Relationship between peroxisome proliferator-activated receptor-gamma activation and the ameliorative effects of ascochlorin derivatives on type II diabetes.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a crucial factor in the development of insulin resistance associated with type II diabetes. We previously found that 4-O-carboxymethyl ascochlorin, a derivative of ascochlorin, ameliorates diabetes and activates PPAR-gamma. Here, we compared the relationship between the amelioration of type II diabetes in db/db mice lacking leptin receptor, and PPAR-gamma activation by 4-O-carboxymethyl-ascochlorin, as well as by 4-O-methyl-ascochlorin, a derivative that does not activate PPAR-gamma. Administration of these compounds significantly reduces blood glucose in a dose-dependent manner, whereas blood cholesterol is significantly elevated in 4-O-carboxymethyl-ascochlorin-treated mice but is significantly decreased in 4-O-methyl-ascochlorin-treated mice. Pioglitazone, a potent PPAR-gamma agonist with a thiazolidinedione structure, reduces glucose but elevates cholesterol blood levels. These results suggest that ascochlorin derivatives ameliorate diabetes through a mechanism that is probably independent of PPAR-gamma activation, although PPAR-gamma activation could be partially involved in the ameliorative effect in certain derivatives.
Magae
Junji
J
Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae-shi, Tokyo, Japan. jmagae@sannet.ne.jp
Tsuruga
Mie
M
Maruyama
Ayako
A
Furukawa
Chiharu
C
Kojima
Shuji
S
Shimizu
Hirohiko
H
Ando
Kunio
K
D000475:Alkenes / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D010636:Phenols / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics
D000475:Alkenes; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010636:Phenols; D054411:Receptors, Leptin; D002784:Cholesterol; C415745:ascochlorin