Journal
BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 32, Issue -, Pages 817-821Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BST0320817
Keywords
gene silencing; glucose; insulin signalling; phosphoinositide 3-kinase (PI3K); phospholipase C gamma; protein kinase C gamma/xi siRNA
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Funding
- NIDDK NIH HHS [5 P30 DK32520, DK60837, DK30898, DK30648] Funding Source: Medline
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Using siRNA-mediated gene silencing in cultured adipocytes, we have dissected the insulin-signalling pathway leading to translocation of GLUT4 glucose transporters to the plasma membrane. RNAi (RNA interference)-based depletion of components in the putative TC10 pathway (CAP, CrkII and c-Cbl plus Cbl-b) or the phospholipase Cgamma pathway failed to diminish insulin signalling to GLUT4. Within the phosphoinositide 3-kinase pathway, loss of the 5'-phosphatidylinositol 3,4,5-trisphosphate phosphatase SHIP2 was also without effect, whereas depletion of the 3'-phosphatase PTEN significantly enhanced insulin action. Downstream of phosphatidylinositol 3,4,5-trisphosphate and PDK1, silencing the genes encoding the protein kinases Akt1/PKBalpha, or CISK(SGK3) or protein kinases Clambda/xi had little or no effect, but loss of Akt2/PKBbeta significantly attenuated GLUT4 regulation by insulin. These results show that Akt2/PKBbeta is the key downstream intermediate within the phosphoinositide 3-kinase pathway linked to insulin action on GLUM in cultured adipocytes, whereas PTEN is a potent negative regulator of this pathway.
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