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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/E842    most recent 90528.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Aoki, K. Articles by Terauchi, Y. Search for Related Content PubMed PubMed Citation Articles by Aoki, K. Articles by Terauchi, Y.

Role of the liver in glucose homeostasis in PI 3-kinase p85-deficient mice

¹Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama; ²Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo; ³Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi; ⁴Division of Applied Nutrition, National Institute of Health and Nutrition, Tokyo; ⁵Department of Laboratory Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; ⁶Department of Medicine, Ikeda Municipal Hospital, Ikeda; ⁷Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba; and ⁸Laboratory for Vertebrate Body Plan, Center for Developmental Biology, Institute of Physical and Chemical Research (RIKEN), Kobe, Japan

Submitted 22 June 2008 ; accepted in final form 10 January 2009

Phosphoinositide 3-kinase (PI3K) p85-deficient mice exhibit hypoglycemia as a result of increased insulin sensitivity and glucose uptake in peripheral tissues. Although PI3K is central to the metabolic actions of insulin, its mechanism of action in liver is not well understood. In the present study, we investigated hepatic insulin signaling and glucose homeostasis in p85-deficient and wild-type mice. In the livers of p85-deficient mice, p50 played a compensatory role in insulin-stimulated PI3K activation by binding to insulin receptor substrate (IRS)-1/2. In p85-deficient mice, the ratio of p50 over p110 catalytic subunit of PI3K in the liver was higher than in the muscles. PI3K activity associated with IRS-1/2 was not affected by the lack of p85 in the liver. Insulin-stimulated Akt and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activities in the liver were similar in p85-deficient and wild-type mice. A hyperinsulinemic-euglycemic clamp study revealed that the glucose infusion rate and the rate of disappearance were higher in p85-deficient mice than in wild-type mice but that endogenous glucose production tended to be higher in p85-deficient mice than in wild-type mice. Consistent with this finding, the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in livers after fasting was higher in p85-deficient mice than in wild-type mice. After mice were fasted, the intrahepatic glucose-6-phosphate level was almost completely depleted in p85-deficient mice. The glycogen content fell to nearly zero as a result of glycogenolysis shortly after the initiation of fasting in p85-deficient mice. The absence of an increase in insulin-stimulated PI3K activation in the liver of p85-deficient mice, unlike the muscles, may be associated with the molecular balance between the regulatory subunit and the catalytic subunit of PI3K. Gluconeogenesis was rather elevated in p85-deficient mice, compared with in wild-type mice, and the liver seemed to partially compensate for the increase in glucose uptake in peripheral tissues.

phosphoinositide 3-kinase; regulatory subunit; catalytic subunit