Pioglitazone Enhances β-Arrestin2 Signaling and Ameliorates Insulin Resistance in Classical Insulin Target Tissues

Abstract

<b><i>Introduction:</i></b> Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on β-arrestin2 signaling in classical insulin target tissues. <b><i>Methods:</i></b> Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. <b><i>Results:</i></b> The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the β-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased β-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. <b><i>Conclusion:</i></b> To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases β-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.