Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase.

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作者：

Y Terauchi，Y Tsuji，S Satoh，H Minoura，K Murakami，A Okuno，K Inukai，T Asano，Y Kaburagi，K Ueki

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摘要：

The hallmark of , the most common , is a defect in -stimulated in peripheral tissues. Although a role for -3-kinase () activity in -stimulated and isoform 4 () translocation has been suggested in vitro, its role in vivo and the molecular link between activation of and translocation has not yet been elucidated. To determine the role of in , we generated with a targeted disruption of the gene encoding the p85alpha regulatory subunit of (; refs 3-5). -/- showed increased sensitivity and due to increased in skeletal muscle and adipocytes. -stimulated activity associated with substrates (IRSs) was mediated via full-length alpha in wild-type , but via the alpha alternative splicing isoform of the same gene in -/- . This isoform switch was associated with an increase in -induced generation of phosphatidylinositol(3,4,5)((3,4,5)P3) in -/- adipocytes and facilitation of translocation from the low-density () fraction to the (PM). This mechanism seems to be responsible for the phenotype of -/- , namely increased and . Our work provides the first direct evidence that and its regulatory subunit have a role in in vivo.

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关键词：

Animals Mice, Knockout Mice Muscle, Skeletal Subcellular Fractions Hypoglycemia Isoenzymes Insulin Deoxyglucose Glucose