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

Hiroki Kakuta, Fuminori Ohsawa, Shoya Yamada, Makoto Makishima, Akihiro Tai, Hiroyuki Yasui, Yutaka Yoshikawa

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)629-633
Number of pages5
JournalBiological and Pharmaceutical Bulletin
Volume35
Issue number4
DOIs
Publication statusPublished - Apr 2012
Externally publishedYes

Keywords

  • Adverse effect
  • Glucose-lowering action
  • Hepatomegaly
  • Retinoid X receptor
  • Triglyceride elevation
  • Type 2 diabetes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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