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Restoration of Glucokinase Expression in the Liver Normalizes Postprandial Glucose Disposal in Mice With Hepatic Deficiency of PDK1

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

Address correspondence and reprint requests to Wataru Ogawa, Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan 657-0011. E-mail: ogawa{at}med.kobe-u.ac.jp

Abbreviations: ALT, alanine aminotransferase; AxCAGck, adenoviral vector-encoding rat glucokinase; ERK, extracellular signal–related kinase; FAS, fatty acid synthase; G6P, glucose 6-phosphate; G6PC, glucose-6-phosphatase; GS, glycogen synthase; IGFBP1, IGF-1 binding protein; IRS, insulin receptor substrate; P13K, phosphoinositide 3-kinase; PCK-1, phosphoenolpyruvate carboxykinase; PDK1, phosphoinositide-dependent kinase-1; PFU, plaque-forming units; PGC1, peroxisome proliferator–activated receptor- coactivator 1; PK, pyruvate kinase insulin receptor substrate; SCD-1, stearoyl-CoA desaturase-1; SREBP, sterol regulatory element–binding protein

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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