title: Activation of PI 3-kinase by the hexosamine biosynthesis pathway.
abstract: It has been shown that hyperglycaemia-induced defects in glucose transport and insulin action are mediated by increased flux of excess glucose through the hexosamine biosynthesis pathway (HBP). We have previously demonstrated that in rat adipocytes, increased flux through the HBP activates protein kinase C (PKC). The aim of the present study was to explore the mechanism for HBP-mediated activation of PKC. We show that activation of the HBP by either high glucose or glucosamine causes the translocation of PKC-zeta/lambda and PKC-epsilon but not other PKC isoforms tested (alpha, beta, delta). This translocation was inhibited by wortmannin, a PI 3-kinase inhibitor. Both high glucose and glucosamine caused widespread cellular activation of PI 3-kinase. We demonstrate that HBP-mediated activation of PI 3-kinase has an insulin-like effect to translocate GLUT4. We conclude that an acute increase of glucose flux through the HBP activates PI 3-kinase.
authors.affiliation: The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Filippis
authors.forename: Anthony
authors.initials: A
authors.lastname: Filippis
authors.forename: Stella
authors.initials: S
authors.lastname: Clark
authors.forename: Joseph
authors.initials: J
authors.lastname: Proietto
mesh_terms: D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005944:Glucosamine / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D051275:Glucose Transporter Type 4; D006595:Hexosamines / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051275:Glucose Transporter Type 4; D006595:Hexosamines; D007527:Isoenzymes; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D005947:Glucose; D005944:Glucosamine