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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/E925    most recent 90445.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, S. Articles by Ramanadham, S. Search for Related Content PubMed PubMed Citation Articles by Zhang, S. Articles by Ramanadham, S.

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

Department of Medicine, Mass Spectrometry Resource and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri

Submitted 16 May 2008 ; accepted in final form 3 February 2009

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 β-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 β-cell apoptosis by activating the mitochondrial apoptotic pathway. These findings therefore highlight the importance of considering β-cell viability and function when assessing loss of glycemic control and the course of development of diabetes in HIV⁺ subjects receiving a protease inhibitor.

human immunodeficiency virus; insulinoma cells; pancreatic islets; β-cell death; insulin secretion; cytochrome c