title: Synergistic improvement in insulin resistance with a combination of fenofibrate and rosiglitazone in obese type 2 diabetic mice.
abstract: Peroxisome proliferator-activated receptor (PPAR) α, which is abundant in the liver, increases lipoprotein lipase activity, resulting in a decrease of triglyceride (TG) levels. PPARγ, which is abundant in adipose tissue, stimulates adipocyte differentiation and adipogenesis, and results in an increase in insulin sensitivity. Fenofibrate, a PPARα agonist, is commonly used to treat dyslipidemia, and rosiglitazone, a PPARγ 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.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chungnam National University, Daejeon, 305-764, Korea.
authors.forename: Woon-Seok
authors.initials: WS
authors.lastname: Choi
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Yohan
authors.initials: Y
authors.lastname: Kim
authors.forename: In-Su
authors.initials: IS
authors.lastname: Kim
authors.forename: Wei-Yun
authors.initials: WY
authors.lastname: Zhang
authors.forename: Chang-Seon
authors.initials: CS
authors.lastname: Myung
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D008078:Cholesterol, LDL / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D011345:Fenofibrate / Q000008:administration & dosage / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D008078:Cholesterol, LDL; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011345:Fenofibrate