Journal of Cellular Biochemistry

Indinavir and nelfinavir inhibit proximal insulin receptor signaling and salicylate abrogates inhibition: Potential role of the NFkappa B pathway

Authors

  • Wan Iryani W. Ismail,

    1. Division of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa
    2. Faculty of Pharmacy, Division of Pharmaceutical Biotechnology, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
    Search for more papers by this author
  • Judy A. King,

    1. Division of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa
    2. National Health Laboratory Service, Groote Schuur Hospital, Cape Town 7925, South Africa
    Search for more papers by this author
  • Khawar Anwar,

    1. Division of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa
    Search for more papers by this author
  • Tahir S. Pillay

    Corresponding author
    1. Division of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa
    2. National Health Laboratory Service, Groote Schuur Hospital, Cape Town 7925, South Africa
    3. Department of Chemical Pathology, University of Kwazulu-Natal, Durban 4041, South Africa
    4. Department of Chemical Pathology, University of Pretoria, Pretoria 0001, South Africa
    • Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.
    Search for more papers by this author

  • Conflicts of interest: nothing to declare.

Abstract

The molecular basis of insulin resistance induced by HIV protease inhibitors (HPIs) remains unclear. In this study, Chinese hamster ovary cells transfected with high levels of human insulin receptor (CHO-IR) and 3T3-L1 adipocytes were used to elucidate the mechanism of this side effect. Indinavir and nelfinavir induced a significant decrease in tyrosine phosphorylation of the insulin receptor β-subunit. Indinavir caused a significant increase in the phosphorylation of insulin receptor substrate-1 (IRS-1) on serine 307 (S307) in both CHO-IR cells and 3T3-L1 adipocytes. Nelfinavir also inhibited phosphorylation of Map/ERK kinase without affecting insulin-stimulated Akt phosphorylation. Concomitantly, levels of protein tyrosine phosphatase 1B (PTP1B), suppressor of cytokines signaling-1 and -3 (SOCS-1 and -3), Src homology 2B (SH2B) and adapter protein with a pleckstrin homology domain and an SH2 domain (APS) were not altered significantly. When CHO-IR cells were pre-treated with sodium salicylate (NaSal), the effects of indinavir on tyrosine phosphorylation of the IR β-subunit and phosphorylation of IRS-1 at S307 were abrogated. These data suggest a potential role for the NFκB pathway in insulin resistance induced by HPIs. J. Cell. Biochem. 114: 1729–1737, 2013. © 2013 Wiley Periodicals, Inc.

Ancillary