title: Antidiabetic and hypolipidemic effects of a novel dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, E3030, in db/db mice and beagle dogs.
abstract: We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma, in an animal model of diabetes, C57BL/KsJ-db/db mice (db/db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARalpha and PPARgamma transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARalpha, mouse PPARalpha, dog PPARalpha, human PPARgamma, mouse PPARgamma, and dog PPARgamma with EC(50) values of 65, 920, 87, 34, 73, and 34 nM, respectively, in the chimeric GAL4-PPAR receptor transactivation reporter assay. In db/db mice orally administered E3030 decreased blood glucose, triglyceride (TG), non-esterified fatty acids (NEFA), and insulin levels and increased blood adiponectin levels during a 14-day experimental period. Significant effects on blood glucose and adiponectin levels were observed at a dose of 3 mg/kg or greater. Furthermore, significant effects on blood TG, NEFA, and insulin levels were observed at doses of 1 mg/kg or more. An oral glucose tolerance test (OGTT) performed on Day 15 showed that E3030 at 3 mg/kg improved glucose tolerance in this model. Fourteen days of oral treatment with E3030 at a dose of 0.03 mg/kg or greater showed remarkable TG- and non high-density lipoprotein (non-HDL) cholesterol-lowering effects in beagle dogs. These results were similar to those observed for the PPARalpha agonist fenofibrate. E3030 also reduced apo C-III levels on Days 7 and 14, and elevated lipoprotein lipase (LPL) levels on Day 15. These results indicate that the TG- and non-HDL cholesterol-lowering actions of E3030 involve combined effects on reduction of apo C-III and elevation of LPL, resulting in increased lipolysis. The experimental results in animals suggest that E3030 has potential for use in the treatment of various aspects of metabolic dysfunction in type 2 diabetes, including dyslipidemia, hyperglycemia, hyperinsulinemia, and impaired glucose disposal.
authors.affiliation: Vitamin E Information and Technology Section, Eisai Co. Ltd., 1-3 Tokodai 5-chome, Tsukuba, Ibaraki, Japan. s-kasai@hhc.eisai.co.jp
authors.forename: Shunji
authors.initials: S
authors.lastname: Kasai
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshitomi
authors.forename: Taro
authors.initials: T
authors.lastname: Hihara
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Matsuura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Harada
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shinoda
authors.forename: Isao
authors.initials: I
authors.lastname: Tanaka
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D001056:Apolipoproteins C / Q000097:blood; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004285:Dogs; D011345:Fenofibrate / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D008071:Lipoprotein Lipase / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; D001056:Apolipoproteins C; D008076:Cholesterol, HDL; C532927:E3030 compound; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007202:Indicators and Reagents; D009570:Nitriles; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase; D011345:Fenofibrate; D000077205:Pioglitazone