title: Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study.
abstract: 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 microM and the 2-h area under the curve was 13.5 +/- 3.1 microM.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 microUI/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.
authors.affiliation: Department of Medicine, University of California, Berkeley, California, USA.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Noor
authors.forename: Tara
authors.initials: T
authors.lastname: Seneviratne
authors.forename: Francesca T
authors.initials: FT
authors.lastname: Aweeka
authors.forename: Joan C
authors.initials: JC
authors.lastname: Lo
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Schwarz
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mulligan
authors.forename: Morris
authors.initials: M
authors.lastname: Schambelan
authors.forename: Carl
authors.initials: C
authors.lastname: Grunfeld
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005947:Glucose / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged
chemical_list: D017320:HIV Protease Inhibitors; D007328:Insulin; D019469:Indinavir; D005947:Glucose