drf-2725 and Diabetes-Mellitus

Combination therapies are increasingly common in the clinical management of type 2 diabetes. We investigated to what extent combined treatment with the human glucagon-like peptide-1 (GLP-1) analogue liraglutide and the dual PPARalpha/gamma agonist ragaglitazar would improve glycaemic control in overtly diabetic Zucker diabetic fatty (ZDF) rats.. Ninety overtly diabetic male ZDF rats were stratified into groups with matched haemoglobin A1c (HbA1c) (9.0+/-0.1%). Liraglutide (15 and 50 microg/kg subcutaneously twice daily), ragaglitazar (1 and 3 mg/kg perorally once daily) and their vehicles were studied as monotherapy and in combination in a 3x3 factorial design.. After 4-week treatment, synergistic effects on HbA1c, non-fasting morning blood glucose (BG) and/or 24-h BG profiles were observed with three of the four combinations. The relationship between plasma insulin and BG in combination-treated animals approached that of historical lean ZDF rats representing normal glucose homeostasis, suggesting that insulin secretion and insulin sensitivity were markedly improved. Increased insulin immunostaining in islets further supports the improved beta-cell function and/or insulin sensitivity in combination-treated animals. The synergistic effect on glycaemic control was found without a similar synergistic increase in beta-cell mass in the combination groups.. Our data demonstrate that combination treatment with a human GLP-1 analogue and a dual PPARalpha/gamma agonist through distinct mechanism of actions synergistically improves glycaemic control in the ZDF rat.

Topics: Animals; Blood Glucose; Cell Proliferation; Diabetes Mellitus; Disease Models, Animal; Drug Synergism; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeodomain Proteins; Homeostasis; Hypoglycemic Agents; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Liraglutide; Oxazines; Phenylpropionates; Rats; Rats, Zucker; Trans-Activators

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

(-)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPAR alpha and PPAR gamma. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.

Topics: Animals; Biological Availability; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Hyperlipidemias; Hypoglycemic Agents; Insulin Resistance; Mice; Oxazines; Phenylpropionates; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Stereoisomerism; Transcription Factors; Triglycerides