Type 1 Diabetes Mellitus in the SARS-CoV-2 Pandemic: Oxidative Stress as a Major Pathophysiological Mechanism Linked to Adverse Clinical Outcomes

Abstract

Recent reports have demonstrated the association between type 1 diabetes mellitus (T1DM) and increased morbidity and mortality rates during coronavirus disease (COVID-19) infection, setting a priority of these patients for vaccination. Impaired innate and adaptive immunity observed in T1DM seem to play a major role. Severe, life-threatening COVID-19 disease is characterized by the excessive release of pro-inflammatory cytokines, known as a “cytokine storm”. Patients with T1DM present elevated levels of cytokines including interleukin-1a (IL), IL-1β, IL-2, IL-6 and tumor necrosis factor alpha (TNF-α), suggesting the pre-existence of chronic inflammation, which, in turn, has been considered the major risk factor of adverse COVID-19 outcomes in many cohorts. Even more importantly, oxidative stress is a key player in COVID-19 pathogenesis and determines disease severity. It is well-known that extreme glucose excursions, the prominent feature of T1DM, are a potent mediator of oxidative stress through several pathways including the activation of protein kinase C (PKC) and the increased production of advanced glycation end products (AGEs). Additionally, chronic endothelial dysfunction and the hypercoagulant state observed in T1DM, in combination with the direct damage of endothelial cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may result in endothelial and microcirculation impairment, which contribute to the pathogenesis of acute respiratory syndrome and multi-organ failure. The binding of SARS-CoV-2 to angiotensin converting enzyme 2 (ACE2) receptors in pancreatic b-cells permits the direct destruction of b-cells, which contributes to the development of new-onset diabetes and the induction of diabetic ketoacidosis (DKA) in patients with T1DM. Large clinical studies are required to clarify the exact pathways through which T1DM results in worse COVID-19 outcomes.

Oxidative Stress-Related Mechanisms in SARS-CoV-2 Infections

“…The viral protein Spike interaction with ACE2 leads to an excessive production of angiotensin II (Ang II) and activation of NADPH oxidase which subsequently results in enhancing oxidative stress mechanisms (in contrast to what happens during other viral infections) but also releasing inflammatory molecules [ 59 ]. In the course of SARS-CoV-2 infection, angiontensin II availability is increased through the high affinity and resulting binding the virus to ACE2 [ 60 ]. ACE2 in SARS-CoV-infected cells has been shown to be also involved in postinfection regulation, including immune response, viral genome replication, and cytokine secretion [ 61 ].…”

“…The viral [59]. In the course of SARS-CoV-2 infection, angiontensin II availability is increased through the high affinity and resulting binding the virus to ACE2 [60]. ACE2 in SARS-CoV-infected cells has been shown to be also involved in postinfection regulation, including immune response, viral genome replication, and cytokine secretion [61].…”

Does Oxidative Stress Management Help Alleviation of COVID-19 Symptoms in Patients Experiencing Diabetes?

“…Diabetes is considered to be one of the major indicators for severe COVID-19 prognosis, as more diabetic patients (diabetes type-2 is mainly evident, with limited evidence from diabetes Type-1) showed severe COVID-19 symptoms and deaths after exposure to SARS-CoV-2 virus [1,[13][14][15]. A meta-analysis concluded that the diabetic patients showed a 200% increased probability of death with severe COVID-19 symptoms than non-diabetic patients [16].…”

“…Together these enzymes produce excess ROS and can be the causative agent(s) for diabetes-like diseases [18]. Another recent study reported that presence of diabetes mellitus type 1 results in increased morbidity and mortality rates during coronavirus (COVID-19) disease [13]. Diabetic patients displayed higher cell counts of leukocytes and neutrophils in their blood during admission with comparatively severe COVID-19 symptoms than non-diabetic patients.…”

Covid-19 and Type 1 Diabetes: A Scientometric Assessment of Global Publications based on the Scopus Database

“…[5][6][7] In addition, the pathophysiological mechanisms linked to adverse clinical outcomes in Covid-19 affected T1D patients are just beginning to get elucidated. 8 However, several facets of Covid-related T1D are still not well understood. A recent systematic review that included 15 original investigative studies on the association between Covid-19 and T1D reported wide variability in the studied outcomes such as the length of hospital stay, need for hospitalization and intensive care, DKA rates, and severe hypoglycemia.…”