Abstract
An association between inflammatory processes and the pathogenesis of insulin resistance has been increasingly suggested. The IkappaB kinase-beta (IKK-beta)/ nuclear factor-kappaB (NF-kappaB) pathway is a molecular mediator of insulin resistance. S-Adenosyl-L-methionine (SAM) has both antioxidative and anti-inflammatory properties. We investigated the effects of SAM on the glucose transport and insulin signaling impaired by the tumor necrosis factor alpha (TNFalpha) in 3T3-L1 adipocytes. SAM partially reversed the basal and insulin stimulated glucose transport, which was impaired by TNFalpha. The TNFalpha-induced suppression of the tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1) and Akt in 3T3-L1 adipocytes was also reversed by SAM. In addition, SAM significantly attenuated the TNFalpha-induced degradation of IkappaB-alpha and NF-kappaB activation. Interestingly, SAM directly inhibited the kinase activity of IKK-beta in vitro. These results suggest that SAM can alleviate TNFalpha mediated-insulin resistance by inhibiting the IKK-beta/NF-kappaB pathway and thus can have a beneficial role in the treatment of type 2 diabetes mellitus.
Highlights
Mounting evidence suggests that inflammatory processes are related to the pathogenesis of insulin resistance
We demonstrate that SAM could improve the tumor necrosis factor α (TNFα)-induced impairment of the SAM improved glucose transport impaired by TNFα
To investigate the effect of SAM on insulin resistance, we tested whether SAM could reverse the impaired glucose transport which was induced by TNFα in 3T3-L1 adipocytes
Summary
Mounting evidence suggests that inflammatory processes are related to the pathogenesis of insulin resistance. The IκB kinase-β (IKK-β)/NF-κB pathway is a molecular mediator of insulin resistance (Shoelson et al, 2003). Various inflammatory stimuli activate IKK-β and anti-inflammatory agents with IKK-β-inhibiting properties have been suggested to improve insulin resistance (Shoelson et al, 2006). Glucose uptake through GLUT is increased (Schinner et al, 2005). Inflammatory cytokines such as tumor necrosis factor α The serine phosphorylation inhibits activation of IR or IRS-1 and results in insulin resistance (Aguirre et al, 2000; Gao et al, 2002). IKKβ is indirectly involved in insulin resistance by activating NF-κB which stimulates other inflammatory mediators (Baud and Karin, 2001)
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