RIESENBERG K, SCHLAEFFER F, BEN-ROMANO R, RUDICH A, BASHAN N; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. H-1949.
Soroka Med. Ctr. & Ben-Gurion Univ. Beer Sheva, Israel, Beer Sheva, Israel.
BACKGROUND: The metabolic syndrome associated with HPI, as part of the highly active antiretroviral therapy (HAART), is an increasingly recognized concern in the management of HIV positive patients. Nethertheless, the cellular mechanisms responsible for the observed abnormalities are still not clear. We have previously reported that prolonged exposure of 3T3-L1 adipocytes to NFV induces IR associated with reduction in insulin stimulated GLUT4 translocation. The aim of the present study was to identify the molecular mechanisms for the reduction in insulin action. METHODS: Fully differentiated 3T3-L1 adipocytes were exposed for 18 h to NFV after which cells were exposed to insulin and the insulin signaling cascade was screened. RESULTS: In NFV treated cells, insulin stimulated IRS1 tyrosine phosphorylation, and its association with PI3 kinase, and PI3 kinase activation were intact. However NFV treatment severely impaired insulin but not PDGF stimulation of both Ser473 and Thr308 PKB phosphorylation with any effect on PKB content. Since PP2A is the enzyme, which dephosphorylates PKB, its amount and activity were measured in NFV treated cells. Neither elevation in PP2A content nor in its activity was found suggesting that the insulin-stimulated activation of PDK1 by phosphoinositides is impaired by NFV treatment. Indeed, insulin stimulated translocation of PKB and PKCz as well as phosphorylation of p70S6 kinase were all impaired in NFV treated cells. These suggest that insulin stimulated PDK1 activation is impaired by prolonged NFV treatment, which may lead to reduction in insulin sensitivity. CONCLUSIONS: The HPI NFV induces insulin resistance in adipocytes by inhibition of insulin ability to activate PDK1 and downstream effectors.
Publication Types:
Keywords:
- 1-Phosphatidylinositol 3-Kinase
- Adipocytes
- HIV Protease Inhibitors
- Humans
- Insulin
- Insulin Resistance
- Nelfinavir
- Phosphorylation
- Protein-Serine-Threonine Kinases
- Proto-Oncogene Proteins
- Receptor, Insulin
- Signal Transduction
Other ID:
UI: 102265549
From Meeting Abstracts