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

Yasuo Okamoto, Wataru Ogawa, Akihiko Nishizawa, Hiroshi Inoue, Kiyoshi Teshigawara, Shinichi Kinoshita, Yasushi Matsuki, Eijiro Watanabe, Ryuji Hiramatsu, Hiroshi Sakaue, Tetsuo Noda, Masato Kasuga

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28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1000-1009
Number of pages10
JournalDiabetes
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2007

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Okamoto, Y., Ogawa, W., Nishizawa, A., Inoue, H., Teshigawara, K., Kinoshita, S., Matsuki, Y., Watanabe, E., Hiramatsu, R., Sakaue, H., Noda, T., & Kasuga, M. (2007). Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1. Diabetes, 56(4), 1000-1009. https://doi.org/10.2337/db06-1322