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.

Impact of a long‐term high‐fructose diet on systemic metabolic profiles of mice

“…Previous studies have shown that high fructose mainly affects lipid peroxidation, butanoate metabolism, and fatty acid biosynthesis and metabolism. 17,18 Although the regulatory roles of amino acids as important substrates involved in metabolic pathways have been reported previously, [23][24][25] the amino acid components found by these studies were inconsistent. In the present study, high fructose led to dramatic alterations in l-serine, glycine, threonine, l-valine, l-aspartic acid, l-glutamic acid, pyroglutamic acid, tyrosine, and l-phenylalanine, suggesting that high fructose intake promoted changes in amino acids components.…”