Background: Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.
Methods: Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.
Results: There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60−−180 min) insulin reached comparable levels (394 ± 13 versus 390 ± 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 ± 2.2 μM and the 2-h area under the curve was 13.5 ± 3.1 μM⋅h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg⋅min per μ UI/ml (95% confidence interval for change, 3.7–6.1;P < 0.001) on indinavir (average decrease, 34.1 ± 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg⋅min (P < 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.
Conclusions: A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.
From the From the Department of aMedicine, University of California, the bMetabolism and Endocrine Sections, San Francisco Department of Veterans Affairs Medical Center, the Department of cPharmacology University of California, the dDivision of Endocrinology, San Francisco General Hospital, San Francisco and the eDepartment of Nutritional Sciences, University of California, Berkeley, Berkeley, California, USA.
Requests for reprints to: C. Grunfeld, Department of Veterans Affairs Medical Center, Metabolism Section (111F), 4150 Clement Street, San Francisco, CA 94121, USA.
Note: Presented in part at the Third International Workshop on Lipodystrophy and Adverse Drug Reactions in HIV. Athens, October 2001.
Received: 26 November 2001;
revised: 17 December 2001; accepted: 19 December 2001.
Sponsorship: Supported by a Pilot Study grant from the Center for AIDS Clinical Research at UCSF (CARC- 2000 to C.G.) and by grants from the Universitywide AIDS Research Program (ID01-SF-14 to C.G. and 99-SF-44 to M.N.) and the National Institutes of Health (NIH) DK52615 to K.M and DK45833 to M.S. The studies were conducted in the General Clinical Research Center at San Francisco General Hospital supported by a grant (RR-00083) from the National Center for Research Resources (NCRR), NIH. J.L. is a Clinical Associate Physician supported by the NCRR. C.G. is supported by the University of California AIDS Clinical Research Center and the Research Service of the Department of Veterans Affairs.