The effect of HIV protease inhibitors on insulin binding, triglyceride synthesis, lipolysis, and insulin signaling in 3T3-L1 adipocytes (Immune deficiency)

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 125I-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.