title: PP2A inhibition results in hepatic insulin resistance despite Akt2 activation.
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 phosphorylation and inhibited FoxO1in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Galbo
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Bjørn
authors.initials: B
authors.lastname: Quistorff
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis; D006003:Glycogen / Q000096:biosynthesis; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D006003:Glycogen; D009419:Nerve Tissue Proteins; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C494923:Akt2 protein, rat