Small molecule inhibition of NOX-1 reduces diabetes conversion in NOD mice

Abstract

Inflammation is a major contributor to beta cell destruction leading to diabetes. Generation of reactive oxygen species (ROS) by inflammatory signals facilitates beta cell dysfunction. Disruption of the ROS-generating enzyme NADPH oxidase-1 (NOX-1) confers protection to beta cells. Selective small molecule inhibitors of NOX-1 that confer protection to mouse or human beta cells (ML171 or GKT137831) have been systemically administered to NOD mice. A brief (4 week) administration of the NOX-1 inhibitors reduced the conversion of NOD mice to diabetes, relative to vehicle control. Histologic analysis of islet morphology showed mice administered the NOX-1 inhibitors had a predominant organization of leukocytes that was restricted to the peri-islet region, in contrast to leukocyte invasion of the islet that was predominantly seen in vehicle control mice. The data support the therapeutic potential of NOX-1 inhibition in diabetes and suggest a role for NOX-1 in the cross talk between inflammatory cells, beta cells and the integrity of the islet extracellular matrix.