Reactive Oxygen Species Enhance Insulin Sensitivity

Abstract

SUMMARY Chronic reactive oxygen species (ROS) production by mitochondria may contribute to the development of insulin resistance, a primary feature of type 2 diabetes. In recent years it has become apparent that ROS generation in response to physiological stimuli such as insulin may also facilitate signaling by reversibly oxidizing and inhibiting protein tyrosine phosphatases (PTPs). Here we report that mice lacking one of the key enzymes involved in the elimination of physiological ROS, glutathione peroxidase 1 (Gpx1), were protected from high fat diet-induced insulin resistance. The increased insulin sensitivity in Gpx1−/− mice was attributed to insulin-induced phosphatidylinositol-3-kinase/Akt signaling and glucose uptake in muscle and could be reversed by the anti-oxidant N-acetylcysteine. Increased insulin signaling correlated with enhanced oxidation of the PTP family member PTEN, which terminates signals generated by phosphatidylinositol-3-kinase. These studies provide causal evidence for the enhancement of insulin signaling by ROS in vivo.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

“…Grey and black bars represent control and Pgc-1β -overexpressing muscles, respectively relationship exists between ROS production and insulin action. Intermittent, low-level ROS production has been reported to enhance insulin action via improvements in insulin signal transduction [50]. However, other recent studies have shown that excessive or persistent generation of ROS in mitochondria contributes to the pathogenesis of insulin resistance [10,11].…”

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

“…Thus it has been shown that insulin stimulates the generation of ROS, since when insulin binds to its receptor, a short burst of cellular ROS is produced, acting as second messenger that mediates insulin signalling [34,35]. Furthermore, Loh et al [36] demonstrated that subtle increases in ROS production were in fact associated with improved insulin sensitivity in mice deficient in the cytosolic antioxidant GPx1, suggesting that ROS may even help enhance insulin sensitivity. At the same time, overabundance of GPx1 resulted in hyperglycaemia, hyperinsulinaemia and insulin resistance in mice [37], indicating that H 2 O 2 quenching disrupts insulin action.…”

Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes

“…Interestingly, studies have also shown that a transient physiological increase in ROS may be essential for a training-induced increase in insulin sensitivity in type 2 diabetes patients [20] and for protection against high-fat diet-induced insulin resistance in rodents [21]. Both these studies [20,21] suggest that ROS have a beneficial effect when increased ROS is transient, but are harmful when the increased concentration is sustained, as seen in response to chronic hyperglycaemia and dyslipidaemia.…”