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

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 feasibili...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2012/04/01, Vol.35(4), pp.629-633
Main Authors: Kakuta, Hiroki, Ohsawa, Fuminori, Yamada, Shoya, Makishima, Makoto, Tai, Akihiro, Yasui, Hiroyuki, Yoshikawa, Yutaka
Format: Article
Language:eng ; jpn
Subjects:
adverse effect
glucose-lowering action
hepatomegaly
retinoid X receptor
triglyceride elevation
type 2 diabetes
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Summary: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.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.35.629