Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1.
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.
Okamoto
Yasuo
Y
Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan 657-0011.
Ogawa
Wataru
W
Nishizawa
Akihiko
A
Inoue
Hiroshi
H
Teshigawara
Kiyoshi
K
Kinoshita
Shinichi
S
Matsuki
Yasushi
Y
Watanabe
Eijiro
E
Hiramatsu
Ryuji
R
Sakaue
Hiroshi
H
Noda
Tetsuo
T
Kasuga
Masato
M
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
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