Metformin Improves Insulin Signaling in Obese Rats via Reduced IKKβAction in a Fiber-Type Specific Manner

[摘要] Metformin is a widely used insulin-sensitizing drug, though its mechanisms are not fully understood. Metformin has been shown to activate AMPK in skeletal muscle; however, its effects on the inhibitor ofκB kinaseβ(IKKβ) in this same tissue are unknown. The aim of this study was to (1) determine the ability of metformin to attenuate IKKβaction, (2) determine whether changes in AMPK activity are associated with changes in IKKβaction in skeletal muscle, and (3) examine whether changes in AMPK and IKKβfunction are consistent with improved insulin signaling. Lean and obese male Zuckers received either vehicle or metformin by oral gavage daily for four weeks (four groups of eight). Proteins were measured in white gastrocnemius (WG), red gastrocnemius (RG), and soleus. AMPK phosphorylation increased (P<.05) in WG in both lean (57%) and obese (106%), and this was supported by an increase in phospho-ACC in WG. Further, metformin increased IκBαlevels in both WG (150%) and RG (67%) of obese rats, indicative of reduced IKKβactivity (P<.05), and was associated with reduced IRS1-pSer307(30%) in the WG of obese rats (P<.02). From these data we conclude that metformin treatment appears to exert an inhibitory influence on skeletal muscle IKKβactivity, as evidenced by elevated IκBαlevels and reduced IRS1-Ser307phosphorylation in a fiber-type specific manner.

[学科分类] 内分泌与代谢学