RIESENBERG K, RUDICH A, VANOUNOU S, TIROSH A, HARMAN-BOEHM I, BASHAN N, SCHLAEFFER F; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. I-227.

Soroka Med. Ctr. and Ben-Gurion Univ., Beer-Sheva, Israel

BACKGROUND: The metabolic syndrome associated with HIV protease inhibitors (HPI), as part of the highly active antiretroviral therapy (HAART), is an increasingly recognized concern in the management of HIV positive patients. Nevertheless, the cellular mechanisms responsible for the observed abnormalities are still not clear. We have recently reported, that exposure of 3T3-L1 adipocytes to micromolar concentrations of the HPI nelfinavir (NFV) results in inhibition of insulin stimulated glucose uptake and increases lipolysis (free fatty acid and glycerol release). These could be attributed to reduced insulin stimulated glucose transporter (GLUT4) translocation and protein kinase B (PKB) phosphorylation. The aim of the current study is to further analyze the effect of HPI on the insulin signaling in adipocytes. METHODS: Fully differentiated 3T3-L1 adipocytes were exposed for 18 h to escalating concentrations of NFV up to 40 micro-M. RESULTS: Assessing cell lysates revealed, that NFV treatment did not affect the activation of the insulin receptor and the tyrosine phosphorylation of its major substrate - IRS1. Furthermore, the interaction of IRS1 with the enzyme PI 3-kinase following insulin stimulation was intact in NFV treated adipocytes. However, NFV treatment severely impaired the insulin stimulation of both Ser473 and Thr308 PKB phosphorylation with no effect on total PKB content. In addition, the insulin stimulated phosphorylation of ERK1/2 and p70 S6 kinase were significantly decreased in treated cells. Pre and co-treatment with troglitazone, a novel insulin sensitizer drug, inhibited the activation of basal lipolysis induced by NFV, but could not prevent the reduction in insulin stimulated glucose transport. CONCLUSION: The HPI NFV induces insulin resistance by inhibition of insulins ability to activate its downstream effectors. Therapeutic interventions for HPI induced insulin resistance are warranted.

Publication Types:

• Meeting Abstracts

Keywords:

• 1-Phosphatidylinositol 3-Kinase
• Adipocytes
• Biological Transport
• HIV Protease Inhibitors
• Humans
• Insulin
• Insulin Resistance
• Lipolysis
• Monosaccharide Transport Proteins
• Nelfinavir
• Phosphoproteins
• Phosphorylation
• Protein-Serine-Threonine Kinases
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-akt
• Receptor, Insulin
• Ribosomal Protein S6 Kinases, 70-kDa
• Signal Transduction
• insulin receptor substrate-1 protein

Other ID:

• GWAIDS0029596

UI: 102269228

From Meeting Abstracts