,13) In this study, we established postprandial hypertriglyceridemia models using two different diabetic animals, obese Zucker fatty (ZF) rats with insulin resistance and Goto-Kakizaki (GK) rats with impaired insulin secretion.…”

H+-Dependent Transport Mechanism of Nateglinide in the Brush-Border Membrane of the Rat Intestine

“…Since nateglinide is absorbed rapidly form the intestine, it is likely to be absorbed via a specific transporter(s) (Sato et al, 1991;Ikenoue et al, 1997). It has been reported that nateglinide is actively transported in an absorptive direction across Caco-2 cell monolayers, although nateglinide itself is not transported by PepT1 or MCT1 (Terada et al, 2000;Okamura et al, 2002).…”

“…1). Although nateglinide stimulates insulin secretion via the same mechanism as that by which insulin secretion is stimulated by sulfonylureas, it quickly reaches the maximal serum concentration and is eliminated quite rapidly after oral administration (Shinkai et al, 1988;Sato et al, 1991;Ikenoue et al, 1997). Therefore, nateglinide can compensate for impaired insulin secretion to prevent postprandial hyperglycemia without causing prolonged hypoglycemia.…”

Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane

“…Since nateglinide is absorbed rapidly form the intestine, it is likely to be absorbed via a specific transporter(s) [2,3]. However, nateglinide is not transported by PEPT1 or MCT1 [8,9].…”

“…It is known that sulfonylurea therapy has several disadvantages, such as excess hypoglycemia between meals, due to the long duration of action of these agents. Nateglinide, on the other hand, can compensate for impaired insulin secretion to prevent postprandial hyperglycemia without causing prolonged hypoglycemia because it quickly reaches the maximal serum concentration and is eliminated quite rapidly after oral administration [1][2][3]. These characteristics of nateglinide are expected to be useful in the treatment of type 2 diabetes.…”