ObjectiveTo determine whether initiation of antiretroviral therapy that includes the protease inhibitor indinavir causes insulin resistance or abnormal B-cell function in study subjects with HIV infection.MethodsNonwasted, HIV-infected study subjects who did not have concurrent diabetes were prospectively evaluated by oral and intravenous glucose tolerance testing at baseline, at 2 weeks after starting indinavir monotherapy, and at another 6 weeks after initiating indinavir-based triple-therapy.ResultsMean CD4 count at entry was 282 cells/&mgr;l and median HIV RNA was 33,000 copies/ml; all experienced a virologic response. Fasting glucose increased from 83.2 ± 3.7 mg/dl at baseline to 86.8 ± 3.2 at week 2 and 91.7 ± 3.5 at week 8 (p= .003). Insulin sensitivity by minimal model analysis decreased by 30.5% over 8 weeks, from 3.83 ± 0.63 min−1per &mgr;U/ml × 10−4to 3.09 ± 0.53 at week 2 and 2.66 ± 0.35 at week 8 (p= .01). Insulin secretion by the acute insulin response to intravenous glucose did not change (baseline 822 ± 283 &mgr;U/ml × min, week 8 880 ± 289;p= 0.4), and the insulin response to oral glucose (30 minute insulin:glucose ratio) fell from 1.69 ± 0.54 &mgr;U/ml per mg/dl at baseline to 1.18 ± 0.34 at week 8 (p= .05).ConclusionDuring 8 weeks of indinavir-based therapy, fasting glucose increased and insulin sensitivity decreased, without a compensatory increase in insulin release. This combination of insulin resistance without augmented B-cell response may explain the hyperglycemia and other metabolic abnormalities seen in some protease inhibitor–treated patients.