RAGE/NF-κB pathway mediates hypoxia-induced insulin resistance in 3T3-L1 adipocytes.

There is growing evidence in support of an independent association between obstructive sleep apnea (OSA) and type 2 diabetes, and in which hypoxia may play an important role. Hypoxia is the hallmark feature and the most important pathophysiologic pathway of OSA. Recently, receptor for advanced glycation end products (RAGE) was found to be involved in the pathogenesis of insulin resistance (IR). However, whether RAGE contributes to the IR of adipocytes under hypoxia remains unknown. In the present study, we found that hypoxia reduced glucose consumption and upregulated RAGE expression in 3T3-L1 adipocytes in a time-dependent manner. RAGE knockdown efficiently attenuated hypoxia-induced IR, including inhibiting serine phosphorylation of insulin receptor substrate-1 (IRS-1), increasing the expression of phosphorylated Akt (Ser473), and improving insulin-stimulated glucose uptake. In addition, hypoxia activated nuclear transcription factor κB (NF-κB). However, RAGE knockdown inhibited hypoxia-induced NF-κB activity in adipocytes. Finally, an NF-κB inhibitor (PDTC) significantly reduced the hypoxia-induced upregulation of RAGE expression and IR. Therefore, this study indicates that the RAGE/NF-κB pathway mediates hypoxia-induced IR in 3T3-L1 adipocytes, and suggests that RAGE may be a potential therapeutic target for suppressing IR in OSA.