3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 23-26 October 2001, Athens, Greece

INHIBITION OF CELLULAR GLUCOSE UPTAKE BY INDINAVIR

Antiviral Therapy 2001; 6(Suppl. 4):3 (abstract no. 1)

H Murata, P Hruz and M Mueckler
Washington University School of Medicine, St Louis, Mo.,USA

BACKGROUND: We have recently shown that retroviral protease inhibitors used as therapy for HIV infection can inhibit the transport activity of the Glut4 glucose transporter isoform.

OBJECTIVES: To determine the relative sensitivities of Glut isoforms to inhibition by the protease inhibitor indinavir and to determine the kinetic mechanism of indinavir-mediated Glut4 inhibition.

METHODS: The rates of sugar uptake were measured in Xenopus laevis oocytes heterologously expressing mammalian Glut isoforms. Dixon plots were generated from measurements of 2-deoxyglucose uptake in insulin-stimulated primary rat adipocytes in the presence of 0-50 μM concentrations of indinavir.

RESULTS: Among the classical transporter isoforms, the sensitivity to inhibition by indinavir in decreasing order is: Glut4 >> Glut2 >> Glut3 >> Glutl. The fructose transport activity of GlutS and the 2-deoxyglucose transport activity of the recently identified GlutS appear to be insensitive to indinavir. 2-Deoxyglucose uptake measurements in insulin-stimulated primary rat adipocytes indicate a non-competitive mode of transport inhibition by indinavir with Ki estimated to be approximately 10 μM.

CONCLUSIONS: Indinavir appears to be a relatively selective inhibitor of the Glut4 isoform. As the concentration of indinavir required to significantly inhibit insulin-stimulated glucose uptake in rat adipocytes is well within the physiological range achieved in therapy (<10 μM), we propose that direct inhibition of Glut4 contributes to the insulin resistance observed in patients receiving this drug.

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