Article

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

  1. Wan Iryani W. Ismail1,3,
  2. Judy A. King1,2,
  3. Khawar Anwar1,
  4. Tahir S. Pillay1,2,4,*

DOI: 10.1002/jcb.24513

Additional Information

Author Information

  1. 1

    Division of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa

  2. 2

    National Health Laboratory Service, Groote Schuur Hospital, Cape Town 7925, South Africa

  3. 3

    Division of Pharmaceutical Biotechnology, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia

  4. 4

    Department of Chemical Pathology, University of Kwazulu-Natal, Durban 4041, South Africa

*P.O. Box 59056, Umbilo, Durban, South Africa, 4075.

  1. †

    This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: [10.1002/jcb.24513].

Publication History

  1. Accepted manuscript online: 5 FEB 2013 08:17AM EST
  2. Manuscript Accepted: 24 JAN 2013
  3. Manuscript Revised: 22 DEC 2012
  4. Manuscript Received: 4 OCT 2012

Funded by

  • National Research Foundation (Rated Researcher Incentive funding) of South Africa
  • National Health Laboratory Service, South Africa
  • Young Lecturer Scheme under Universiti Teknologi MARA
  • Ministry of Higher Education of Malaysia

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Keywords:

  • HIV protease inhibitors;
  • insulin resistance;
  • salicylate

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 signalling-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. © 2013 Wiley Periodicals, Inc.

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