Chronic Binge Alcohol and Antiretroviral Therapy Administration Differentially Contribute to Metabolic Dysregulation in SIV-Infected Male Rhesus Macaques

摘要

Prevalence of alcohol use disorders (AUD) are higher among people living with HIV (PLWH). The advent and continued development of antiretroviral therapies (ART) has significantly reduced mortality due to HIV, shifting the course of infection to more of a chronic illness. Prolonged ART regimens and lifestyle choices such as alcohol consumption exacerbate comorbidities including metabolic syndrome and Type 2 diabetes in PLWH. Using a non-human primate model of non-ART treated young male rhesus macaques infected with Simian Immunodeficiency Virus (SIV), previous studies have demonstrated that chronic binge alcohol (CBA) administration causes adverse metabolic effects at end-stage disease. The studies in this dissertation were aimed to determine the effects of CBA and ART on metabolic parameters during the asymptomatic phase of SIV disease in male macaques. The results showed that CBA reduced acute insulin response to glucose (AIRg) and disposition index (DI), insulin secretion during the first 20 minutes of frequently sampled glucose tolerance tests (FSIVGTTs), and C-peptide values. CBA also reduced glucose effectiveness (SG), defined as the glucose-stimulated suppression of further glucose output, and reduced plasma adipokines, adiponectin and resistin. These findings suggest CBA-mediated reductions in whole-body glucose insulin dynamics. The insulin responsiveness of peripheral tissues, including the liver and skeletal muscle was also determined. At study endpoint, there were no CBA-mediated effects altering skeletal muscle insulin signaling. However, ART produced differential effects on skeletal muscle protein expression, reducing phosphatase and tensin homolog (PTEN), a phosphatase that attenuates insulin signaling, and also reducing total mammalian Target of Rapamycin (mTOR) and ribosomal protein S6 (rpS6) protein expression. In addition, in the liver, ART increased phosphorylation of AMP-activated protein kinase alpha (AMPKalpha). ART also increased gene expression of key metabolic enzymes required for gluconeogenesis and fatty acid synthesis and hepatic tumor necrosis factor alpha (TNFalpha) gene expression. CBA-mediated reduced insulin secretion, plasma adiponectin, and glucose effectiveness, when paired with the ART-mediated upregulation of hepatic genes to increase glucose output and inflammation, suggests that CBA and ART differentially promote adverse metabolic effects in an organ-specific manner that potentially alters glucose homeostasis.