Dose-dependent effects of TZD

Treatment of insulin resistance (IR) in diabetic patients using thiazolidinediones (TZD) is associated with unwanted side effects. The use of TZD in combination treatments with other pharmaceuticals may allow for lowering of both, the dose of TZD and the risk of the side effects. The insulin-sensitizing effect of TZD is thought to results from activation of PPARγ, associated with the induction of adiponectin and stimulation of AMP-activated protein kinase (AMPK). However, our recent data suggest the mechanism underlying effects of sub-optimal doses of TZD on insulin sensitivity may depend on the induction of delta-9 desaturase (SCD1), translated into changes of plasma lipid profile and high plasma levels of palmitoleate, which could augment insulin sensitivity. Methods: 3-mo-old male C57BL/6 mice were assigned to 8-week-treatment using the diets: 1) high-fat diet (cHF); 2) cHF diet admixed with a low dose of rosiglitazone- 10mg/kg diet (cHF+R10); and 3) cHF diet admixed with a high dose of rosiglitazone- 100mg/kg diet (cHF+R100). Results: Rosiglitazone in a dose-depend manner induces adiponectin plasma levels during the development of obesity by high-fat feeding. The stimulatory effect of rosiglitazone is specific for high molecular weight form of adiponectin (cHF-0.26±0.01 vs. cHF+R10–0.39±0.02 vs. cHF+R100–0.49±0.02 AU). Only the high dose of rosiglitazone significantly induced activity of α2 isoform of AMPK in the liver. The low-dose of rosiglitazone markedly increased hepatic lipid content, while the high dose of rosiglitazone tended to decrease it. Gene expression analysis revealed significant induction of SCD1 expression by low dose of rosiglitazone as compared with the cHF and the cHF+R100 mice. Expression of CIDEA, which is crucial for lipid droplet formation and inhibits AMPK activity, was the highest in the cHF+R10 mice. Conclusion: We show different mechanisms contribute to the insulin-sensitizing effect rosiglitazone, depending on the dose of the drug.