Effects of the dual PPAR-[alpha]/[gamma] agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat

• Published in: Diabetes, obesity & metabolism Vol. 15; no. 2; p. 164
• Main Authors: Bénardeau, A, Verry, P, Atzpodien, E.-A, Funk, J. M, Meyer, M, Mizrahi, J, Winter, M, Wright, M. B, Uhles, S, Sebokova, E
• Format: Journal Article
• Language: English
• Published: Oxford Wiley Subscription Services, Inc 01.02.2013
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12006

Aims To evaluate the effects of aleglitazar, a dual peroxisome proliferator-activated receptor-[alpha]/[gamma] agonist, on the development of diabetes-related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats. Methods Six-week-old, male ZDF rats received aleglitazar 0.3mg/kg/day or vehicle as food admix for 13weeks (n=10 per group). Age-matched male Zucker lean rats served as non-diabetic controls. Plasma and renal markers were measured at several time points. Histopathology and quantitative immunohistochemistry were performed at 13weeks. Results Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3±0.3 vs. 26.1±1.0mmol/l) were significantly reduced at 12weeks with aleglitazar versus vehicle-treated ZDF rats (both p<0.01), while aleglitazar preserved near-normal plasma insulin levels. Aleglitazar prevented the development of hypertriglyceridaemia (1.4±0.1 vs. 8.5±0.9mmol/l) and reduced plasma non-esterified fatty acids (0.09±0.02 vs. 0.26±0.04mmol/l) relative to vehicle-treated animals (both p<0.01). Urinary glucose and protein concentrations were significantly reduced at 13weeks with aleglitazar versus vehicle-treated rats (both p<0.01). Consistent with its effect on glycaemic control, aleglitazar protected [beta]-cell morphology, as evidenced by preservation of islet integrity, and reduction of [beta]-cell apoptosis and islet fibrosis. Aleglitazar prevented renal glomerular hypertrophy, podocyte degeneration, glomerulosclerosis, tubulo-interstitial lesions and development of cataracts. Conclusions Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes-associated structural and functional changes in the ZDF rat. [PUBLICATION ABSTRACT]