Mechanisms for the Deterioration in Glucose Tolerance Associated With HIV Protease Inhibitor Regimens
The mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitorcontaining regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, ␤-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
... sensitivity as well as pancreatic ␤-cell function. We evaluated ␤-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. ␤-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 ϳ50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). ␤-Cell function decreased by ϳ50% (P ؍ 0.002), as assessed by HOMA, and firstphase insulin release decreased by ϳ25%, 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 ␤-cell to compensate. Diabetes 52: 918 -925, 2003 U se of protease inhibitors has remarkably improved long-term survival after HIV infection (1,2). However, up to 60% of HIV-infected patients treated with these agents develop either impaired glucose tolerance (IGT) or type 2 diabetes (3-6), and it now appears to be well established that regimens including protease inhibitors are associated with insulin resistance (2,5,7,8). Noor et al. (9,10) have shown that acute and 4-week protease inhibitor exposure of normal volunteers reduces glucose disposal during euglycemichyperinsulinemic clamp experiments. Moreover, in vitro studies have demonstrated that protease inhibitors reduce insulin-stimulated glucose uptake in adipocytes and skeletal muscle (11, 12) . Knowledge of the mechanisms responsible for deterioration in glucose tolerance during protease inhibitorcontaining regimens is still incomplete. It is unclear whether protease inhibitors adversely affect pancreatic ␤-cell function (4, 8) and what effect they have on glucose production and free fatty acid (FFA) turnover. Protease inhibitors are aspartate endopeptidase inhibitors (13-15). Because an aspartate endopeptidase is involved in converting proinsulin to insulin, the observation that plasma proinsulin levels are increased in protease inhibitortreated patients (5) suggests that these drugs may directly impair pancreatic ␤-cell function. Increased plasma FFA levels have been found in protease inhibitor-treated patients (16), and it is not known whether this is due to increased release or decreased utilization. This study was undertaken to prospectively assess the effect of protease inhibitor-based treatment regimens on pancreatic ␤-cell function and to determine the sites of insulin resistance. We studied 13 HIV-infected subjects with normal glucose tolerance before and after 12 weeks of protease inhibitor-based treatment and 14 healthy normal volunteers using hyperglycemic clamp experiments in combination with isotopic determination of glucose and FFA turnover. Eight of the patients had been on a chronic regimen containing nucleoside reverse transcriptase inhibitors (NRTIs) to which a protease inhibitor was added, and five patients were drug naïve and were started on a combination of an NRTI and a protease inhibitor.