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Diabetes Obes Metab. 2013 Feb;15(2):164-74. doi: 10.1111/dom.12006. Epub 2012 Oct 3.

Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat.

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  • 1pRED, Pharma Research & Early Development, DTA Cardiovascular & Metabolism, F. Hoffmann-La Roche AG, Basel, Switzerland.

Abstract

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.

© 2012 Blackwell Publishing Ltd.

PMID:
22958363
[PubMed - indexed for MEDLINE]
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