Potent Antidiabetic Effects of Rivoglitazone, a Novel Peroxisome Proliferator–Activated Receptor-γ Agonist, in Obese Diabetic Rodent Models

Abstract

Abstract. The pharmacological effects of rivoglitazone, a novel thiazolidinedione-derivative peroxisome proliferator-activated receptor (PPAR)-γ agonist, were characterized in vitro and in vivo. Rivoglitazone activated human PPARγ more potently compared with rosiglitazone and pioglitazone and had little effect on PPARα and PPARδ 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 PPARγ agonist and has a potent glucoselowering effect via improvement of the insulin resistance in diabetic animal models.

Evolving role of adiponectin in cancer-controversies and update

“…Other PPARγ agonists that show promise include rivoglitazone and troglitazone 175 . Rivoglitazone has been shown to have beneficial effects on the insulin resistance, type 2 diabetes and atherosclerosis in vivo partly through its substantial effects on APN 176,177 .…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…There were many dropouts within 6 months during the trials because of side effects (Truitt et al, 2010), and its efficacy has been questioned, although some reported a much stronger HbA 1c reduction compared with pioglitazone. Its ED 50 (0.20 mg/kg) for the glucoselowering effect was a hundred times lower than that of pioglitazone and rosiglitazone (Kanda et al, 2009). It is selective in that it has only a small effect on PPAR␣ and PPAR␦ activity (Kanda et al, 2009).…”

“…Its ED 50 (0.20 mg/kg) for the glucoselowering effect was a hundred times lower than that of pioglitazone and rosiglitazone (Kanda et al, 2009). It is selective in that it has only a small effect on PPAR␣ and PPAR␦ activity (Kanda et al, 2009). The dose-limiting side effects such as expansion of the plasma volume (low hematocrit) and weight gain should be overcome: mitoglitazone (MSDC-0160) is an insulin sensitizer not directly interacting with PPAR␥ and may lack these side effects.…”

In Vitro Metabolism of Rivoglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, in Rat, Monkey, and Human Liver Microsomes and Freshly Isolated Hepatocytes

“…1), is a novel thiazolidinedione (TZD) that selectively activates the nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) (Kanda et al, 2009). TZD-containing drugs, pioglitazone and rosiglitazone, are a clinically important new class of oral antidiabetic agents for the treatment of type 2 diabetes mellitus.…”