title: Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat.
abstract: OBJECTIVE
  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.
authors.affiliation: pRED, Pharma Research & Early Development, DTA Cardiovascular & Metabolism, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Bénardeau
authors.forename: P
authors.initials: P
authors.lastname: Verry
authors.forename: E-A
authors.initials: EA
authors.lastname: Atzpodien
authors.forename: J M
authors.initials: JM
authors.lastname: Funk
authors.forename: M
authors.initials: M
authors.lastname: Meyer
authors.forename: J
authors.initials: J
authors.lastname: Mizrahi
authors.forename: M
authors.initials: M
authors.lastname: Winter
authors.forename: M B
authors.initials: MB
authors.lastname: Wright
authors.forename: S
authors.initials: S
authors.lastname: Uhles
authors.forename: E
authors.initials: E
authors.lastname: Sebokova
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002386:Cataract / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology*; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D011924:Rats, Zucker; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D013876:Thiophenes; C542437:aleglitazar