The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy

Abstract

Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes. The etiology of this characteristic clinical syndrome remains unknown. We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner (63% inhibition observed with 100 M indinavir). Indinavir treatment did not affect early insulin signaling events or the translocation of intracellular Glut1 or Glut4 glucose transporters to the cell surface. To determine whether indinavir may be directly affecting the intrinsic transport activity of glucose transporters, the Glut1 and Glut4 isoforms were heterologously expressed and analyzed in Xenopus laevis oocytes. Indinavir at 100 M had no effect on Glut1 transport activity in Xenopus oocytes, whereas Glut4 activity was significantly inhibited (45% inhibition). Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients.

The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

“…In the ritonavir-treated group, a decreased tyrosine phosphorylation ratio of IRS-1 Ϯ insulin was observed at both 1.0 M and 10.0 M ritonavir (Ϯinsulin treatment groups, 1.5 and 1.53, respectively). Others (9,19,20) have reported that no early signal changes could be observed with the use of PI, while decreased PKB phosphorylation has been shown to occur with the use of Nelfinavir (20). The differences seen could relate to the protocols employed in our study when compared with others that were quite different.…”

“…There has been much controversy concerning the effects or lack thereof of PI on insulin signaling (9,19,20). Thus, we decided to investigate insulin effects on IRS-1 in 3T3 L1 adipocytes 11 days postinduction of differentiation.…”

“…The degree of lipodystrophy in patients varies but has been reported to be greater than 80% in one study (5). The cause of these HAART associated perturbations is unknown and has been suggested to involve multiple sites (7)(8)(9)(10). Unlike the reverse transcriptase inhibitors that suppress replication of the viral genome, the protease inhibitors inhibit virus maturation, limiting the infectivity of the virus particles (11).…”

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

“…The first proposed mechanism to explain HPI-induced insulin resistance was the acute inhibition of glucose transport through GLUT4 [13]. Additional mechanisms have since been proposed, suggesting that "multiple hits" may affect the normal function of various cell types exposed to these agents.…”

“…These include induction of adipocyte apoptosis [9], interference with terminal adipocyte differentiation [9,10,11], direct inhibition of the insulin-responsive glucose transporter GLUT4 [12,13,14] and interference with intracellular insulin signals leading to the deregulation of glucose and lipid metabolism [15]. None of these cellular mechanisms is necessarily mutually exclusive of the others [16,17].…”