title: Feasibility of structural modification of retinoid X receptor agonists to separate blood glucose-lowering action from adverse effects: studies in KKA(y) type 2 diabetes model mice.
abstract: Retinoid X receptor (RXR) agonists are reported to exhibit blood glucose-lowering action owing to peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR activation, but may also cause adverse effects such as blood triglyceride elevation. In order to examine the feasibility of separating the glucose-lowering action from the adverse effects, we examined the effects of RXR agonists (NEt-TMN), NEt-3IB, and NEt-3IP, which have different heterodimer-activating patterns, in KKA(y) type 2 diabetes model mice. We found that NEt-3IB induced lower degrees of hepatomegaly and blood triglyceride (TG) elevation than the other RXR agonists, even though all of them showed similar blood glucose-lowering action on repeated administration. These findings indicate that structural modification of RXR agonists is a potentially effective strategy to reduce adverse effects while retaining desired activities.
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan. kakuta@pharm.okayama-u.ac.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.forename: Fuminori
authors.initials: F
authors.lastname: Ohsawa
authors.forename: Shoya
authors.initials: S
authors.lastname: Yamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D009929:Organ Size; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D047488:Retinoid X Receptors; D014280:Triglycerides; D002784:Cholesterol