Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-ζ

R. Ben-Romano, A. Rudich, A. Tirosh, R. Potashnik, T. Sasaoka, K. Riesenberg, F. Schlaeffer, N. Bashan

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 μmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated. Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/ interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

Original languageEnglish
Pages (from-to)1107-1117
Number of pages11
JournalDiabetologia
Volume47
Issue number6
StatePublished - 1 Jun 2004

Keywords

  • 3T3-L1 adipocyte
  • HIV protease inhibitor
  • Insulin resistance
  • Nelfinavir
  • PKB
  • PKC-ζ
  • Plasma membrane

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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