Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats.
This study has investigated the effects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-gamma agonist. The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy. ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-alpha and PPAR-gamma, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.
Shibata
T
T
Central Pharmaceutical Research Institute, Japan Tobacco, Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, Japan.
Takeuchi
S
S
Yokota
S
S
Kakimoto
K
K
Yonemori
F
F
Wakitani
K
K
D015502:Absorptiometry, Photon; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002386:Cataract / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002839:Chromans / Q000494:pharmacology; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control; D003929:Diabetic Neuropathies / Q000473:pathology / Q000517:prevention & control; D004435:Eating / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D009765:Obesity; D010179:Pancreas / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000819:agonists*; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone; C112329:JTT 501