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Effects of the dual PPAR ‐α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat
Author(s) -
Bénardeau A.,
Verry P.,
Atzpodien E.A.,
Funk J. M.,
Meyer M.,
Mizrahi J.,
Winter M.,
Wright M. B.,
Uhles S.,
Sebokova E.
Publication year - 2013
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12006
Subject(s) - medicine , endocrinology , diabetes mellitus , glomerulosclerosis , islet , kidney , proteinuria
Aims To evaluate the effects of aleglitazar, a dual peroxisome proliferator‐activated receptor‐α/γ 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 0.3 mg/kg/day or vehicle as food admix for 13 weeks (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 13 weeks. Results Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3 ± 0.3 vs. 26.1 ± 1.0 mmol/l) were significantly reduced at 12 weeks 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 ± 0.9 mmol/l) and reduced plasma non‐esterified fatty acids (0.09 ± 0.02 vs. 0.26 ± 0.04 mmol/l) relative to vehicle‐treated animals (both p < 0.01). Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar versus vehicle‐treated rats (both p < 0.01). Consistent with its effect on glycaemic control, aleglitazar protected β‐cell morphology, as evidenced by preservation of islet integrity, and reduction of β‐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.