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_6 label "Selventa" provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
large_corpus.bel version "1.4" provenance.
large_corpus.bel authoredBy _6 provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
assertion wasDerivedFrom _5 provenance.
assertion hadPrimarySource 15777261 provenance.
_5 wasQuotedFrom 15777261 provenance.
_5 value "In principle, there are at least three mechanisms by which insulin could modulate GLUT4 function contributing to increase glucose uptake. First, insulin could promote translocation of pre-existing intracellular sequestered populations of GLUT4 proteins to the cell surface. Second, insulin could alter the intrinsic transport activity of GLUT4 proteins at the cell surface, by direct modifications of GLUT4 itself or by interaction with other regulatory molecules. Third, insulin could up-regulate the amount of GLUT4 protein by increased biosynthesis, decreased degradation or both (Watson & Pessin 2001). Although these mechanisms are not mutually exclusive, the first model has been the most intensively studied. It is well established the participation of PI3K in insulin-induced GLUT4 redistribution to the plasma membrane in adipocytes and myocytes (Martin et al. 1996). Two classes of Ser/Thr kinases have been proposed to act downstream of PI3K, Akt/ PKB and the atypical protein kinase (PK) C isoforms f and k (Kohn et al. 1998, Bandyopadhyay et al. 1999). Conversely, the use of ML-9 compound as an inhibitor of PKB/Akt enzymatic activity (Smith et al. 2000) has revealed that the activation of PKB/Akt was necessary for insulin-induced GLUT4 translocation in brown adipocytes (Hernandez et al. 2001). Moreover, the chemical compound okadaic acid, a potent inhibitor of proteins Ser/Thr phosphatase 1 and 2A, has been useful to investigate the role of protein kinase C zeta (PKCf) on insulin-induced glucose uptake. Primary brown adipocytes pre-treated with this compound have blunted insulin-induced PKCf activity, but not PKB/Akt or p70S6K phosphorylation. The metabolic consequence of PKCf inhibition is a blockade of insulin-induced glucose uptake (Valverde et al. 2000). These results summarized in Figure 2 indicate that PKB/Akt and PKCf activation seems to be an absolute requirement for the acute insulin induction of glucose uptake in foetal brown adipocytes. Furthermore, we have shown that inhibition of phospholipase C gamma (PLCc) activity either with the chemical compound U73122 (Kayali et al. 1998) or with an inhibitor peptide or with a dominant-negative construct, precluded insulin stimulation of glucose uptake, GLUT4 translocation and actin reorganization, as wortmannin did. These data indicate that PLCc, activated at least partially by PI3K, is a link between insulin receptor (IR) and PKCf through the production of phosphatidic acid (PA), and could mediate insulin-induced glucose uptake and GLUT4 translocation (Lorenzo et al. 2002). Concerning the second model, a potential role for p38MAPK in the activation of GLUT4 transporter by insulin, independent of GLUT4 translocation to the plasma membrane has been proposed in 3T3-L1 adipocytes and L6 myotubes (Sweeney et al. 1999). In this regard, we have recently found that rosiglitazone produced a modest but significant increase in basal glucose uptake that is dependent of p38MAPK activation in brown adipocytes (Hernandez et al. 2003b)." provenance.