title: Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma 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) gamma 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 gamma 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.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, Kashima 2 chome, Osaka 532-8514, Japan. hideaki.minoura@jp.astellas.com
authors.forename: Hideaki
authors.initials: H
authors.lastname: Minoura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takeshita
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Miyuki
authors.initials: M
authors.lastname: Mabuchi
authors.forename: Jiro
authors.initials: J
authors.lastname: Hirosumi
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
authors.forename: Jiro
authors.initials: J
authors.lastname: Seki
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Manda
authors.forename: Makoto
authors.initials: M
authors.lastname: Ita
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
chemical_list: C496142:3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide; D001562:Benzimidazoles; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin; D005947:Glucose; D000077205:Pioglitazone