10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

INHIBITION OF THE INSULIN RECEPTOR KINASE BY ANTIRETROVIRAL PROTEASE INHIBITORS

Antiviral Therapy 2008; 13(Suppl. 4):A29 (abstract no. P-08)

WIW Ismail and TS Pillay
Division of Chemical Pathology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, South Africa

BACKGROUND: HIV protease inhibitors (HPIs) are potent antiretroviral agents. Unfortunately, prolonged use of these drugs causes many complications among patients, including insulin resistance, lipodystrophy, hyperglycaemia and type 2 diabetes mellitus. The incidence of these complications is increasing as patients with HIV infection who are on treatment experience prolonged lifespans. The molecular basis for these drug-induced metabolic syndromes is still unknown and few studies have attempted to address this.

OBJECTIVES: In this study we have sought to elucidate how HPIs may affect the insulin signalling pathway in Chinese hamster ovary cells transfected with high levels of human insulin receptor and in differentiated 3T3-L1 murine adipocytes. We have also examined the effects of these drugs on lipoprotein lipase (LPL) in the adipocytes, as LPL levels have been found altered in patients treated with HPIs who later develop lipodystrophy.

METHODS: We investigated the effects of HPIs on cells treated with saquinavir and indinavir for 16 h and then stimulated with insulin. Insulin-stimulated tyrosine phosphorylation was analysed by immunoblotting with antiphosphotyrosine antibody.

RESULTS: We found that saquinavir (30–40 µM) displayed potent inhibition of the tyrosine phosphorylation of the insulin receptor ß-subunit and insulin receptor substrate proteins in both cell types. Indinavir (50 µM) had similar effects on insulin signalling, but with a different dose- response profile. Thus, both drugs displayed potency differences in their effects on insulin signalling, which may influence the propensity to cause the side effect of insulin resistance seen in patients. The inhibition of insulin signalling appears to be at a proximal level and involves a direct effect on the insulin receptor. We postulated that the inhibition of the insulin receptor kinase may occur because of changes in the level or activity of tyrosine phosphatases and suppressor of cytokine signaling 1 (SOCS-1). However, we found that protein tyrosine phosphatase-1B (PTP1B) and anti-SOCS-1 levels were not altered.

CONCLUSIONS: We conclude that the effects of HPIs to cause insulin resistance does not involve PTP1B or SOCS-1 protein, but may involve other regulatory proteins.

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2008-11-06
P-08

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