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

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

Barry J Goldstein et al. Diabetes. 2005 Feb.

Erratum in

  • Diabetes. 2005 Apr;54(4):1249. Kalyankar, Mahadev [corrected to Mahadev, Kalyankar]

Abstract

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.

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Figures

FIG. 1.
FIG. 1.

Regulation of PTP catalytic activity by oxidation, reduction, and conjugation. The catalytic cysteine residue of PTPs is especially reactive because the low pKa of the sulfhydryl favors a relatively ionized state of the cysteinyl hydrogen (51). When subjected to ROS, including those elicited by cellular insulin stimulation, the cysteine side-chain undergoes stepwise oxidation to increasingly inert forms (27,60,157). The inactive sulfenic derivative may be reduced to regenerate the active thiol form of the protein. Alternatively, it may be directly conjugated with glutathione (GSH) in the cell, producing a catalytically inert PTP derivative that can be reactivated by biochemical reduction or through the action of glutathione reductases (63). Recently, the sulfenic derivative of PTP1B has been shown to undergo an intramolecular rearrangement, forming a novel sulfenyl-amide derivative that also sequesters the PTP in an inactive state (68,69). The sulfenyl-amide form may actually be an obligate intermediate in this reaction scheme because its altered protein conformation opens a groove adjacent to the catalytic center that may render it particularly susceptible to reduction with cytosolic glutathione compared with the sulfenic derivative. GSSH, oxidized glutathione.

FIG. 2.
FIG. 2.

Postulated effectors of insulin-induced ROS via Nox4 and influences on downstream events in the insulin action cascade. Insulin stimulation of its target cells, especially adipocytes, elicits a burst of superoxide, with rapid generation of H2O2 catalyzed by cellular superoxide dismutase (SOD). As discussed in the text, the Nox homolog Nox4 may mediate a major part of the insulin-induced ROS generation in adipocytes (98). However, the mechanism(s) coupling Nox4 with the insulin receptor is not known. Potential effectors of the insulin activation of Nox activity may include the G-proteins rac and Gαi2, the flavocytochrome b558 subunit p22phox, or interactions with novel Nox adaptor proteins (perhaps homologous to NOXO1 [Nox organizer 1] or NOXA1 [Nox activator 1]), among other possibilities. Insulin-stimulated ROS are believed to interact with a limited set of cellular proteins that contain catalytic thiol side-chains known to be particularly susceptible to biochemical oxidation (see Table 1). Inhibition of these signaling proteins, e.g., PTPs, leads to enhanced tyrosine autophosphorylation of the receptor and its substrate proteins as well as alterations in downstream signaling in the insulin action cascade. See text for further discussion and references.

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