Pro-oxidant/antioxidant balance controls pancreatic ß-cell differentiation through the ERK1/2 pathway.

ABSTRACT

During embryogenesis, the intrauterine milieu affects cell proliferation, differentiation, and function by modifying gene expression in susceptible cells, such as the pancreatic ß-cells. In this limited energy environment, mitochondrial dysfunction can lead to overproduction of reactive oxygen species (ROS) and to a decline in ß-cell function. In opposition to this toxicity, ROS are also required for insulin secretion. Here we investigated the role of ROS in ß-cell development. Surprisingly, decreasing ROS production in vivo reduced ß-cell differentiation. Moreover, in cultures of pancreatic explants, progenitors were highly sensitive to ROS stimulation and responded by generating ß-cells. ROS enhanced ß-cell differentiation through modulation of ERK1/2 signaling. Gene transfer and pharmacological manipulations, which diminish cellular ROS levels, also interfered with normal ß-cell differentiation. This study highlights the role of the redox balance on ß-cell development and provides information that will be useful for improving ß-cell production from embryonic stem cells, a step in cell therapy for diabetes.