2013
DOI: 10.18632/aging.100611
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Abstract: In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphoryla… Show more

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Cited by 33 publications
(33 citation statements)
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References 37 publications
(44 reference statements)
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“…To this end, central insulin signaling dysregulation has been demonstrated in post-mortem hippocampal and cortical samples from subjects with both mild cognitive impairment (MCI) and early AD (Talbot et al, 2012a; Watson and Craft, 2004). The insulin receptor (IR), the insulin receptor substrate-1 (IRS-1), the phosphoinositide-dependent kinase-1 (PDK1), and the alpha serine/threonine-protein kinase (AKT) are regulated through stoichiometric activation/inactivation phosphorylation profiles and form the components of a highly integrated intracellular insulin signaling pathway that undergoes diminished function in AD (Boura-Halfon and Zick, 2009a; Galbo et al, 2013, 2011; Gual et al, 2005; Long-Smith et al, 2013; Steen et al, 2005; Stuart et al, 2014; Talbot et al, 2012; Wang et al, 2009; Yarchoan and Arnold, 2014; Zhang et al, 2016). …”
Section: Introductionmentioning
confidence: 99%
“…To this end, central insulin signaling dysregulation has been demonstrated in post-mortem hippocampal and cortical samples from subjects with both mild cognitive impairment (MCI) and early AD (Talbot et al, 2012a; Watson and Craft, 2004). The insulin receptor (IR), the insulin receptor substrate-1 (IRS-1), the phosphoinositide-dependent kinase-1 (PDK1), and the alpha serine/threonine-protein kinase (AKT) are regulated through stoichiometric activation/inactivation phosphorylation profiles and form the components of a highly integrated intracellular insulin signaling pathway that undergoes diminished function in AD (Boura-Halfon and Zick, 2009a; Galbo et al, 2013, 2011; Gual et al, 2005; Long-Smith et al, 2013; Steen et al, 2005; Stuart et al, 2014; Talbot et al, 2012; Wang et al, 2009; Yarchoan and Arnold, 2014; Zhang et al, 2016). …”
Section: Introductionmentioning
confidence: 99%
“…Of note, these mechanistic studies relied on cell-permeable short-chain ceramides with cytotoxic properties and often used at unphysiologic concentrations [85]. Interestingly, pharmacologic inhibition of PP2A in rats paradoxically worsened hepatic insulin resistance despite activation of AKT, suggesting that activation of PP2A would not be sufficient to induce hepatocellular insulin resistance [91]. Additionally, proximal insulin signaling is impaired in insulin resistant liver, which is difficult to reconcile with AKT as the main site for insulin resistance [43,92,93].…”
Section: Ceramides In Hepatic Insulin Resistancementioning
confidence: 99%
“…There is evidence that PP2A activity is regulated by changes in lipid metabolism (43)(44)(45)(46)(47)(48). For example, it can be activated by changes in free fatty acid or cholesterol levels (44,46), whereas it can be inhibited by increased gluconeogenesis and lipogenesis (43).…”
Section: Figure 11 Pp2amentioning
confidence: 99%
“…For example, it can be activated by changes in free fatty acid or cholesterol levels (44,46), whereas it can be inhibited by increased gluconeogenesis and lipogenesis (43). PP2A activity is also regulated during insulin signaling (43,48).…”
Section: Figure 11 Pp2amentioning
confidence: 99%