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Am J Physiol Endocrinol Metab 284: E966-E971, 2003; doi:10.1152/ajpendo.00149.2002
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Vol. 284, Issue 5, E966-E971, May 2003

Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice

Ken Yajima1,4, Hiroshi Hirose1, Haruhisa Fujita2, Yoshiko Seto2, Hiroshi Fujita2, Kaname Ukeda2, Kiichi Miyashita2, Toshihide Kawai1, Yukihiro Yamamoto1, Takeo Ogawa1, Taketo Yamada3, and Takao Saruta1

1 Department of Internal Medicine, 2 Institute for Advanced Medical Research, and 3 Department of Pathology, Keio University School of Medicine, Tokyo 160-8582; and 4 Department of Internal Medicine, Hamamatsu Red Cross Hospital, Hamamatsu 430-0907, Japan

Although peroxisome proliferator-activated receptor (PPAR)gamma 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 PPARgamma agonist, pioglitazone, and a PPARalpha 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 PPARgamma agonist-treated groups. Also, PPARgamma agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARgamma and -alpha agonists. We conclude that combination therapy with PPARgamma and PPARalpha agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.

peroxisome proliferator-activated receptor; glucose-stimulated insulin secretion; glucolipotoxicity; insulin resistance; type 2 diabetes with obesity


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