Protease inhibitors are a crucial component of highly active antiretroviral therapy for HIV infection. However, the use of these drugs is associated with hyperglycemia, hyperlipidemia, and lipodystrophy [1-3]. The underlying mechanisms leading to these metabolic alterations are unknown. We evaluated peripheral insulin sensitivity in 24 HIV-positive patients treated with protease inhibitors, 8 therapy-naive HIV-positive patients, and 18 HIV-negative controls (Figure 1) using an intravenous insulin tolerance test [4].

View larger version (6K): [in this window] [in a new window]   Figure 1. Insulin sensitivity of 18 HIV-negative controls (squares), 8 HIV-positive therapy-naive patients (diamonds), and 24 HIV-positive patients treated with protease inhibitors (11 with normal glucose tolerance [black triangles] and 13 with abnormal tolerance [white triangles]). Solid lines represent medians, and the dotted line indicates the cutoff between normal and abnormal insulin sensitivity (92 µmol/L per minute).

Patients treated with protease inhibitors had a significantly lower median insulin sensitivity (67 µmol/L per minute) than did untreated patients (156 µmol/L per minute; P < 0.001) and controls (177 µmol/L per minute; P < 0.001). Untreated patients did not differ significantly from controls (P > 0.2). With stratification according to oral glucose tolerance, insulin sensitivity was significantly higher in the treated patients with normal glucose tolerance (121 µmol/L per minute; n = 11) than in those with impaired or diabetic glucose tolerance (55 µmol/L per minute; n = 13). We used the mean insulin sensitivity of the HIV-negative controls – 2 SDs (92 µmol/L per minute) to distinguish between normal and abnormal insulin sensitivity. All controls and untreated patients had normal insulin sensitivity. All treated patients with impaired (n = 4) or diabetic (n = 9) oral glucose tolerance had abnormal insulin sensitivity. Of note, in the treated patients with normal oral glucose tolerance, both normal (n = 5) and abnormal (n = 6) insulin sensitivity was seen.

These data suggest that treatment with protease inhibitors can lead to abnormal insulin sensitivity. In some patients, this can result in impaired or even diabetic oral glucose tolerance. A possible explanations for the reported peripheral insulin resistance is interference with insulin receptors or glucose transporters. Other factors, such as perturbance of insulin secretion or alterations of anti-insulinergic factors, may also be involved. Abnormal insulin sensitivity was seen in patients treated with all currently available protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir).