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Diabetes 52:918-925, 2003
© 2003 by the American Diabetes Association, Inc.
Mechanisms for the Deterioration in Glucose Tolerance Associated With HIV Protease Inhibitor Regimens
1 Department of Medicine, University of Rochester School of Medicine, Rochester, New York
2 Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, New York
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, ß-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 ß-cell function. We evaluated ß-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. ß-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 
50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). ß-Cell function decreased by 50% (P = 0.002), as assessed by HOMA, and first-phase insulin release decreased by 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 ß-cell to compensate.
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