title: The dual PPARalpha/gamma agonist, ragaglitazar, improves insulin sensitivity and metabolic profile equally with pioglitazone in diabetic and dietary obese ZDF rats.
abstract: In 6- and 10-week-old obesity-prone (fa/fa) Zucker diabetic fatty (ZDF) rats, effects of prevention and intervention therapies, respectively, were compared between PPARalpha/gamma agonist, ragaglitazar (RAGA) and separate PPARgamma and alpha agonists, pioglitazone (PIO) and bezafibrate (BF). In a separate study, lean (+/+) ZDF rats fed highly palatable chow to induce dietary obesity and insulin resistance were treated similarly. To test insulin-secretory capacity, all animals underwent a hyperglycaemic clamp. Insulin sensitivity was improved equally by RAGA and PIO in fa/fa rats subjected to both prevention and intervention treatments (e.g., prevention HOMA-IR: -71 and -72%, respectively), as was hyperglycaemia (both -68%). BF had no effect on either parameter in any study. Plasma lipids were markedly reduced (by 48-77%) by RAGA in all studies, equivalent to PIO, but to a greater extent than BF. RAGA improved beta-cell function (HOMA-beta) more than three-fold with prevention and intervention therapies, whereas PIO showed improvement only in intervention therapy. Consistent with improved insulin sensitivity, glucose infusion rate during the clamp was 60% higher in RAGA-treated animals subjected to prevention therapy, but there was little additional insulin-secretory response, suggesting that insulin secretion was already maximal.Thus, RAGA and PIO equally improve metabolic profile in ZDF rats, particularly when administered early in the course of diabetes. They also improve beta-cell function, although this is better demonstrated through indices incorporating fasting insulin and glucose concentrations than through the hyperglycaemic clamp technique in this model.
authors.affiliation: Department of Veterinary Preclinical Sciences, University of Liverpool, Brownlow Hill/Crown St., Liverpool L69 7ZJ, UK. lucyp@liverpool.ac.uk
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Pickavance
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Karsten
authors.initials: K
authors.lastname: Wassermann
authors.forename: John P H
authors.initials: JP
authors.lastname: Wilding
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D004734:Energy Metabolism / Q000187:drug effects; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010078:Oxazines / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010179:Pancreas / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D000077205:Pioglitazone; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D010078:Oxazines; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D045162:Thiazolidinediones; C432703:ragaglitazar; D000077205:Pioglitazone; D001629:Bezafibrate