Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane.
Dehydroepiandrosterone (DHEA) has been shown to modulate glucose utilization in humans and animals, but the mechanisms of DHEA action have not been clarified. We show that DHEA induces a dose- and time-dependent increase in glucose transport rates in both 3T3-L1 and human adipocytes with maximal effects at 2 h. Exposure of adipocytes to DHEA does not result in changes of total GLUT4 and GLUT1 protein levels. However, it does result in significant increases of these glucose transporters in the plasma membrane. In 3T3-L1 adipocytes, DHEA increases tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and stimulates IRS-1- and IRS-2-associated phosphatidylinositol (PI) 3-kinase activity with no effects on either insulin receptor or Akt phosphorylation. In addition, DHEA causes significant increases of cytosolic Ca(2+) concentrations and a parallel activation of protein kinase C (PKC)-beta(2). The effects of DHEA are abrogated by pretreatment of adipocytes with PI 3-kinase and phospholipase C gamma inhibitors, as well as by inhibitors of Ca(2+)-dependent PKC isoforms, including a specific PKC-beta inhibitor. Thus, DHEA increases glucose uptake in both human and 3T3-L1 adipocytes by stimulating GLUT4 and GLUT1 translocation to the plasma membrane. PI 3-kinase, phospholipase C gamma, and the conventional PKC-beta(2) seem to be involved in DHEA effects.
Perrini
Sebastio
S
Department of Emergency and Organ Transplantation, Section on Internal Medicine, Endocrinology and Metabolic Diseases, Bari, Italy.
Natalicchio
Annalisa
A
Laviola
Luigi
L
Belsanti
Gaetana
G
Montrone
Carmela
C
Cignarelli
Angelo
A
Minielli
Vincenza
V
Grano
Maria
M
De Pergola
Giovanni
G
Giorgino
Riccardo
R
Giorgino
Francesco
F
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D021381:Protein Transport / Q000187:drug effects
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D003687:Dehydroepiandrosterone; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose; D002118:Calcium