Effects of peroxisome proliferator‐activated receptor‐α and ‐γ agonist, JTT‐501, on diabetic complications in Zucker diabetic fatty rats

• Published in: British journal of pharmacology 2000-06, Vol.130 (3), p.495-504
• Main Authors: Shibata, Tsutomu, Takeuchi, Satomi, Yokota, Seiko, Kakimoto, Kochi, Yonemori, Fumihiko, Wakitani, Korekiyo
• Format: Article
• Language: English
• Subjects: Absorptiometry, Photon; Animals; Biological and medical sciences; Body Weight - drug effects; Bone Density - drug effects; Bone Diseases, Metabolic - etiology; Bone Diseases, Metabolic - pathology; Bone Diseases, Metabolic - prevention & control; Cataract - etiology; Cataract - pathology; Cataract - prevention & control; Chromans - pharmacology; Diabetes Complications; Diabetes Mellitus - genetics; Diabetes Mellitus - pathology; diabetic complication; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; Diabetic Neuropathies - pathology; Diabetic Neuropathies - prevention & control; Eating - drug effects; General and cellular metabolism. Vitamins; Hypoglycemic Agents - pharmacology; Isoxazoles - pharmacology; JTT‐501; Male; Medical sciences; Neural Conduction - drug effects; Obesity; Pancreas - pathology; Peroxisome proliferator‐activated receptor (PPAR)‐α and PPAR‐γ agonist; Pharmacology. Drug treatments; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - agonists; Thiazoles - pharmacology; Thiazolidinediones; Time Factors; Transcription Factors - agonists; Troglitazone; Zucker diabetic fatty (ZDF) rat
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703328

This study has investigated the effects of JTT‐501, a peroxisome proliferator‐activated receptor (PPAR)‐α and PPAR‐γ 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‐γ 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‐α and PPAR‐γ, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes. British Journal of Pharmacology (2000) 130, 495–504; doi:10.1038/sj.bjp.0703328