Chronic Binge Alcohol (CBA) Administration Increases Protein Tyrosine Phosphatase 1B (PTP1B) Protein Expression in Fed Simian Immunodeficiency Virus (SIV) Infected Rhesus Macaques

Chronic alcohol consumption, HIV infection, and anti‐retroviral therapy (ART) have independently been shown to impair whole body insulin responsiveness. Previous studies from our group have shown that skeletal muscle of CBA administered SIV‐infected (CBA/SIV) male rhesus macaques has upregulated ubiquitin‐proteasome pathway activity, enhanced pro‐inflammatory cytokine, and suppressed IGF‐I expression at end stage SIV infection. These findings suggest that CBA may impair insulin‐mediated anabolic responses at end‐stage disease. Whether systemic and skeletal muscle metabolic alterations are present at earlier time points of SIV infection or are affected by ART administration was not known. In this study, we tested the hypothesis that CBA decreases whole body insulin sensitivity and insulin signaling in the skeletal muscle during the asymptomatic stage of SIV infection in male rhesus macaques and proposed that this would be further aggravated by ART. CBA or sucrose (SUC) was administered intragastrically for 3 mos prior to inoculation with SIVmac251 and continued until necropsy. At 2.5 mos. post‐SIV infection, daily administration of ART (tenofovir and emtricitabine) was initiated in half of the SUC/SIV and CBA/SIV macaques. Frequently sampled intravenous glucose tolerance tests were performed to analyze glucose‐insulin dynamics, including acute insulin response to glucose (AIRg), disposition index (DI), and insulin sensitivity index, using a homeostatic model. One week prior to necropsy, a controlled feeding protocol was performed with infusion of a Carnation breakfast supplement (9.283 mL/kg/h) beginning 1.5 hours after CBA or SUC administration, continued for one hour, followed by a quadriceps femoris biopsy. One week after the feeding protocol, fasted‐state muscle biopsy was collected. At study endpoint (14 mo CBA, 11 mo SIV) CBA/SIV macaques had a significantly reduced (p<0.05) AIRg and DI and circulating levels of adiponectin, relative to SUC/SIV macaques, irrespective of ART status. Western blot analysis of fasted‐and fed‐state skeletal muscle samples revealed a statistically significant increase in fed‐state PTP1B, a negative regulator of insulin signaling, in CBA/SIV relative to SUC/SIV macaques and irrespective of ART status. These findings suggest that CBA impairs insulin‐mediated effects in CBA/SIV macaques and warrant future studies elucidating the specific alterations in the insulin signaling cascade that are modulated by CBA.Support or Funding InformationThe work was supported by National Institutes of Health (NIH) grants: P60AA09803, T32AA07577, and F30AA024030‐01A1.