Protease inhibitors used in the treatment of HIV+ induce beta-cell apoptosis via the mitochondrial pathway and compromise insulin secretion

Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E925-35. doi: 10.1152/ajpendo.90445.2008. Epub 2009 Feb 10.


Inclusion of HIV protease inhibitors (PIs) in the treatment of people living with HIV+ has markedly decreased mortality but also increased the incidence of metabolic abnormalities, causes of which are not well understood. Here, we report that insulinopenia is exacerbated when Zucker fa/fa rats are exposed to a PI for 7 wk, suggesting that chronic PI exposure adversely affects pancreatic islet beta-cell function. In support of this possibility, we find increased apoptosis, as reflected by TUNEL fluorescence analyses, and reduced insulin-secretory capacity in insulinoma cells and human pancreatic islet cells after in vitro exposures (48-96 h) to clinically relevant PIs (ritonavir, lopinavir, atazanavir, or tipranavir). Furthermore, pancreatic islets isolated from rats administered an HIV-PI for 3 wk exhibit greater cell death than islets isolated from vehicle-administered rats. The higher incidence of HIV-PI-induced cell death was associated with cleavage and, hence, activation of caspase-3 and poly(ADP)-ribose polymerase but not with activation of phospho-pancreatic endoplasmic reticulum (ER) kinase or induction of ER stress apoptotic factor C/EBP homologous protein. Exposure to the HIV-PIs, however, led to activation of mitochondria-associated caspase-9, caused a loss in mitochondrial membrane potential, and promoted the release of cytochrome c, suggesting that HIV-PIs currently in clinically use can induce beta-cell apoptosis by activating the mitochondrial apoptotic pathway. These findings therefore highlight the importance of considering beta-cell viability and function when assessing loss of glycemic control and the course of development of diabetes in HIV+ subjects receiving a protease inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use
  • Apoptosis / drug effects*
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical
  • HIV Seropositivity / drug therapy*
  • HIV Seropositivity / metabolism
  • HIV Seropositivity / pathology
  • HIV-1 / immunology*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / pathology
  • Insulin-Secreting Cells / virology
  • Male
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / physiology
  • Protease Inhibitors / adverse effects*
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Rats
  • Rats, Zucker
  • Signal Transduction / drug effects


  • Anti-HIV Agents
  • Insulin
  • Protease Inhibitors