DOES A COMBINATION OF ROSIGLITAZONE AND FENOFIBRATE (PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR (PPAR) γ AND α AGONISTS RESPECTIVELY) ACHIEVE MORE BENEFICIAL EFFECTS THAN ROSIGLITAZONE (A PPAR γ AGONIST) IN DIABETIC RATS?
Hussam A.S. Murad and Khaled A. Mahmoud
Department of Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University
Type II or non–insulin-dependent diabetes mellitus (NIDDM) is a progressive disorder characterized by impaired glucose tolerance as a result of insulin resistance. The syndrome is associated with hyperglycemia, dyslipidemia, obesity and in the long term, cardiovascular complications, leading to impaired life quality and increased mortality. Unfortunately, none of the available antidiabetic drugs has proved sufficiently effective in restoring normal glucose metabolism alone or in combination therapy as the disease progresses. Thiazolidinediones (glitazones) improve glucose metabolism by increasing peripheral insulin sensitivity, in addition, they decrease serum triglycerides both in diabetic and normal rodents and humans. They act through activation of peroxisome proliferator activated receptor γ(PPARγ). Fibrates are hypolipidemic drugs that act primarily on liver through activation of peroxisome proliferator activated receptor α (PPAR α). Normally PPAR-γis highly expressed in adipose tissue with low expression in nonadipose tissues. In contrast, PPAR-α is expressed in nonadipose tissues at higher levels and it regulates intracellular lipid homeostasis through upregulation of fatty acid oxidative enzymes mainly in the liver and skeletal muscle. Also it increases insulin sensitivity and reduce lipid accumulation in skeletal muscle. The present study was conducted to compare effects of rosiglitazone (a PPARγagonist) with those of a combination of rosiglitazone and fenofibrate (PPARγand α agonists respectively) on fasting blood glucose, lipids (cholesterol ,triglycerides, high density lipoproteins (HDL) cholesterol and low density lipoproteins (LDL) cholesterol), insulin and glycosylated hemoglobin (HbA1c) in streptozotocin-nicotinamide (STZ-NA)-induced type 2 diabetes in rats. The results of the present study showed that rosiglitazone (3 mg/kg/day) produced less statistically significant reductions than rosiglitazone (3 mg/kg/ day) plus fenofibrate (95 mg/kg/day) for 4 weeks in fasting blood glucose, serum cholesterol, triglycerides, LDL, insulin and HbA1c levels in STZ-NA diabetic rats. Also rosiglitazone produced a less statistically significant increase than rosiglitazone plus fenofibrate in HDL in the diabetic rats. Consequently, from the present work it is concluded that a combination of rosiglitazone and fenofibrate (PPAR γand α agonists respectively) may achieve more beneficial therapeutic effects than rosiglitazone (a PPAR γagonist) in treatment of type 2 diabetic patients.