MECHANISM OF INSULIN SIGNAL ON GLUCOSE TRANSPORT IN KNOCKOUT MICE

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In adipose and muscle tissue, the major targets of insulin-induced glucose transport, it is known that glucose transporter isoform GLUT4 translocates from a large intracellular pool to the cell surface in response to insulin, although the signaling mechanism regulating this process is not fully understood. Insulin enhances tyrosine phosphorylation of several endogenous substrates such as insulin receptor substrate (IRS)-1, IRS-2, Grb2-associated binder-1 (GRB1) and Shc. Phosphatidylinositol (PI) 3-kinase play the important role for insulin signal transduction on glucose transport. Insulin is thought to activated this enzyme via binding to phosphotyrosine-containing proteins such as IRS-1 and IRS-2 and pp60. To investigate the relationship between endogenous substrates and glucose transport in adipose cells, we analyzed mice with targeted disruption of the endogenous substrate gene, IRS-1. Insulin-stimulated PI 3-kinase activity in the antiphosphotyrosine immnoprecipitates is 54.3 % of wild type in adipose cells from the mice. Pp60 was the major tyrosine phosphorylated protein and predominantly associated with PI 3-kinase, whereas tyrosine phosphorylation of IRS-2 and its association with this enzyme are very low. In these cells, glucose transport, glucose transport and GLUT4 translocation are decreased to 52 % and 67.9 % of those from wild-type, respectively, sensitivity of insulin to stimulate glucose transport was also impaired. These data suggested that 1) IRS-1 plays a major role in insuln-induced translocation of GLUT4 in adipose cells from wild-type mice, and 2) pp60 takes in this process via activation of PI 3-kinase in the absence of IRS-1.