Potent antidiabetic effects of rivoglitazone, a novel peroxisome proliferator-activated receptor-gamma agonist, in obese diabetic rodent models.
The pharmacological effects of rivoglitazone, a novel thiazolidinedione-derivative peroxisome proliferator-activated receptor (PPAR)-gamma agonist, were characterized in vitro and in vivo. Rivoglitazone activated human PPARgamma more potently compared with rosiglitazone and pioglitazone and had little effect on PPARalpha and PPARdelta activity in luciferase reporter assays. In Zucker diabetic fatty (ZDF) rats, 14-day administration of rivoglitazone decreased the plasma glucose and triglyceride (TG) levels in a dose-dependent manner. The glucose-lowering effect of rivoglitazone was much more potent than those of pioglitazone (ED(50): 0.19 vs. 34 mg/kg) and rosiglitazone (ED(50): 0.20 vs. 28 mg/kg). In addition, rivoglitazone showed potent antidiabetic effects in diabetic db/db mice. In Zucker fatty rats, rivoglitazone at a dose of 0.1 mg/kg clearly ameliorated insulin resistance and lowered plasma TG levels by accelerating the clearance of plasma TG. Gene expression analysis in the liver and heart of ZDF rats treated with rivoglitazone for 14 days suggested that rivoglitazone may reduce hepatic glucose production and modulate the balance of the cardiac glucose/fatty acid metabolism in diabetic animals. In summary, we showed that rivoglitazone is a potent and selective PPARgamma agonist and has a potent glucose-lowering effect via improvement of the insulin resistance in diabetic animal models.
Kanda
Shoichi
S
Biological Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Nakashima
Ryutaro
R
Takahashi
Kanako
K
Tanaka
Jun
J
Ogawa
Junko
J
Ogata
Tsuneaki
T
Yachi
Makoto
M
Araki
Kazushi
K
Ohsumi
Jun
J
D052242:Adiponectin / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy*; D047495:PPAR gamma / Q000819:agonists*; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D012680:Sensitivity and Specificity; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D052242:Adiponectin; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; C521549:rivoglitazone; D005947:Glucose