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Diabetes Publish Ahead of Print published online ahead of print January 31, 2007
DOI: 10.2337/db06-1322
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Original Research

Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1

Yasuo Okamoto1, Wataru Ogawa1, Akihiko Nishizawa1, Hiroshi Inoue1, Kiyoshi Teshigawara1, Shinichi Kinoshita1, Yasushi Matsuki2, Eijiro Watanabe2, Ryuji Hiramatsu2, Hiroshi Sakaue1, Tetsuo Noda3, and Masato Kasuga1

1Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
2Genomics Science Laboratories, Dainippon Sumitomo Pharmaceuticals Co. Ltd., Takarazuka, Japan
3Department of Cell Biology, Japanese Foundation for Cancer Research (JFCR), Cancer Institute, Tokyo, Japan

Correspondence: ogawa{at}med.kobe-u.ac.jp

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.


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Copyright © 2007 by the American Diabetes Association.