Chronic binge alcohol impairs glucose‐insulin dynamics in SIV‐infected female rhesus macaques

Abstract

Background Antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Older PLWH, especially post-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. We have previously shown that chronic binge alcohol (CBA) reduces the acute insulin response to a glucose challenge in SIV-infected male macaques and that at-risk alcohol use decreases HOMA-β (a marker for pancreatic beta cell function) in PLWH. Meanwhile, the role of estrogen in pancreatic health maintenance is not fully understood. The objective of this study was to determine the effect of CBA and ovarian hormone loss, resulting from ovariectomy (OVX), on glucose-insulin dynamics and pancreatic integrity in SIV-infected female rhesus macaques. Hypothesis We hypothesized that chronic binge alcohol and ovariectomy would decrease insulin response to a glucose challenge and impair insulin and glucagon expression in pancreatic islets. Methods 28 adult female macaques were used in the study. CBA or isovolumetric water (VEH) was administered through an intragastric catheter for 30 minutes, 5 days a week, with blood alcohol concentrations reaching 50-60 mM. 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. Using a modified frequently sampled intravenous glucose tolerance test (FSIVGTT), blood glucose and serum insulin values were measured. Glucose and insulin dynamic measures including the acute insulin response to glucose (AIRg), insulin sensitivity (Si), disposition index (DI), and glucose effectiveness (Sg) were determined using minimal model software. Insulin and glucagon expression was determined in formalin-fixed, paraffin-embedded pancreatic tissue collected at study endpoint. Corrected total cell fluorescence for insulin and glucagon were calculated using ImageJ software. To confirm these results, total RNA was isolated from pancreas and mRNA expression of insulin and glucagon determined using quantitative PCR. Results There was a main effect of CBA to decrease AIRg (p=0.02) and increase Si (p=0.01). There were no statistically significant effects of OVX on AIRg (p=0.06) or Si (p=0.4). There were also no statistically significant effects of CBA or OVX on DI or Sg. Neither CBA nor OVX altered the protein or mRNA expression of insulin and glucagon in pancreatic islets. Conclusion CBA decreased the acute endogenous insulin release in response to a glucose challenge without significantly altering basal pancreatic islet expression of insulin and glucagon, while OVX did not significantly alter any of these measures. These results indicate that CBA impairs the immediate release of insulin from beta cell insulin secretory vesicles, and we speculate that CBA dysregulates the metabolic signaling pathway of insulin secretion. Determining mechanisms of pancreatic endocrine dysfunction will inform therapeutic strategies to improve alcohol-mediated impaired glucose insulin dynamics in the context of SIV/HIV.