Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
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Feasibility of Structural Modification of Retinoid X Receptor Agonists to Separate Blood Glucose-Lowering Action from Adverse Effects: Studies in KKAy Type 2 Diabetes Model Mice
Hiroki KakutaFuminori OhsawaShoya YamadaMakoto MakishimaAkihiro TaiHiroyuki YasuiYutaka Yoshikawa
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2012 Volume 35 Issue 4 Pages 629-633

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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 KKAy 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.

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© 2012 The Pharmaceutical Society of Japan
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