title: Protease inhibitors used in the treatment of HIV+ induce beta-cell apoptosis via the mitochondrial pathway and compromise insulin secretion.
abstract: 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.
authors.affiliation: Washington University School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, 660 S. Euclid Ave., Box 8127, St. Louis, MO 63110, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Carper
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Lei
authors.forename: W Todd
authors.initials: WT
authors.lastname: Cade
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Yarasheski
authors.forename: Sasanka
authors.initials: S
authors.lastname: Ramanadham
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D011480:Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D007328:Insulin; D011480:Protease Inhibitors