A primary defect leading to the development of type 2 diabetes is insulin resistance of the glucose transport system in skeletal muscle. One factor known to induce insulin resistance is oxidative stress. A by>product of lipid peroxidation is the reactive aldehyde 4-hydroxynonenal (4-HNE), an oxidant that induces a number of deleterious consequences on cell function. However, the impact of 4-HNE on the glucose transport system in rat slow>twitch skeletal muscle is currently not known. Therefore, we assessed the impact of 4-HNE on insulin signaling factors (IRS-1 protein expression and phosphorylation of Akt Ser473 (pAkt) and AS160 Thr642 (pAS160)) and on glucose transport activity in mammalian slow-twitch muscle. Strips of soleus muscle from lean Zucker rats were incubated with 4-HNE (50 μM) in the absence or presence of insulin (5 mU/ml) for up to 6 hr. Insulin>stimulated glucose transport activity (determined using 2-deoxyglucose uptake) was decreased by 4-HNE at 2 hr (30%), 4 hr (26%), and 6 hr (39%) (all pproduct and oxidant 4-HNE induces insulin resistance of glucose transport activity in rat slow>twitch skeletal muscle, initially associated with impaired phosphorylation (and therefore reduced activation) of AS160. Longer durations of 4-HNE exposure led to a greater impairment of Akt phosphorylation and to a selective loss of IRS-1 protein. These results provide further support for an important role of oxidative stress in the etiology of skeletal muscle insulin resistance
