The dual PPARα/γ agonist, ragaglitazar, improves insulin sensitivity and metabolic profile equally with pioglitazone in diabetic and dietary obese ZDF rats

摘要

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 PPARα/γ agonist, ragaglitazar (RAGA) and separate PPARγ and α 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 β-cell function (HOMA-β) 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 β-cell function, although this is better demonstrated through indices incorporating fasting insulin and glucose concentrations than through the hyperglycaemic clamp technique in this model.