Proceedings of the National Academy of Sciences · 2006 · 153 citations · 31 references
Life SciencesBiochemistryMolecular BiologyCell SignalingMetabolic RegulationSignal TransductionDiabetes MellitusHepatic PathophysiologyInsulin ResistanceLiver PhysiologyPhosphoinositide SignalingProtein Phosphatase SignalingImpaired Insulin SensitivityInsulin ActionPhosphoinositide 3-Kinase PathwayPhosphoinositide 3-Kinase SignalingPhosphoinositide 3-Kinase-akt ActivationPi3k SignalingPositive RegulationRegulatory Subunits
The phosphoinositide 3-kinase (PI3K) pathway is central to the metabolic actions of insulin on liver. Here, we show that mice with a liver-specific deletion of the p85alpha regulatory subunit of PI3K (L-Pik3r1KO) exhibit a paradoxical improvement of hepatic and peripheral insulin sensitivity. Although PI3K enzymatic activity is diminished in L-Pik3r1KO livers because of a reduced level of regulatory and catalytic subunits of PI3K, insulin-stimulated Akt activity is actually increased. This increased Akt activity correlates with increased phosphatidylinositol (3,4,5)-trisphosphate levels which are due, at least in part, to diminished activity of the (3,4,5)-trisphosphate phosphatase PTEN. Thus, the regulatory subunit p85alpha is a critical modulator of insulin sensitivity in vivo not only because of its effects on PI3K activation, but also as a regulator of PTEN activity.
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Insulin signalling and the regulation of glucose and lipid metabolism
Alan R. Saltiel, C. Ronald Kahn · Nature · 2001 · 5.3K citations · Full text
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Dongsheng Cai, Minsheng Yuan, Daniel Frantz et al. · Nature Medicine · 2005 · 2.2K citations · Full text