LAUSR

Abstract Elimination of glucose transporter 4 (GLUT4) inevitably induces insulin resistance (IR), aggravating inflammation‐ and oxidative stress‐related disorders. However, the underlying molecular mechanisms remain incompletely understood. In this study, we identified miR‐17 as an important regulator of IR by targeting GLUT4. MiR‐17 expression was found significantly elevated in skeletal tissues of rats with type 2 diabetes mellitus (T2DM), along with marked downregulation of GLUT4 protein level. Luciferase reporter gene assay demonstrated a direct interaction between miR‐17 and the 3’untranslated region of GLUT4 mRNA. Correlation analyses (Spearman, Pearson, and Kendall) revealed that miR‐17 level was negatively correlated with GLUT4 expression. Additionally, loss‐ and gain‐of‐function analyses showed that overexpression of miR‐17 impaired glucose metabolism in L6 rat skeletal muscle cell line. In contrast, knockdown of endogenous miR‐17 ameliorated glucose metabolism, accompanied by elevation of GLUT4 protein level. These findings unraveled a novel mechanism for IR that involves repression of GLUT4 by miR‐17 and suggested miR‐17 as a potential molecular target for the development of new therapeutic approaches for the treatment of T2DM. HighlightsMiR‐17 is the most up‐regulated skeletal‐enriched miRNA in T2DM rats.GLUT4 is a direct target gene of miR‐17 and a critical regulator of glucose metabolism.The miR‐17/GLUT4 axis is, at least in part, responsible for insulin resistance.