title: Indinavir and nelfinavir inhibit proximal insulin receptor signaling and salicylate abrogates inhibition: potential role of the NFkappa B pathway.
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.
authors: Division of Chemical Pathology, University of Cape Town, Cape Town 7925, South Africa.
authors: Wan Iryani W
authors: WI
authors: Ismail
authors: Judy A
authors: JA
authors: King
authors: Khawar
authors: K
authors: Anwar
authors: Tahir S
authors: TS
authors: Pillay
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D019469:Indinavir / Q000009:adverse effects* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019888:Nelfinavir / Q000009:adverse effects* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D020156:Salicylic Acid / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000890:Anti-Infective Agents; D017320:HIV Protease Inhibitors; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D016328:NF-kappa B; C518910:SH2B1 protein, human; D019469:Indinavir; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D019888:Nelfinavir; D020156:Salicylic Acid