The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes

The pathogenic processes involving in the development of diabetes range from autoimmune destruction of pancreatic beta-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The major contributing factor for excessive beta-cell death includes oxidative stress-mediated mitochondrial damage, which creates an imbalance in redox homeostasis. Yet, beta-cells have evolved adaptive mechanisms to endure a wide range of stress conditions to safeguard its potential functions. These include `Nrf2/Keap1' pathway, a key cellular defense mechanism, to combat oxidative stress by regulating phase II detoxifying and antioxidant genes. During diabetes, redox imbalance provokes defective Nrf2-dependent signaling and compromise antioxidant capacity of the pancreas which turnout beta-cells to become highly vulnerable against various insults. Hence, identification of small molecule activators of Nrf2/Keap1 pathway remains significant to enhance cellular defense to overcome the burden of oxidative stress related disturbances. This review summarizes the molecular mechanism behind Nrf2 activation and the impact of Nrf2 activators in diabetes and its complications. (C) 2014 Elsevier Ltd. All rights reserved.