RT Journal Article
SR Electronic
T1 The Sulfonylurea Glimepiride Regulates Intracellular Routing of the Insulin-Receptor Complexes through Their Interaction with Specific Protein Kinase C Isoforms
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 322
OP 330
DO 10.1124/mol.59.2.322
VO 59
IS 2
A1 Marta Letizia Hribal
A1 Rossella D'Alfonso
A1 Barbara Giovannone
A1 Davide Lauro
A1 Yong Yu Liu
A1 Patrizia Borboni
A1 Massimo Federici
A1 Renato Lauro
A1 Giorgio Sesti
YR 2001
UL http://molpharm.aspetjournals.org/content/59/2/322.abstract
AB Sulfonylureas may stimulate glucose metabolism by protein kinase C (PKC) activation. Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. Association of PKC-βII and -ε with insulin receptors was increased in glimepiride-treated cells. Selective depletion of cellular PKC-βII and -ε by exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) or treatment of cells with PKC-βII inhibitor G06976 reversed the effect of glimepiride on intracellular insulin-receptor processing. Glimepiride increased the effects of insulin on glucose incorporation into glycogen by enhancing both sensitivity and maximal efficacy of insulin. Exposing cells to TPA or G06976 inhibitor reversed these effects. Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. These data suggest a novel mechanism of action of sulfonylurea, which may have a therapeutic impact on the treatment of type 2 diabetes.