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

Abstract

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.

Impact of Alcohol on Bone Health in People Living With HIV: Integrating Clinical Data From Serum Bone Markers With Morphometric Analysis in a Non‐Human Primate Model

“…Adult (6‐ to 9‐year‐old) female Indian rhesus macaques ( Macaca mulatta ) were randomized based on in vitro SIV infectivity kinetics to either chronic binge alcohol (CBA) or isovolumetric water (VEH) groups as previously described. ( 36 ) Macaques were administered alcohol at a concentration of 30% (w/v) in water (30 minutes infusion; 5 days/week; 12–15 g/kg/week) intragastrically. Peak plasma alcohol concentrations averaged 50 to 60 mM (~0.23% blood alcohol content) 2 hours after alcohol initiation.…”

Chronic Binge Alcohol and Ovarian Hormone Loss Dysregulate Circulating Immune Cell SIV Co-Receptor Expression and Mitochondrial Homeostasis in SIV-Infected Rhesus Macaques

“…Adult (6–9 years old) female Indian rhesus macaques ( Macaca mulatta ) were randomized based on in vitro peripheral blood mononuclear cell (PBMC) SIV infectivity assays as previously described [ 12 , 28 ] (12 & 28 also reported using this cohort of animals). Macaques were administered alcohol intragastrically at a concentration of 30% ( wt / vol ) in water (30 min infusion; 5 days/wk; 12–15 g/kg/wk).…”

“…In 2018, women accounted for 18% of new HIV infections, and HIV-infected women have an earlier onset of menopause, with a mean age range of 46–48 years [ 9 , 10 , 11 ]. The hormonal changes that occur with menopause alter multiple physiological processes [ 12 ]. However, the effect of ovarian hormone loss on HIV pathogenesis and AUD remains to be fully understood.…”

Pathophysiological Consequences of At-Risk Alcohol Use; Implications for Comorbidity Risk in Persons Living With Human Immunodeficiency Virus

“…Clinical studies show that alcohol decreases circulating basal insulin secretion ( Bonnet et al, 2012 ) and decreases circulating insulin and c-peptide response to glucose ( Patto et al, 1993 ). Preclinical studies show that chronic binge alcohol significantly impairs endocrine pancreatic response to a glucose load in SIV-infected macaques ( Ford et al, 2016 ; Simon et al, 2021 ). Similarly, rodents on a chronic alcohol diet have decreased circulating insulin levels ( Rasineni et al, 2019 ), and decreased pancreatic expression of glucokinase, glucose transporter-2 ( Kim et al, 2010 ), and gamma-aminobutyric acid (GABA) receptors ( Wang et al, 2014 ).…”