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HIV‐1 protease inhibitors suppress insulin secretion in pancreatic β cells : role of oxidative stress and endoplasmic reticulum stress and protection by thymoquinone (TQ)
Author(s) -
Chandra Surabhi,
Mondal Debasis,
Agrawal Krishna C
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1131.2
Subject(s) - nelfinavir , unfolded protein response , endoplasmic reticulum , oxidative stress , insulin , endocrinology , pharmacology , medicine , insulin resistance , chemistry , biochemistry , immunology , viral load , human immunodeficiency virus (hiv) , antiretroviral therapy
The advent of protease inhibitors (PIs) in highly active anti‐retroviral therapy (HAART) has considerably reduced the mortality in HIV‐1 positive patients; however, HAART is associated with cardiovascular dysfunction, lipodystrophy, and insulin resistance syndrome (IRS). The molecular mechanism(s) of IRS remain largely unknown. We determined the role of PI‐induced oxidative and endoplasmic reticulum (ER) stress in decreasing insulin secretion in rat pancreatic β‐cells (INS‐1). Exposure to the PIs, nelfinavir (5–10 μM) and atazanavir (8–20 μM), but not saquinavir, significantly decreased pre‐pro‐insulin gene expression and insulin secretion (50%) within 24 h. There was a significant increase (50%) in ROS levels and ER stress molecules (Grp78 and phospho eIF2α‐2–2.5 fold) in cells treated with nelfinavir (10 μM) but not with atazanavir. Nelfinavir (10 μM) suppressed (40%) superoxide dismutase (Cu/Zn SOD) and glutathione levels. Simultaneous treatment with TQ (2.5 μM), an active ingredient of black seed oil, significantly inhibited ROS production and ER stress in cells exposed to nelfinavir and increased glucose mediated insulin secretion to normal levels. These results suggest a role of ROS and ER stress in nelfinavir‐induced pancreatic β‐cell dysfunction and demonstrate TQ as a potential therapeutic agent for ameliorating IRS in HAART treated patients. (Supported by NHLBI grant # 1R01 HL73691)