Synergistic Improvement in Insulin Resistance with a Combination of Fenofibrate and Rosiglitazone in Obese Type 2 Diabetic Mice

Peroxisome proliferator-activated receptor (PPAR) a, which is abundant in the liver, increases lipoprotein lipase activity, resulting in a decrease of triglyceride (TG) levels. PPAR gamma, which is abundant in adipose tissue, stimulates adipocyte differentiation and adipogenesis, and results in an increase in insulin sensitivity. Fenofibrate, a PPAR alpha agonist, is commonly used to treat dyslipidemia, and rosiglitazone, a PPAR gamma agonist, is effective in improving glycemic control. To examine the synergistic effects of rosiglitazone in combination with fenofibrate, an obese type 2 diabetes mellitus (DM) mouse model was established by the combined administration of streptozotocin and nicotinamide and fed on a high-fat diet (35% of energy as fat) for 3 weeks. The mice had significantly higher plasma glucose concentrations and insulin resistance, as examined by an oral glucose tolerance test and insulin challenge test compared with normal mice. After establishing a dose-response curve for each drug, the drugs were orally administered for 3 weeks either alone or in combination. After individual administration of fenofibrate, HDL cholesterol levels significantly increased, and plasma glucose and TG levels decreased in obese type 2 DM mice. The individual administration of rosiglitazone showed increased insulin resistance (QUICKI). However, HDL cholesterol and TG levels were not significantly changed. In a combination of fenofibrate at 25 mg/kg and rosiglitazone at 1.25 mg/kg there was a decrease in plasma glucose and TG levels, and a combination of fenofibrate at 50 mg/kg and rosiglitazone at 2.5 mg/kg showed an increase in plasma HDL cholesterol levels. Moreover, parameters related to insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) were improved significantly. Thus, our results show that combination therapy with lower doses of fenofibrate and rosiglitazone ameliorates the type 2 DM condition to a greater extent than high doses of either individual monotherapy.