HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: Protection with thymoquinone

Surabhi Chandra, Debasis Mondal, Krishna C. Agrawal

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The highly active anti-retroviral therapy (HAART) regimen has considerably reduced the mortality rate in HIV-1 positive patients. However, long-term exposure to HAART is associated with a metabolic syndrome manifesting cardiovascular dysfunction, lipodystrophy, and insulin resistance syndrome (IRS). The inclusion of HIV-1 protease inhibitors (PIs) in HAART has been linked to the induction of IRS. Although several molecular mechanisms of PI-induced effects on insulin action have been postulated, the deleterious effects of PIs on insulin production by pancreatic β-cells have not been fully investigated and therapeutic strategies to ameliorate insulin dysregulation at this level have not been targeted. The present study showed that exposure to several different PIs, nelfinavir (5-10 μM), saquinavir (5-10 μM) and atazanavir (8-20 μM), decreases glucose stimulated insulin secretion from rat pancreatic β-cells (INS-1). Nelfinavir significantly increased reactive oxygen species (ROS) generation and suppressed cytosolic, but not mitochondrial superoxide dismutase (SOD) levels. Nelfinvair also decreased both glutathione and ATP and increased UCP2 levels in these cells. Simultaneous treatment with thymoquinone (TQ) (2.5 μM), an active ingredient of black seed oil, significantly inhibited the effect of nelfinavir on augmented ROS production and suppressed SOD levels. Both TQ and black seed oil exposure increased glucose stimulated insulin secretion and ameliorated the suppressive effect of nelfinavir. The present findings imply a direct role of ROS in PI induced deleterious effects on pancreatic β-cells. Our findings also suggest that TQ may be used as a potential therapeutic agent to normalize the dysregulated insulin production observed in HAART treated patients.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalExperimental Biology and Medicine
Volume234
Issue number4
DOIs
StatePublished - Apr 1 2009

Fingerprint

HIV Protease Inhibitors
Oxidative stress
Protease Inhibitors
Nelfinavir
Oxidative Stress
Insulin
Glucose
Reactive Oxygen Species
Oilseeds
Therapeutics
Superoxide Dismutase
Insulin Resistance
Seeds
Oils
Metabolic Syndrome X
Saquinavir
Lipodystrophy
Human immunodeficiency virus 1 p16 protease
thymoquinone
Glutathione

Keywords

  • HIV-1 protease inhibitors
  • Insulin secretion
  • Oxidative stress
  • Rat insulinoma cells (INS-1)
  • Thymoquinone

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release : Protection with thymoquinone. / Chandra, Surabhi; Mondal, Debasis; Agrawal, Krishna C.

In: Experimental Biology and Medicine, Vol. 234, No. 4, 01.04.2009, p. 442-452.

Research output: Contribution to journalArticle

@article{e3c9c428d59140489e39651146fbfd7b,
title = "HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: Protection with thymoquinone",
abstract = "The highly active anti-retroviral therapy (HAART) regimen has considerably reduced the mortality rate in HIV-1 positive patients. However, long-term exposure to HAART is associated with a metabolic syndrome manifesting cardiovascular dysfunction, lipodystrophy, and insulin resistance syndrome (IRS). The inclusion of HIV-1 protease inhibitors (PIs) in HAART has been linked to the induction of IRS. Although several molecular mechanisms of PI-induced effects on insulin action have been postulated, the deleterious effects of PIs on insulin production by pancreatic β-cells have not been fully investigated and therapeutic strategies to ameliorate insulin dysregulation at this level have not been targeted. The present study showed that exposure to several different PIs, nelfinavir (5-10 μM), saquinavir (5-10 μM) and atazanavir (8-20 μM), decreases glucose stimulated insulin secretion from rat pancreatic β-cells (INS-1). Nelfinavir significantly increased reactive oxygen species (ROS) generation and suppressed cytosolic, but not mitochondrial superoxide dismutase (SOD) levels. Nelfinvair also decreased both glutathione and ATP and increased UCP2 levels in these cells. Simultaneous treatment with thymoquinone (TQ) (2.5 μM), an active ingredient of black seed oil, significantly inhibited the effect of nelfinavir on augmented ROS production and suppressed SOD levels. Both TQ and black seed oil exposure increased glucose stimulated insulin secretion and ameliorated the suppressive effect of nelfinavir. The present findings imply a direct role of ROS in PI induced deleterious effects on pancreatic β-cells. Our findings also suggest that TQ may be used as a potential therapeutic agent to normalize the dysregulated insulin production observed in HAART treated patients.",
keywords = "HIV-1 protease inhibitors, Insulin secretion, Oxidative stress, Rat insulinoma cells (INS-1), Thymoquinone",
author = "Surabhi Chandra and Debasis Mondal and Agrawal, {Krishna C.}",
year = "2009",
month = "4",
day = "1",
doi = "10.3181/0811-RM-317",
language = "English (US)",
volume = "234",
pages = "442--452",
journal = "Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)",
issn = "1535-3702",
publisher = "Society for Experimental Biology and Medicine",
number = "4",

}

TY - JOUR

T1 - HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release

T2 - Protection with thymoquinone

AU - Chandra, Surabhi

AU - Mondal, Debasis

AU - Agrawal, Krishna C.

