An oxide transport chain essential for balanced insulin action

Background and aims: Patients with overnutrition, obesity, the atherometabolic syndrome, and type 2 diabetes typically develop fatty liver, atherogenic dyslipoproteinemia, hyperglycemia, and hypertension. These features share an unexplained origin - namely, imbalanced insulin action, also called pathway-selective insulin resistance and responsiveness. To control glycemia, these patients require hyperinsulinemia that then overdrives ERK and hepatic de-novo lipogenesis. We previously reported that NADPH oxidase-4 regulates balanced insulin action, but the model appeared incomplete. Methods: We conducted structure-function studies in liver cells to search for additional molecular mediators of balanced insulin action. Results: We found 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 superoxide (O-2(center dot-)). NADPH oxidase-4 forms a novel, tight complex with superoxide dismutase-3, to efficiently transfer O-2(center dot-) for quantitative conversion into hydrogen peroxide. The pathway ends when aquaporin-3 channels H2O2 across the plasma membrane to inactivate PTEN. Accordingly, aquaporin-3 forms a novel complex with PTEN in McArdle hepatocytes and in unpassaged human primary hepatic parenchymal cells. Molecular or chemical disruption of any component of the NSAPP chain, from NADPH oxidase-4 up to PTEN, leaves PTEN persistently active, thereby recapitulating the same deadly pattern of imbalanced insulin action seen clinically. Conclusions: The NSAPP pathway functions as a master regulator of balanced insulin action via ERK, PI3K-AKT, and downstream targets of AKT. Unraveling its dysfunction in overnutrition might clarify the molecular cause of the atherometabolic syndrome and type 2 diabetes.