Abstract and Introduction
Precipitated by chronic psychological stress, immune system dysregulation, and a hyperinflammatory state, the sequelae of postacute COVID-19 (long COVID) include depression and new-onset diabetes. We hypothesize that exercise counters the neuropsychiatric and endocrine sequelae of long COVID by inducing the release of circulating factors that mediate the anti-inflammatory response, support brain homeostasis, and increase insulin sensitivity.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that causes coronavirus disease 2019 (COVID-19) and has contributed to millions of deaths globally. In some cases, persistent symptoms and development of sequelae occur 4 to 12 wk after onset of acute COVID-19 symptoms (long COVID). The antibody response is consistent with durable immunity against secondary COVID-19 disease. Nevertheless, SARS-CoV-2 mRNA and protein are active in the small intestinal epithelium of some individuals nearly 6 months after a COVID-19 diagnosis.
The underlying pathophysiology of COVID-19 is multifaceted, and the components seem inextricably linked. The variability of the clinical disease trajectories in patients with COVID-19 is marked by disparities that outweigh commonalities. Therefore, understanding the cellular mechanisms and critically evaluating convergence among observations become necessary to arrive at an informed strategy for managing the risk of long COVID and preventing its escalation.
SARS-CoV-2 bind to the ACE2 receptor expressed on pancreatic β cells and induce cell damage that can worsen preexisting diabetes or precipitate the onset of diabetes.[4,5] Diabetic ketoacidosis typically observed in type 1 diabetes, which is an autoimmune condition, occurs in patients without a preexisting diabetes diagnosis weeks to months after resolution of COVID-19. Cytokines such as interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) are elevated in patients with severe COVID-19.
Physical inactivity is associated with an increased risk for development of type 2 diabetes and more severe outcomes from COVID-19. The odds that a physically inactive person will encounter severe COVID-19 outcomes exceed that of most chronic diseases. We hypothesize that exercise promotes the release of circulating mediators that are central to attenuation of the long-term neuroendocrine symptoms of COVID-19 (Figure 1). In this review, we present biological insights into maladaptive stress patterns that predispose individuals to clinical depression and glucose dysregulation characteristic of type 2 diabetes. We evaluate the evidence to support our testable hypothesis that exercise can prevent or mitigate the long-term sequelae of COVID-19.
The development of hyperglycemia arising from disruption of immune metabolic homeostasis in COVID-19. High glucose levels induced by psychological stress, lingering inflammation, and β-cell dysfunction can lead to activation of the NLRP3 inflammasome in pancreatic β cells. As a result, pro–IL-1β is processed to the biologically active IL-1β. IL-1β released from β cells causes the recruitment and activation of macrophages, which prompts the release of more IL-1β. High local concentrations of IL-1β in the β-cell microenvironment may inhibit insulin secretion and trigger β-cell dysfunction and apoptosis. This leads to further increases in levels of glucose, thereby causing IL-1β autostimulation and establishing a vicious cycle. Exercise induces the release of circulating factors that mediate the anti-inflammatory response, support brain homeostasis, and increase insulin sensitivity. The net effect is the lowering of glucose levels and could be envisioned as a remission-induction therapy to counter the sequelae of COVID-19 (graphics program: Biorender). IL-1β, Interleukin-1β; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3.
Exerc Sport Sci Rev. 2022;50(2):65-72. © 2022 American College of Sports Medicine