Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species

Abstract

Regulated production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) adequately balanced by antioxidant systems is a prerequisite for the participation of these active substances in physiological processes, including insulin action. Yet, increasing evidence implicates ROS and RNS as negative regulators of insulin signaling, rendering them putative mediators in the development of insulin resistance, a common endocrine abnormality that accompanies obesity and is a risk factor of type 2 diabetes. This review deals with this dual, seemingly contradictory, function of ROS and RNS in regulating insulin action: the major processes for ROS and RNS generation and detoxification are presented, and a critical review of the evidence that they participate in the positive and negative regulation of insulin action is provided. The cellular and molecular mechanisms by which ROS and RNS are thought to participate in normal insulin action and in the induction of insulin resistance are then described. Finally, we explore the potential usefulness and the challenges in modulating the oxidant-antioxidant balance as a potentially promising, but currently disappointing, means of improving insulin action in insulin resistance-associated conditions, leading causes of human morbidity and mortality of our era.

Insulin resistance is a cellular antioxidant defense mechanism

“…This indicates that O 2 •Ϫ production is increased under these conditions and its rapid dismutation to H 2 O 2 may be mediating a positive effect on insulin action (26). It should be noted that longer term exposure of cells to high levels of H 2 O 2 leads to IR (26). However, this occurs via covalent modification of Akt, an effect that we have not observed in more physiological models of IR (5).…”

“…It is also of interest that overexpression of MnSOD in L6 cells had no effect on insulin action in control cells whereas in insult-treated cells we observed a supercompensatory effect on insulin action. This indicates that O 2 •Ϫ production is increased under these conditions and its rapid dismutation to H 2 O 2 may be mediating a positive effect on insulin action (26). It should be noted that longer term exposure of cells to high levels of H 2 O 2 leads to IR (26).…”

“…While a general link between IR and oxidative stress has been proposed (23)(24)(25), evidence supporting a specific role for mitochondrial O 2 •Ϫ in IR in muscle and fat cells is scarce (26). Mitochondrial O 2 •Ϫ is primarily formed at Complex I (NADH dehydrogenase) or Complex III (cytochrome bc 1 ) of the ETC (11,14,21).…”

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

“…The major symptoms are thirst, hunger, emaciation, and weakness, eventually lead to coma. DM is associated with the increased production of free radicals or decreased activity of the antioxidant systems, which leads to development of oxidative stress [104,105]. The hyperglycemic condition induces increased free radical production via four different routes namely, 1) increased glycolysis, results in increased ratio between the rate of oxidation of G3P to 1, 3-DPG, following increased NADH/NAD ?…”

An oxidative stress paradox: time for a conceptual change?

“…There is precedent for such a mechanism. Studies performed in adipose tissue have also demonstrated beneficial (and necessary) effects of enhanced H 2 O 2 production [14]. It is also important to consider that compared with O 2 • − and HO• − , H 2 O 2 is much less oxidative.…”