Relationship between peroxisome proliferator-activated receptor-γ activation and the ameliorative effects of ascochlorin derivatives on type II diabetes

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) 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-γ. Here, we compared the relationship between the amelioration of type II diabetes in db/db mice lacking leptin receptor, and PPAR-γ activation by 4-O-carboxymethyl-ascochlorin, as well as by 4-O-methyl-ascochlorin, a derivative that does not activate PPAR-γ. 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-γ 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-γ activation, although PPAR-γ activation could be partially involved in the ameliorative effect in certain derivatives. © 2009 Japan Antibiotics Research Association.