Background:  Lower levels of adiponectin, a hormone secreted by adipose tissue, have been associated with insulin resistance and increased visceral adipose tissue. Both HIV-induced lipoatrophy and lipohypertrophy are associated with lower adiponectin levels, but the cause is unknown. HIV protease inhibitors have been studied as a possible etiology of lower adiponectin levels. Protease inhibitors have different effects on insulin resistance; previously we demonstrated that indinavir induces insulin resistance whereas lopinavir/ritonavir has little effect on insulin sensitivity. Therefore we measured adipocytokine levels in HIV-negative men treated with either indinavir or lopinavir/ritonavir for 4 weeks.

Methods:  As previously reported, 10 HIV-negative men were treated with indinavir 800 mg 3 times daily or lopinavir 400 mg/ritonavir 100 mg twice daily. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and body composition were measured before and at the end of four weeks of treatment. Adiponectin and leptin levels were measured by radioimmunoassay (Linco Research, Inc., St. Charles, MO) in serum obtained after overnight fasting.

Results:  Serum adiponectin levels increased during therapy with indinavir (9.5±1.6 to 10.7±1.8 mg/mL; p = 0.009), which induced insulin resistance, and even more so with lopinavir/ritonavir (11.0±1.5 to 14.0±2.1 mg/mL; p = 0.005), which had little or no effect on insulin sensitivity. Leptin levels did not change. There was no correlation between changes in adiponectin levels and changes in body composition or induction of insulin resistance.

Conclusion:  The increased adiponectin levels induced by indinavir and lopinavir/ritonavir treatment can not directly explain the lower levels of adiponectin found in patients with HIV-associated lipohypertrophy and lipoatrophy, although many were on protease inhibitors. The increase in adiponectin in vivo contrasts with the decrease in adiponectin expression in 3T3 adipocytes acutely treated in vitro with indinavir, ritonavir, saquinavir, nelfinavir, zidovudine, or stavudine. Because adiponectin levels are increased by both indinavir, which induces insulin resistance, and by lopinavir/ritonavir, which has no effect on insulin sensitivity, these data argue against protease inhibitor induced insulin resistance as the cause of the increased adiponectin levels. The cause for increased adiponectin levels during protease inhibitor treatment remains to be elucidated.

Keywords: HIV Protease Inhibitors; adiponectin; lopinavir