Hepatic miR-125b inhibits insulin signaling pathway by targeting PIK3CD.

Insulin resistance is often characterized as the most critical factor contributing to the development of (T2D) type 2 diabetes. MicroRNAs (miRNAs) are endogenous non-coding short single-stranded RNAs that function as negative regulators in many physiological and pathological processes. The objective of this study was to evaluate the roles of miR-125b in the regulation of insulin sensitivity in hepatocytes. We found that hepatic miR-125b levels were significantly increased in the patients with type 2 diabetes, high fat diet (HFD) mice, ob/ob and db/db mice. In vitro, miR-125b was also significantly up-regulated in tumor necrosis factor-alpha- (TNF-α) and glucosamine-induced insulin resistance conditions. Furthermore, miR-125b overexpression impaired the insulin signaling pathway in HepG2 cells, L02c cells, and primary hepatocytes. Inhibition of miR-125b improved insulin sensitivity, especially in insulin-resistant cells induced by either TNF-α or glucosamine. We demonstrated that miR-125b targeted the 3'-untranslated region (3'-UTR) of phosphoinositide 3-kinase catalytic subunit delta (PIK3CD) mRNA. The hepatic PIK3CD protein levels were markedly decreased in patients with type 2 diabetes, HFD, ob/ob, and db/db mice. Inhibition of PIK3CD markedly attenuated the improvement of insulin sensitivity induced by miR-125b inhibitors. More importantly, overexpressing miR-125b in mice causes insulin resistance and impairs glucose homeostasis. Together, these findings indicate that miR-125b inhibits insulin sensitivity by targeting PIK3CD in hepatocytes, supporting hepatic miR-125b, or PIK3CD are potential therapeutic target of insulin resistance.