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3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV23-26 October 2001, Athens, Greece |
L6 MYOTUBES: THE EFFECTS OF ANTIRETROVIRAL PROTEASE INHIBITORS ON SUGAR TRANSPORT AND CELLULAR GLUCOSE TRANSPORTERS
Antiviral Therapy 2001; 6(Suppl. 4):35 (abstract no. 48)
SP Colby-Germinario1, C Cammalleri1, 2 and RJ Germinario1, 2, 3, 4
1 Lady Davis Institute SMBD-Jewish General Hospital, Montreal, QC, Canada; 2 McGill University, Montreal, QC, Canada; 3 Concordia University, Montreal, QC, Canada; and 4 Department of Biology, McGill AIDS Centre, Montreal, QC, Canada
BACKGROUND: The knowledge that muscle is a major site of insulin action and that insulin resistance is a prominent component of the lipodystrophy syndrome has lead us to investigate the effects of protease inhibitors (PI) on L6 myotubes in vitro.
OBJECTIVES: Our goals were to determine the effects of several PI on basal and insulin-stimulated sugar transport in L6 myotubes and to investigate PI effects on the translocation of GLUTS 1, 3 and 4.
DESIGN: Sugar transport was monitored by the uptake of 3H 2-deoxy D-glucose (2-DG). Additionally, the effects of the PI on cellular glucose transporter content and translocation were determined using subcellular fractionation and Western analysis. The PI studied included ritonavir, saquinavir and indinavir.
RESULTS: Little toxicity (<15%) was observed at concentrations of 10 μM with the three PI evaluated. Basal 2-DG transport was significantly increased at all concentrations of saquinavir tested (1, 10 and 50 μM; P<0.05, one-way ANOVA, n=3). Similarly, indinavir and ritonavir exposure resulted in increased basal 2- DG transport at 10 and 50 μM concentrations (P<0.05, one-way ANOVA, n=3). The basal 2-DG transport increases seen with indinavir and ritonavir were 160 and 200% as compared to the 160% increase seen in the insulin-treated (67 nM) group. While insulin increased GLUT1, GLUT3 and GLUT4 transporter translocation to the plasma membrane fraction, no increased GLUT transporter (ie, 1, 3 or 4) content was observed in the plasma membrane of ritonavir-treated L6 myotubes. Further, total cell transporter content for all three transporters was similar to or higher than seen in ritonavir-treated versus control cells.
CONCLUSIONS: Our data suggest that translocation of GLUT transporters may not be the mechanism involved in PI-induced increased 2-DG transport. Regarding the insulin resistance seen in highly active antiretroviral therapy-treated AIDS patients, our results provide clues to uncovering key factors involved.
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