Chronic binge alcohol and ovariectomy-mediated impaired insulin responsiveness in SIV-infected female rhesus macaques.

OBJECTIVE Aging people living with HIV (PLWH), especially post-menopausal women may be at higher risk of comorbidities associated with HIV, ART, hypogonadism and at-risk alcohol use. Our studies in simian immunodeficiency virus (SIV)-infected male macaques demonstrated that chronic binge alcohol (CBA) reduced acute insulin response to glucose (AIRG), and at-risk alcohol use decreased HOMA-β in PLWH. The objective of this study was to examine the impact of ovariectomy (OVX), on glucose-insulin dynamics and integrity of pancreatic endocrine function in CBA/SIV-infected female macaques. METHODS Female macaques were administered CBA (12-15 g/kg/week) or isovolumetric water (VEH) intragastrically. Three months after initiation of CBA/VEH administration, all macaques were infected with SIVmac251, and initiated on anti-retroviral therapy (ART) 2.5 months post-infection. After one month of ART, macaques were randomized to OVX or sham surgeries (N=7-8/group), and euthanized 8 months post-OVX (study endpoint). Frequently sampled intravenous glucose tolerance tests (FSIVGTT) were performed at selected timepoints. Pancreatic gene expression and islet morphology were determined at study endpoint. RESULTS There was a main effect of CBA to decrease AIRG at Pre-SIV and study endpoint. There were no statistically significant OVX effects on AIRG (p=0.06). CBA and OVX decreased expression of pancreatic markers of insulin docking and release. OVX increased endoplasmic stress markers. CONCLUSIONS CBA but not OVX impaired glucose-insulin expression dynamics in SIV-infected female macaques. Both CBA and OVX altered integrity of pancreatic endocrine function. These findings suggest increased vulnerability of PLWH to overt metabolic dysfunction, that may be exacerbated by alcohol use and ovarian hormone loss.