A Vicious Cycle: Elucidating the Molecular Pathogenesis of Type 2 Diabetes Mellitus in People Living With HIV Taking Anti-Retroviral Therapy

Abstract

The human immunodeficiency virus (HIV) has gone from being a mortal disease to becoming a manageable chronic disease mostly due to progress in anti-retroviral therapy (ART); however, metabolic complications such as type 2 diabetes mellitus (T2DM) have been implicated at a higher rate than the general HIV-seronegative population. The pathogenesis of T2DM is still not well-known and there exists lack of communication between different sources which I seek to integrate in this thesis. It is known that T2DM is characterized by insulin resistance which can be propagated by enhanced low-grade chronic inflammation, oxidative stress and lipolysis. HIV infection mainly affects CD4+ T cells which become depleted during acute HIV infection and develop systemic chronic immune activation due to the release and circulation of inflammatory cytokines like IL-6, TNF-α and IL-1β. Additionally, HIV and ART influence microbial translocation, low-grade chronic inflammation, oxidative stress and insulin resistance which overlap and influence each other. Inflammation and ROS in muscle, liver and adipose tissue induce increased lipolysis, reduced lipogenesis, reduced glucose uptake and mitochondrial dysfunction which are exacerbated by HIV and ART. Furthermore, accumulating free fatty acids and lipid intermediates result in increased inflammatory cytokines, ROS, mitochondrial dysfunction, and insulin resistance pointing at a vicious cycle between chronic inflammation, oxidative stress and lipid dysfunction that progresses into T2DM. In this thesis I review current literature on HIV-associated metabolic dysfunctions leading to T2DM and synthesize how these mechanisms cross-talk focusing on overlap between inflammatory, lipolytic and oxidative pathways.