drf-2725 and Body-Weight

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.

Topics: Adipose Tissue; Animals; Bezafibrate; Body Composition; Body Weight; Diabetes Mellitus; Diet; Energy Metabolism; Glucose Clamp Technique; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Obesity; Organ Size; Oxazines; Pancreas; Phenylpropionates; Pioglitazone; PPAR alpha; PPAR gamma; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Leptin; Thiazolidinediones

Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR)gamma and PPARalpha potentially provides beneficial effects over existing PPARgamma and alpha preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPARalpha/gamma agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with treatment with the PPARgamma preferential agonist rosiglitazone. Despite normalization of hyperglycemia and Hb A(1c) and reduction of plasma triglycerides by both compounds in both prevention and early intervention studies, ragaglitazar treatment resulted in overall reduced circulating insulin and improved insulin sensitivity to a greater extent than after treatment with rosiglitazone. In late-intervention therapy, ragaglitazar reduced Hb A(1c) by 2.3% compared with 1.1% by rosiglitazone. Improvement of insulin sensitivity caused by the dual PPARalpha/gamma agonist ragaglitazar seemed to have beneficial impact over that of the PPARgamma-preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats.

Topics: Animals; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Eating; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glycated Hemoglobin; Glycogen; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Liver; Male; Oxazines; Phenylpropionates; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors