Abstract

Retroviral protease inhibitors used as therapy for HIV-infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, central adiposity, hyperlipidaemia, insulin resistance, and in some cases, type 2 diabetes. The etiology of this characteristic clinical syndrome remains unknown. We demonstrate that the HIV protease inhibitors (PIs), saquinavir, indinavir, and ritonavir inhibit adipocyte differentiation of 3T3-L1 preadipocytes. Furthermore, they exert a dose-dependent increase in basal triacylglycerol synthesis followed by a concomitant decrease in insulin-stimulated triacylglycerol synthesis. However, PIs did not stimulate lipolysis under basal or norepinephrine-stimulated conditions in mature 3T3-L1 adipocytes. Also, this study reports an inhibition of specific 125 I-Insulin binding to insulin receptors in the presence of PIs throughout distinct stages of 3T3-L1 adipocyte differentiation. Additionally, this inhibition was found to be reversable upon removal of the PIs during the binding process. However, insulin binding affinities and processing were not affected by PIs. To continue, we investigated whether the HIV protease inhibitor ritonavir altered insulin signaling. In cells not exposed to ritonavir, insulin led to a rapid increase of insulin-receptor substrate-1-phosphorylation. In ritonavir-treated cells, these insulin stimulated increases were reduced by approximately 50%. We conclude that HIV protease inhibitors are capable of selectively inhibiting the insulin response and contributing to the metabolic abnormalities seen in HIV-infected patients