HIV protease inhibitors and insulin resistance: lessons from in-vitro, rodent and healthy human volunteer models

PURPOSE OF REVIEW: Although the use of HIV protease inhibitors is linked to the development of insulin resistance and other metabolic changes that greatly increase the risk for cardiovascular disease, the molecular mechanisms responsible remain incompletely understood. This review summarizes recent advances that have been made in understanding the relative contributions of individual protease inhibitors to both acute and chronic insulin resistance together with newly identified cellular mediators. RECENT FINDINGS: Individual protease inhibitors, alone and in combination, have differing propensities to induce insulin resistance, reflecting relative differences in both affinities for identified molecular targets and pharmacokinetic profiles. Several of the most recent protease inhibitors approved for clinical use or in development appear to be less likely to induce insulin resistance. In addition to direct effects on glucose transporter-4 activity, induction of oxidative stress, proteosome inhibition, alteration of adipokine levels, and changes in suppressors of cytokine signaling-1 have been implicated. SUMMARY: A better understanding of the propensity of individual HIV protease inhibitors to produce insulin resistance will allow the tailoring of individual treatment plans based upon overall risk for diabetes. The elucidation of the molecular mechanisms for alterations in glucose homeostasis will facilitate the development of newer generations of HIV protease inhibitors that maintain their clinical efficacy without contributing to the development of diabetes mellitus and other proatherogenic effects.