10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

PROLONGED EXPOSURE TO HIV PROTEASE INHIBITORS (PIS) INDUCES PANCREATIC ISLET BETA-CELL DEATH AND DYSFUNCTION

Antiviral Therapy 2008; 13(Suppl. 4):A10 (abstract no. O-12)

M Carper, S Zhang, WT Cade, K Yarasheski and S Ramanadham
Washington University School of Medicine, St Louis, MO, USA

OBJECTIVES: We previously reported that prolonged exposure (7 weeks) to indinavir accelerated the diabetic state, exacerbated hyperglycaemia and oral glucose intolerance in Zucker diabetic/fatty (ZDF) and wild-type rats (ZWT). Indinavir and lopinavir/ritonavir were associated with increased tumour necrosis factor-α, suppressor of cytokine signalling-1 (SOCS-1), SREBP-1 protein levels and reduced IRS-2 protein levels in ZDF and ZWT adipose, skeletal muscle and liver tissues. Activation of the SOCS-1 signalling cascade is a recognized contributor to the development of insulin resistance and diabetes. Prolonged protease inhibitor (PI) exposure also promoted significant insulinopaenia in these ZDF rats, raising the possibility that prolonged exposure to current PIs impair beta-cell function and viability. This was examined in the present study.

METHODS: Insulin secretion in response to glucose (0–20 mM) plus forskolin (2.5 µM) and cell viability by TUNEL analyses were examined in 832/13 insulinoma (INS-1) cells and human pancreatic islet cells following 48 or 96 h exposures, respectively, to 20 µM indinavir, ritonavir, lopinavir, atazanavir or tripanavir, and in pancreatic islets isolated from ZWT rats exposed to indinavir (170 mg/kg orally twice a day) or vehicle for 3 weeks. Immunoblotting analyses were used to examine induction of markers of ER stress (phospho-pancreatic ER kinase [PERK]) and of apoptosis (polyADP-ribose polymerase [PARP], caspases 3 and ER factor C/EBP homologous protein [CHOP]). Mitochondrial membrane potential (Δψ) was monitored by flow cytometry.

RESULTS: We found increased apoptosis and reduced insulin secretory capacity in INS-1 and human pancreatic islet cells after exposure to these PIs. Administration of indinavir to ZWT rats resulted in dramatically lower islet yields and induction of greater islet cell death in comparison with vehicle-administered rats. The higher incidence of HIV PI-induced cell death was associated with activation of caspase 3 and cleavage of PARP, but not with activation of PERK or induction of CHOP. Exposure to the HIV PIs, however, caused a loss in Δ (and cytochrome c release from the mitochondria, suggesting that the HIV PIs currently in clinical use can induce beta-cell apoptosis by activating the mitochondrial apoptotic pathway.

CONCLUSIONS: Taken together, these findings reveal for the first time that prolonged in vivo or in vitro exposure to some newer HIV PIs, despite promoting better serum lipid profiles, can cause beta-cell secretory dysfunction and beta-cell death by activating the mitochondrial, but not the ER stress, apoptotic pathway. In summary, our studies identify novel affects of HIV PI on pancreatic islet beta-cells and highlight the importance of considering beta-cell viability and function when assessing glycaemic control and diabetes in HIV-positive patients receiving PIs.

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2008-11-06
O-12

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