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Diabetes. 2003 Apr;52(4):918-25.

Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens.

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  • 1Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA.


The mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitor-containing regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, beta-cell function has not been evaluated in detail. The present study was therefore undertaken to assess the effects of protease inhibitor-containing regimens on hepatic, muscle, and adipose tissue insulin sensitivity as well as pancreatic beta-cell function. We evaluated beta-cell function in addition to glucose production, glucose disposal, and free fatty acid (FFA) turnover using the hyperglycemic clamp technique in combination with isotopic measurements in 13 HIV-infected patients before and after 12 weeks of treatment and in 14 normal healthy volunteers. beta-Cell function and insulin sensitivity were also assessed by homeostasis model assessment (HOMA). Treatment increased fasting plasma glucose concentrations in all subjects (P < 0.001). Insulin sensitivity as assessed by HOMA and clamp experiments decreased by approximately 50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). beta-Cell function decreased by approximately 50% (P = 0.002), as assessed by HOMA, and first-phase insulin release decreased by approximately 25%, as assessed by clamp data (P = 0.002). Plasma FFA turnover and clearance both increased significantly (P < 0.001). No differences at baseline or in responses after treatment were observed between drug naïve patients who were started on a nucleoside reverse transcriptase inhibitor (NRTI) plus a protease inhibitor and patients who had been on long-term NRTI treatment and had a protease inhibitor added. The present study indicates that protease inhibitor-containing regimens impair glucose tolerance in HIV-infected patients by two mechanisms: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue and 2) impairment of the ability of the beta-cell to compensate.

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