Patients with overnutrition, obesity, the atherometabolic syndrome, and type 2 diabetes 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 (DNL).

We discovered an oxide transport chain that is required for balanced insulin action (Atherosclerosis 2016;247:225). The chain, abbreviated “NSAPP”, begins when insulin stimulates NOX4 to generate O2-. NOX4 hands O2- to SOD3 for conversion into H2O2. Aquaporins (AQPs) channel this H2O2 to inactivate PTEN. Disruption of any component, from NOX4 up to PTEN, leaves PTEN persistently active, thereby producing the same deadly pattern of imbalanced insulin action seen clinically.

We now sought to identify which aquaporins mediate balanced insulin signaling in hepatocytes.

Four AQPs had been reported to act as pores for H2O2: AQP1, 3, 8, and 9. We found that global inhibition of all APQs with low-dose AgNO3 recapitulated the clinical pattern of imbalanced insulin signaling, i.e., full two-site phosphorylation of ERK (pT202/Y204-ERK); monophosphorylation of AKT (pT308-AKT) with only weak phosphorylation at Ser473; robust phosphorylation of AKT targets leading to DNL; but impaired AKT-mediated phosphorylation of FOXO1 (needed to suppress hepatic gluconeogenesis).

Our knockdown of AQP3 recapitulated this pattern of imbalanced insulin signaling. Knockdown of AQP1 produced the mirror-image: strongly inhibited pT202/Y204-ERK and pT308-AKT, but intact pS473-AKT. Knockdowns of AQP8 or AQP9 did not affect insulin signaling to either site on ERK or AKT. Importantly, immunoprecipitation of AQP3 brought down PTEN, a previously unknown partner of any aquaporin.

Thus, AQP3 participates in the NSAPP oxide transport chain. AQP1 plays an unexpected role, perhaps as a scaffold. Our findings will facilitate unraveling the molecular basis for NSAPP dysfunction in overnutrition and hence imbalanced insulin action.


X. Wu: None. K. Williams: Stock/Shareholder; Self; Hygieia, Gemphire, Inc.. Advisory Panel; Self; Gemphire, Inc..

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