We have also used primary skin fibroblasts obtained from control and diabetic rats. We observed that high glucose increased reactive oxygen species production, impaired cell polarization, decreased migration speed, protrusion persistence and stability, and adhesion maturation. These Talazoparib effects point to the Rho GTPases as mediators of these effects. In this regard, we observed a significant increase in the activation of the small GTPase Rac1, which is inhibited by antioxidants. Consistently, antioxidants reverted most of the migratory effects caused by high glucose. Together, our data indicates that hyperglycemia impairs cell migration through increased generation of ROS, which induces an abnormal activation of Rac1. Our data show that increased glucose uptake by fibroblasts inhibits cell migration through inadequate activation of the small GTPase Rac1, which depends on the oxidative state of the cell. Intracellular glucose is metabolized through a series of enzymatic reactions that are optimized by molecular oxygen and electron transport, which provides energy for ATP generation; ROS are byproducts of this process. There is strong evidence that excessive glucose increases ROS formation, which in turn overcomes the antioxidant capacity of the cell. This has deleterious effects, including the non-specific oxidation of proteins and lipids, alterations in gene expression and perturbations of different signaling pathways. Our results indicate that ROS generation decreases cell migration by over-activation of the small Rho GTPase Rac1. ROS generation and Rac1 activation are therefore part of a positive feedback loop, as Rac1 increases ROS generation by activating the NADPH oxidase system. Furthermore, activation of Rac1 by a specific guanine-nucleotide-exchange factor suffices to induce glucose uptake into skeletal-muscle cells, thereby contributing to its own glucose- and ROS-dependent activation. In migrating cells, Rac1 is activated near the leading edge and is thought to drive protrusion. Therefore, the local activation of Rac1 near the leading edge may generate a local increase of ROS in this cellular region that oxidizes cysteine residues in different redox-sensitive targets, including signaling adaptors that can modulate the activation of small GTPases such as Rac1 or RhoA. On the other hand, sustained oxidative stress may affect these proteins differently, due to excessive oxidation. Interestingly, increased Rac1 activity was also observed in cardiac fibroblasts from diabetic.