Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets.

Propelled by the identification of a small family of NADPH oxidase (Nox) enzyme homologs that produce superoxide in response to cellular stimulation with various growth factors, renewed interest has been generated in characterizing the signaling effects of reactive oxygen species (ROS) in relation to insulin action. Two key observations made >30 years ago-that oxidants can facilitate or mimic insulin action and that H(2)O(2) is generated in response to insulin stimulation of its target cells-have led to the hypothesis that ROS may serve as second messengers in the insulin action cascade. Specific molecular targets of insulin-induced ROS include enzymes whose signaling activity is modified via oxidative biochemical reactions, leading to enhanced insulin signal transduction. These positive responses to cellular ROS may seem "paradoxical" because chronic exposure to relatively high levels of ROS have also been associated with functional beta-cell impairment and the chronic complications of diabetes. The best-characterized molecular targets of ROS are the protein-tyrosine phosphatases (PTPs) because these important signaling enzymes require a reduced form of a critical cysteine residue for catalytic activity. PTPs normally serve as negative regulators of insulin action via the dephosphorylation of the insulin receptor and its tyrosine-phosphorylated cellular substrates. However, ROS can rapidly oxidize the catalytic cysteine of target PTPs, effectively blocking their enzyme activity and reversing their inhibitory effect on insulin signaling. Among the cloned Nox homologs, we have recently provided evidence that Nox4 may mediate the insulin-stimulated generation of cellular ROS and is coupled to insulin action via the oxidative inhibition of PTP1B, a PTP known to be a major regulator of the insulin signaling cascade. Further characterization of the molecular components of this novel signaling cascade, including the mechanism of ROS generated by insulin and the identification of various oxidation-sensitive signaling targets in insulin-sensitive cells, may provide a novel means of facilitating insulin action in states of insulin resistance.