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Exp Clin Endocrinol Diabetes 2003; 111(8): 491-498
DOI: 10.1055/s-2003-44709
Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Therapeutic Dose of HIV-1 Protease Inhibitor Saquinavir does not Permanently Influence Early Insulin Signaling

P. Algenstaedt 1 , S. Daneshi 1 , B. Schwarzloh 1 , N. Hennigs 1 , A. Hamann 4 , N. Hansen-Algenstaedt 3 , U. Beisiegel 2
  • 1Department of Internal Medicine I, University Hospital Eppendorf, Hamburg, Germany
  • 2Department of Cellular Biology, Institute for Medical Biochemistry und Molecular Biology, University Hospital Eppendorf, Hamburg, Germany
  • 3Department of Orthopedic Surgery, University Hospital Eppendorf, Hamburg, Germany
  • 4Department of Internal Medicine I, University of Heidelberg, Germany
Further Information

Publication History

Received: January 2, 2002 First decision: March 3, 2002

Accepted: April 22, 2003

Publication Date:
09 January 2004 (online)

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Abstract

The introduction of HIV-1 protease inhibitor therapy has significantly improved the expectancy and quality of life for HIV-infected patients. Recent reports have highlighted the development of metabolic complications in patients taking protease inhibitors, including abnormalities in glucose metabolism such as impaired glucose tolerance and type 2 diabetes. The mechanisms by which protease inhibitors induce these metabolic syndromes are not well understood. The aim of this study was to determine whether treatment with the HIV-1 protease inhibitor, saquinavir, influences the early insulin signaling cascade in insulin-sensitive cell lines.

Methods

Insulin-stimulated phosphorylation of insulin receptor (IR-β), insulin receptor substrates (IRS-1 and IRS-2), association of phosphatidylinositol 3-kinase (PI 3-kinase), Ser473-phosphorylation of Akt and Thr202/Tyr204-phosphorylated p44/42 MAP kinase in 3T3L1 adipocytes and FAO hepatoma cells incubated with increasing concentrations of saquinavir for 24, 36 hours, 2, 3 and 6 days were measured.

Results

Phosphorylation of IR-β, IRS-1 and IRS-2 was not permanently affected by incubation with therapeutic doses (2.5 µM) of saquinavir for 36 hours. After 24 hours we observed an increase of IR-β and IRS-1 phosphorylation. However, this initial stimulation of IR-β and IRS-1 phosphorylation was not permanent and did not result in an increased PI 3-kinase association. Phosphorylation of IRS-2 and MAP kinase as well as glucose transport activity was not altered by therapeutic doses. Doses of 10, 25 and 50 µM of saquinavir altered the early insulin signaling events in a dose-dependent manner. However, this effect was primarily due to the cytotoxic effect of higher saquinavir doses. Glucose transport activity was not significantly reduced in 3T3L1 cells treated with 2.5 µM saquinavir in comparison to the control cells stimulated with insulin.

Conclusion

Early insulin signaling cascade, essential for normal glucose metabolism, is not affected by therapeutic doses of saquinavir. The reduction of insulin-induced phosphorylation in higher concentrations is primarily related to cytotoxic effects. Other mechanisms than early insulin signaling must be primarily responsible for the metabolic alterations during saquinavir therapy.

Key words

HIV-1 protease inhibitors - saquinavir - insulin signaling - diabetes type 2

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Dr. Petra Algenstaedt

Medizinische Klinik I
Zentrum für Innere Medizin
Universitätsklinikum Hamburg-Eppendorf

Martinistraße 52

20246 Hamburg

Phone: + 4940428033960, -4755

Fax: + 49 4 04 28 03 68 20

Email: algenstaedt@uke.uni-hamburg.de