Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice.
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.
Yajima
Ken
K
Department of Internal Medicine, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. n62383@sc.itc.keio.ac.jp
Hirose
Hiroshi
H
Fujita
Haruhisa
H
Seto
Yoshiko
Y
Fujita
Hiroshi
H
Ukeda
Kaname
K
Miyashita
Kiichi
K
Kawai
Toshihide
T
Yamamoto
Yukihiro
Y
Ogawa
Takeo
T
Yamada
Taketo
T
Saruta
Takao
T
D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D001835:Body Weight; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004359:Drug Therapy, Combination; D005947:Glucose / Q000494:pharmacology*; D051273:Glucose Transporter Type 2; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D000077205:Pioglitazone; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors / Q000819:agonists*
D051273:Glucose Transporter Type 2; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors; C116017:5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide; D005947:Glucose; D000077205:Pioglitazone; D001629:Bezafibrate