Combination therapy with PPARγ and PPARα agonists increases glucose-stimulated insulin secretion in db/db mice

Ken Yajima, Hiroshi Hirose, Haruhisa Fujita, Yoshiko Seto, Hiroshi Fujita, Kaname Ukeda, Kiichi Miyashita, Toshihide Kawai, Yukihiro Yamamoto, Takeo Ogawa, Taketo Yamada, Takao Saruta

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


Although peroxisome proliferator-activated receptor (PPAR)γ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPARγ agonist, pioglitazone, and a PPARα agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPARγ agonist-treated groups. Also, PPARγ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARγ and -α agonists. We conclude that combination therapy with PPARγ and PPARα agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.

Original languageEnglish
Pages (from-to)E966-E971
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5 47-5
Publication statusPublished - 2003 May 1


  • Glucolipotoxicity
  • Glucose-stimulated insulin secretion
  • Insulin resistance
  • Peroxisome proliferator-activated receptor
  • Type 2 diabetes with obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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