Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor γ agonist, on insulin resistance in Zucker fatty rat

Abstract

Effect of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (FK614), a novel nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) γ agonist, on glucose tolerance and insulin resistance in peripheral tissues and in liver using Zucker fatty rats (genetically obese and insulin-resistant) was evaluated and compared to other insulin sensitizers. FK614 (0.32, 1 and 3.2 mg/kg), two thiazolidinedione PPAR γ agonists, rosiglitazone (0.1, 0.32, 1 and 3.2 mg/kg) and pioglitazone (1, 3.2 and 10 mg/kg), and a biguanide, metformin (320 and 1000 mg/kg), were orally administered to Zucker fatty rats once a day for 14 days. Zucker fatty rats treated with FK614 and rosiglitazone were subjected to evaluation by oral glucose tolerance test. Ameliorating effect of each compound on peripheral and hepatic insulin resistance was evaluated using a euglycemic–hyperinsulineamic clamp procedure. FK614 and rosiglitazone dose-dependently improved impaired glucose tolerance in Zucker fatty rats. In addition, FK614 dose-dependently ameliorated peripheral and hepatic insulin resistance in Zucker fatty rats, with the degree of its effect in peripheral tissues almost equivalent to that in liver when compared at each dose tested. Similar data indicating ameliorating effects on insulin resistance was obtained for rosiglitazone and pioglitazone. Metformin showed less potent effects than other insulin sensitizers and its effect in liver tended to be greater than that in peripheral tissues. These findings suggest clinical potential for FK614 as a treatment of type 2 diabetes, acting by ameliorating insulin resistance both in peripheral tissues and liver.

Introduction

Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring in peripheral tissues (muscle and adipose tissues) and liver, leading to reduced glucose uptake and utilization and increased glucose production, respectively. Amelioration of insulin resistance in both the peripheral tissues and liver is thought to be a reasonable treatment of type 2 diabetes. Recently, two thiazolidinedione derivatives, rosiglitazone and pioglitazone, insulin sensitizers available for clinical use in treatment of type 2 diabetes, were shown to improve glycemic control by ameliorating insulin resistance in both peripheral tissues and liver in type 2 diabetic patients (Bajaj et al., 2003, Tiikkainen et al., 2004, Miyazaki et al., 2001a, Miyazaki et al., 2001b, Miyazaki et al., 2002a, Miyazaki et al., 2002b, Miyazaki et al., 2003). Thiazolidinedione derivatives are agonists for peroxisome proliferator-activated receptor (PPAR) γ, a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors that regulates expression of genes closely related to adipocyte differentiation, glucose and lipid metabolism and appear to function as insulin sensitizers mainly through this nuclear receptor activation (Spiegelman, 1998).

A novel nonthiazolidinedione PPAR γ agonist, 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (FK614), shows potent antidiabetic effects in db/db mice, a representative animal model of type 2 diabetes (Minoura et al., 2004). In addition, FK614 improves impaired glucose tolerance in ob/ob mice without enhancing insulin secretion (Minoura et al., 2004), suggesting it has the ability to improve insulin sensitivity. However, it is not clear whether FK614 ameliorates insulin resistance in peripheral tissues or liver. To answer this question, ameliorating effect of FK614 on insulin resistance in the peripheral tissues and liver was investigated in Zucker fatty rat, an animal with insulin resistance in both the peripheral tissues and liver (Terrettaz and Jeanrenaud, 1983). FK614 was compared with two thiazolidinedione PPAR γ agonists, rosiglitazone and pioglitazone, and a biguanide, metformin, whose mechanism of action is thought to involve suppression of endogenous glucose production mainly by the liver (Cusi et al., 1996, Inzucchi et al., 1998, Stumvoll et al., 1995). Evaluation using a euglycemic–hyperinsulineamic clamp procedure indicated that FK614, as well as rosiglitazone and pioglitazone, potently ameliorates both peripheral and hepatic insulin resistance in Zucker fatty rats.