Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Editorial
. 2012 May;32(5):1063-5.
doi: 10.1161/ATVBAHA.112.246868.

kNOXing on the door of selective insulin resistance

Zhiyong Cheng, Morris F White
Editorial

kNOXing on the door of selective insulin resistance

Zhiyong Cheng et al. Arterioscler Thromb Vasc Biol. 2012 May.
No abstract available

PubMed Disclaimer

Figures

Figure
Figure
Possible mechanisms for selective insulin resistance in diabetes and NAD(P)H oxidase 4 (NOX4)–deficient hepatocytes. Insulin normally activates the IR→IRS→phosphatidyl inositol 3 kinase (PI3K)→AKT signaling cascade that suppresses FoxO and the CRTC2 (cAMP response element binding protein (CREB) complex and activates mammalian target of rapamycin complex 1 (mTORC1). A full activation of AKT requires phosphorylation of T308AKT and S473AKT by PDPK1 and mTORC2, respectively. Impaired insulin action (or insulin resistance) dampens the IR→IRS→PI3K signaling, which promotes FoxO and CREB-mediated gluconeogenic gene expression (eg, phosphoenolpyruvate carboxykinase [PEPCK] and glucose-6-phosphatase [G6P])—the cause of hyperglycemia. However, lipid accumulates during insulin resistance, revealing a selective insulin responsiveness in diabetes mellitus characterized by hyperglycemia with hypertriglyceridemia. Wu and Williams suggest that the mechanism for such selective insulin resistance could include NOX4, the oxidase that elicits a reactive oxygen species (ROS) burst during insulin stimulation and inhibits protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homolog (PTEN)—inhibitors of canonical IR→IRS→PI3K signaling. Unexpectedly, NOX4 deficiency induces atypical AKT phosphorylation (strong pT308AKT but weak pS473AKT), which is associated with FoxO1 and mTORC1 activation. That the NOX4 deficiency diminished pS473 could be a result of (1) inactivation of sirtuin (silent mating type information regulation 2 homolog) 1 (Sirt1) or mTORC2 or (2) activation of PH domain leucine-rich repeat protein phosphatase-1 (PHLPP) or other phosphatases that specifically dephosphorylate S473AKT. Genetic ablation of hepatic Sirt1 inactivates mTORC2, the kinase that funnels PI3K signaling cascade and promotes pS473AKT. Moreover, FoxO1 activity can cause mitochondrial dysfunction and dysregulation of NAD+/NADH, which impairs Sirt1 activity and lipid metabolism. The gray lines denote insulin signaling pathways that are inactive in db/db mice or cells lacking NOX4, and the black lines denote insulin signaling pathways that remain active in cells lacking NOX4 (molecules shown in gray circles are inactive). ChREBP indicates carbohydrate responsive element-binding protein.
See this image and copyright information in PMC

Comment on

References

    1. Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab. 2010;21:589–598. - PMC - PubMed
    1. Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation. 2000;101:660–667. - PMC - PubMed
    1. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14:575–585. - PMC - PubMed
    1. Stefan N, Häring HU. The metabolically benign and malignant fatty liver. Diabetes. 2011;60:2011–2017. - PMC - PubMed
    1. Altarejos JY, Montminy M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011;12:141–151. - PMC - PubMed

MeSH terms