PY - 2009/4/1

Y1 - 2009/4/1

N2 - The highly active anti-retroviral therapy (HAART) regimen has considerably reduced the mortality rate in HIV-1 positive patients. However, long-term exposure to HAART is associated with a metabolic syndrome manifesting cardiovascular dysfunction, lipodystrophy, and insulin resistance syndrome (IRS). The inclusion of HIV-1 protease inhibitors (PIs) in HAART has been linked to the induction of IRS. Although several molecular mechanisms of PI-induced effects on insulin action have been postulated, the deleterious effects of PIs on insulin production by pancreatic β-cells have not been fully investigated and therapeutic strategies to ameliorate insulin dysregulation at this level have not been targeted. The present study showed that exposure to several different PIs, nelfinavir (5-10 μM), saquinavir (5-10 μM) and atazanavir (8-20 μM), decreases glucose stimulated insulin secretion from rat pancreatic β-cells (INS-1). Nelfinavir significantly increased reactive oxygen species (ROS) generation and suppressed cytosolic, but not mitochondrial superoxide dismutase (SOD) levels. Nelfinvair also decreased both glutathione and ATP and increased UCP2 levels in these cells. Simultaneous treatment with thymoquinone (TQ) (2.5 μM), an active ingredient of black seed oil, significantly inhibited the effect of nelfinavir on augmented ROS production and suppressed SOD levels. Both TQ and black seed oil exposure increased glucose stimulated insulin secretion and ameliorated the suppressive effect of nelfinavir. The present findings imply a direct role of ROS in PI induced deleterious effects on pancreatic β-cells. Our findings also suggest that TQ may be used as a potential therapeutic agent to normalize the dysregulated insulin production observed in HAART treated patients.

AB - The highly active anti-retroviral therapy (HAART) regimen has considerably reduced the mortality rate in HIV-1 positive patients. However, long-term exposure to HAART is associated with a metabolic syndrome manifesting cardiovascular dysfunction, lipodystrophy, and insulin resistance syndrome (IRS). The inclusion of HIV-1 protease inhibitors (PIs) in HAART has been linked to the induction of IRS. Although several molecular mechanisms of PI-induced effects on insulin action have been postulated, the deleterious effects of PIs on insulin production by pancreatic β-cells have not been fully investigated and therapeutic strategies to ameliorate insulin dysregulation at this level have not been targeted. The present study showed that exposure to several different PIs, nelfinavir (5-10 μM), saquinavir (5-10 μM) and atazanavir (8-20 μM), decreases glucose stimulated insulin secretion from rat pancreatic β-cells (INS-1). Nelfinavir significantly increased reactive oxygen species (ROS) generation and suppressed cytosolic, but not mitochondrial superoxide dismutase (SOD) levels. Nelfinvair also decreased both glutathione and ATP and increased UCP2 levels in these cells. Simultaneous treatment with thymoquinone (TQ) (2.5 μM), an active ingredient of black seed oil, significantly inhibited the effect of nelfinavir on augmented ROS production and suppressed SOD levels. Both TQ and black seed oil exposure increased glucose stimulated insulin secretion and ameliorated the suppressive effect of nelfinavir. The present findings imply a direct role of ROS in PI induced deleterious effects on pancreatic β-cells. Our findings also suggest that TQ may be used as a potential therapeutic agent to normalize the dysregulated insulin production observed in HAART treated patients.

KW - HIV-1 protease inhibitors

KW - Insulin secretion

KW - Oxidative stress

KW - Rat insulinoma cells (INS-1)

KW - Thymoquinone

UR - http://www.scopus.com/inward/record.url?scp=66449135129&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66449135129&partnerID=8YFLogxK

U2 - 10.3181/0811-RM-317

DO - 10.3181/0811-RM-317

M3 - Article

C2 - 19234050

AN - SCOPUS:66449135129

VL - 234

SP - 442

EP - 452

JO - Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)

JF - Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)

SN - 1535-3702

IS - 4

ER -