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The incidence of alcohol use disorder (AUD) is higher among people living with HIV (PLWH). The advent and continued development of antiretroviral therapy (ART) has significantly reduced mortality, shifting the course of HIV infection to a chronic illness. However, this is associated with an increased incidence of comorbid conditions, including type 2 diabetes mellitus, insulin resistance, and cardiovascular complications. Using a nonhuman primate model of simian immunodeficiency virus (SIV) infection, previous studies have demonstrated that chronic binge alcohol (CBA) administration decreases whole body insulin responsiveness, irrespective of ART administration. The objective of the current study was to determine the effects of CBA and ART on insulin-sensitive peripheral tissues before the development of overt clinical symptoms of SIV disease. Our results show that CBA reduced omental adipocyte cell size, increased collagen expression, and decreased the in vitro differentiation potential of adipose-derived stem cells. In contrast, it did not alter skeletal muscle or omental or hepatic expression of insulin signaling proteins. However, ART significantly decreased skeletal muscle expression of phosphatase and tensin homolog, total mechanistic target of rapamycin, and ribosomal protein S6. In addition, ART increased hepatic phosphorylation of AMP-activated protein kinase α and increased gene expression of key enzymes required for gluconeogenesis and fatty acid synthesis. These findings suggest that CBA and ART differentially promote adverse metabolic effects in an organ-specific manner that may underlie insulin resistance associated with alcohol, SIV, and ART. Whether this is translated in PLWH with AUD remains to be determined. [ABSTRACT FROM AUTHOR]

R2180 --> Background: Antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Older PLWH, especially menopausal women, experience complex interactions of HIV, ART, hormonal status, and lifestyle behaviors such as at‐risk alcohol use, increasing the risk of metabolic comorbidities. Our studies have demonstrated that chronic binge alcohol (CBA) significantly decreases acute insulin response to a glucose challenge in Simian Immunodeficiency Virus (SIV)‐infected macaques, suggesting pathophysiological changes in pancreatic endocrine function. Endoplasmic Reticulum (ER) stress is one of the major mechanisms associated with alcoholic pancreatitis and endocrine pancreatic dysfunction. The objective of this study was to examine the effects of CBA administration and gonadal hormone loss, resulting from ovariectomy (OVX), on pancreatic mechanisms that contribute to impaired glucose‐insulin dynamics in SIV‐infected female macaques. Hypothesis: Chronic binge alcohol and ovariectomy increase pancreatic ER stress and decrease expression of regulators of insulin synthesis. Methods: CBA or isovolumetric water (VEH) was administered through an intragastric catheter for 30 minutes, 5 days a week. Three months after initiation of CBA/VEH administration, macaques were infected with SIVMac251 and 2.5 months later initiated on ART. After 1 month of ART, macaques underwent sham surgery or ovariectomy and euthanized 9 months post‐SIV‐infection. Total RNA was isolated from pancreas collected from macaques (VEH/SHAM= 8, CBA/SHAM= 7, VEH/OVX= 7, CBA/OVX n=7). cDNA was synthesized and qPCR was used to analyze gene expression of markers for ER stress (X‐Box Binding Protein 1, XBP1; Activating Transcription Factor 4, ATF4; and C/EBP Homologous Protein, CHOP) and regulators of insulin synthesis (Homeobox Protein Nkx‐2.2, NKX2.2; insulin promoter factor 1, PDX1; Transcription factor MafA, MAFA; Glucose transporter 2, GLUT2; and Glucokinase). Results: There was a main effect of OVX to increase mRNA expression of ATF4 and XBP1 (p<0.05) in SIV‐infected macaques. There was not a statistically significant effect of CBA or OVX to alter gene expression of CHOP, or insulin synthesis markers, NKX2.2, PDX1, MAFA, GLUT2 and Glucokinase. Conclusions: OVX increased pancreatic expression of ER stress markers without significantly altering expression of regulators of insulin synthesis. We speculate that the increased expression of ER stress markers may result in increased beta cell apoptosis. These findings provide evidence for pancreatic mechanisms that can contribute to the observed impairment of glucose insulin dynamics in SIV infection. [ABSTRACT FROM AUTHOR]