Metformin Improves Insulin Signaling in Obese Rats via Reduced IKK beta Action in a Fiber-Type Specific Manner

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 of kappa B kinase beta (IKK beta) in this same tissue are unknown. The aim of this study was to (1) determine the ability of metformin to attenuate IKK beta action, (2) determine whether changes in AMPK activity are associated with changes in IKK beta action in skeletalmuscle, and (3) examine whether changes in AMPK and IKK beta function 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 I kappa B alpha levels in both WG (150%) and RG (67%) of obese rats, indicative of reduced IKK beta activity (P < .05), and was associated with reduced IRS1-pSer(307) (30%) in the WG of obese rats (P < .02). From these data we conclude that metformin treatment appears to exert an inhibitory influence on skeletalmuscle IKK beta activity, as evidenced by elevated I kappa B alpha levels and reduced IRS1-Ser(307) phosphorylation in a fiber-type specific manner.