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

INDINAVIR INDUCES ACUTE AND REVERSIBLE INSULIN RESISTANCE IN RATS

Antiviral Therapy 2001; 6(Suppl. 4): 3 (abstract no. 2)

PW Hruz, H Murata, H Qiu and M Mueckler
Washington University,St Louis,Mo.,USA

BACKGROUND: HIV protease inhibitors (PIs) have recently been found to cause acute and reversible inhibition of GLUT4 activity in vitro. The contribution of in vivo GLUT4 inhibition to the insulin resistance associated with PI therapy remains unknown.

OBJECTIVE: To determine whether whole body glucose homeostasis and peripheral insulin sensitivity are acutely and reversibly affected by administration of indinavir to rats.

METHODS: Fasted PI-naïve male Wistar rats were given a single 15 mg/kg intravenous dose of indinavir immediately prior to perfor.ming intraperitoneal glucose tolerance tests. Peripheral insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique in rats acutely exposed to constant levels of indinavir by continuous intravenous infusion.

RESULTS: Acute indinavir treatment resulted in a significant elevation of both glucose and insulin levels compared with controls (P<0.05)during the initial 30 min of the glucose tolerance test. Under euglycemic hyperinsulinemic clamp conditions, indinavir treatment was associated with a rapid and reversible decrease in insulin sensitivity. The glucose infusion rate (GIR) required to maintain euglycemia was reduced by 16 and 4S% at indinavir concentrations of 14 and 27 μM, respectively. Restoration of insulin sensitivity was observed within 4 h after stopping the indinavir infusion. Indinavir did not alter the suppression of hepatic glucose output under hyperinsulinemic conditions.

CONCLUSIONS: These data demonstrate that indinavir causes acute and reversible changes in whole body glucose homeostasis in rats and support the contribution of GLUT4 inhibition to the development of insulin resistance in patients treated with PIs.

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