Alcohol is the most frequently abused drug in the US, and approximately 30% of US adult residents have an alcohol use disorder (AUD) during their lives. According to a recent CDC report, the prevalence of HIV infection in the US is 1.15 million individuals. The prevalence of AUD in HIV patients is greater than the prevalence of AUD in the general population. Effective anti-retroviral therapy (ART) has significantly decreased HIV patients' progression to AIDS and has increased the life expectancy of persons living with HIV/AIDS (PLWHA); however, prolonged survival has been associated with metabolic disturbances, including lipodystrophy, insulin resistance, and metabolic syndrome. Chronic alcohol consumption has also been shown to contribute to the development of insulin resistance and lipodystrophy. To our knowledge, there have been no previous studies to investigate the impact of both CBA administration and HIV/SIV on insulin signaling. Our studies, using male rhesus macaques that are chronically administered binge alcohol (CBA) or isocaloric sucrose (SUC), have revealed that CBA administration potentiates a pro-inflammatory and pro-oxidative skeletal muscle milieu and decreases phosphatidylinositol-3-kinase (PI3K) activity and results in upregulation of protein tyrosine phosphatase 1B (PTP1B) expression in skeletal muscle at the end stage of the disease. More recent studies have revealed that CBA significantly increases abdominal fat deposition and significantly decreases circulating adiponectin levels at 11 months post-SIV infection. Furthermore, frequently sampled intravenous glucose tolerance tests in these animals show that at 11 months post-SIV, CBA macaques have a significant decrease in disposition index suggesting impaired insulin responses at target tissues, including skeletal muscle. Reports in the scientific literature and our preliminary data support the central hypothesis that CBA decreases insulin- mediated anabolic responses in skeletal muscle of SIV-infected macaques. The proposed studies to be performed as part of the training plan of the applicant will use an integrated approach to assess the following Specific Aims: 1) To test the prediction that CBA decreases insulin-mediated glucose uptake and glycogen synthesis in skeletal muscle of SIV-infected macaques and 2) To identify the site(s) of insulin signaling cascade disruption in skeletal muscle of SIV-infected macaques following CBA administration. Findings from the proposed studies will provide evidence to elucidate the underlying molecular derangements in skeletal muscle insulin signaling following combination of CBA and SIV/ART and may offer insight into therapeutic targets aimed at ameliorating metabolic dysregulation in persons living with HIV/AIDS.

Public Health Relevance

This application for the NRSA research fellowship will provide a training opportunity for a future physician-scientist. The studies proposed will investigate the detrimental effects of chronic binge alcohol administration on insulin-mediated anabolic responses and insulin signaling in Rhesus macaques infected with Simian Immunodeficiency Virus. The findings from this study will provide the basis for future translational studies in persons living with HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AA024030-02
Application #
9128401
Study Section
Neuroscience Review Subcommittee (AA)
Program Officer
Orosz, Andras
Project Start
2015-08-01
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Physiology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Ford Jr, Stephen M; Simon, Liz; Vande Stouwe, Curtis et al. (2016) Chronic binge alcohol administration impairs glucose-insulin dynamics and decreases adiponectin in asymptomatic simian immunodeficiency virus-infected macaques. Am J Physiol Regul Integr Comp Physiol 311:R888-R897