PT  - JOURNAL ARTICLE
AU  - Marta Letizia Hribal
AU  - Rossella D'Alfonso
AU  - Barbara Giovannone
AU  - Davide Lauro
AU  - Yong Yu Liu
AU  - Patrizia Borboni
AU  - Massimo Federici
AU  - Renato Lauro
AU  - Giorgio Sesti
TI  - The Sulfonylurea Glimepiride Regulates Intracellular Routing of the Insulin-Receptor Complexes through Their Interaction with Specific Protein Kinase C Isoforms
AID  - 10.1124/mol.59.2.322
DP  - 2001 Feb 01
TA  - Molecular Pharmacology
PG  - 322--330
VI  - 59
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/59/2/322.short
4100  - http://molpharm.aspetjournals.org/content/59/2/322.full
SO  - Mol Pharmacol2001 Feb 01; 59
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.