RESUMO
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.
Assuntos
Apoptose/efeitos dos fármacos , Soropositividade para HIV/tratamento farmacológico , HIV-1/imunologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Mitocôndrias/efeitos dos fármacos , Inibidores de Proteases/efeitos adversos , Animais , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Soropositividade para HIV/metabolismo , Soropositividade para HIV/patologia , Humanos , Secreção de Insulina , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/virologia , Masculino , Camundongos , Mitocôndrias/fisiologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Ratos , Ratos Zucker , Transdução de Sinais/efeitos dos fármacosRESUMO
We examined the effects of liquid carbohydrate (CHO) supplementation on markers of anabolism following high-intensity resistance exercise. Nine resistance-trained men consumed either CHO or placebo (PLC) 10 minutes before and immediately following 2 resistance exercise sessions. Cortisol (CORT), insulin (INS), ammonia (AMM), and glucose (GLU) were measured before, immediately after, and 1.5 and 4 hours after exercise. Urinary nitrogen (NH(+3)) was measured 24 hours before and after exercise. There was a significant difference in INS levels immediately after exercise and 1.5 hours after exercise. No significant differences were observed for CORT, AMM, GLU, or NH(+3)between treatments. Significant within-group differences were found for the PLC group: CORT before compared with immediately after exercise; INS before compared with immediately after exercise and before compared with 1.5 hours after exercise; and AMM before compared with immediately after exercise and before compared with 1.5 hours after exercise. Significant within-group differences were found for the CHO group: CORT immediately after compared with 1.5 hours after exercise and immediately after compared with 4 hours after exercise; INS before compared with 1.5 hours after exercise; and AMM before compared with immediately after exercise. Liquid CHO ingestion leads to a more favorable anabolic environment immediately following a resistance exercise bout; however, our indirect measures of protein degradation were not altered by CHO ingestion.