An oxide transport chain essential for balanced insulin signaling

Abstract

Patients with overnutrition, obesity, the atherometabolic syndrome, and type 2 diabetes mellitus exhibit imbalanced insulin action, also called pathway-selective insulin resistance. To control glycemia, they require hyperinsulinemia that then overdrives ERK and hepatic de-novo lipogenesis. We recently reported that NADPH oxidase-4 regulates balanced insulin action. Here, we show that NADPH oxidase-4 is part of a new limb of insulin signaling that we abbreviate \"NSAPP\" after its five major proteins. The NSAPP pathway is an oxide transport chain that begins when insulin stimulates NADPH oxidase-4 to generate [Formula]. NADPH oxidase-4 hands [Formula] to superoxide dismutase-3 for conversion into H2O2. The pathway ends when aquaporin-3 channels H2O2 across the membrane to inactivate PTEN. Disruption of any component of the NSAPP chain, from NADPH oxidase-4 up to PTEN, leaves PTEN persistently active, thereby producing the same deadly pattern of imbalanced insulin action seen clinically. Unraveling the molecular basis for NSAPP dysfunction in overnutrition has now become a top priority.