title: Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1.
abstract: Phosphoinositide-dependent kinase-1 (PDK1) is implicated in the metabolic effects of insulin as a key mediator of phosphoinositide 3-kinase-dependent signaling. Here we show that mice with liver-specific PDK1 deficiency manifest various defects in the metabolic actions of insulin in the liver as well as a type 2 diabetes-like phenotype characterized by marked hyperinsulinemia and postprandial hyperglycemia. The hepatic abundance of glucokinase, an important determinant of glucose flux and glucose-evoked signaling in hepatocytes, was substantially reduced in these mice. Restoration of hepatic glucokinase expression, with the use of an adenoviral vector, induced insulin-like effects in the liver and almost completely normalized the fasting hyperinsulinemia and postprandial hyperglycemia in these animals. These results indicate that, if the hepatic abundance of glucokinase is maintained, ingested glucose is normally disposed of even in the absence of acute activation of proximal insulin signaling, such as the activation of Akt, in the liver.
authors.affiliation: Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan 657-0011.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishizawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Eijiro
authors.initials: E
authors.lastname: Watanabe
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D005941:Glucokinase / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D019518:Postprandial Period; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D007328:Insulin; D005941:Glucokinase; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; C578579:Pdpk1 protein, rat; D017346:Protein Serine-Threonine Kinases; D005947:Glucose