The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing substantial morbidity and mortality. Older age and presence of diabetes mellitus, hypertension, and obesity significantly increases the risk for hospitalization and death in COVID-19 patients. In this Perspective, informed by the studies on SARS-CoV-2, Middle East respiratory syndrome (MERS-CoV), and the current literature on SARS-CoV-2, we discuss potential mechanisms by which diabetes modulates the host-viral interactions and host-immune responses. We hope to highlight gaps in knowledge that require further studies pertinent to COVID-19 in patients with diabetes.
Potential mechanisms that increase the risk of COVID-19 in diabetes.
It is now well recognized that older age and the presence of DM, hypertension, and severe obesity (BMI ≥ 40 kg/m2) increase morbidity and mortality in patients with COVID-19. Considering the high prevalence of cardiovascular disease (CVD), obesity, and hypertension in patients with DM, it is unknown whether DM independently contributes to this increased risk. However, plasma glucose levels and DM are independent predictors for mortality and morbidity in patients with SARS. Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include: 1) higher affinity cellular binding and efficient virus entry, 2) decreased viral clearance, 3) diminished T cell function, 4) increased susceptibility to hyperinflammation and cytokine storm syndrome, and 5) presence of CVD
Augmented ACE2 expression in alveolar AT2 cells, myocardium, kidney, and pancreas may favor increased cellular binding of SARS-CoV-2. Increased expression of ACE2 has been demonstrated in the lung, kidney, heart, and pancreas in rodent models of DM. Insulin administration attenuates ACE2 expression, while hypoglycemic agents such as glucagon-like peptide-1 (GLP-1) agonists (liraglutide) and thiazolidinediones (TZDs; pioglitazone), antihypertensives such as ACE inhibitors, and statins upregulate ACE2. Until recently, whether DM was causally linked to ACE2 expression levels in the lung in humans was unknown. Using a phenome-wide Mendelian randomization study,explored diseases or traits that may be causally linked to increased ACE2 expression in the lung. Interestingly, they found that DM was causally associated with increased lung ACE2 expression. Circulating levels of furin, a cellular protease involved in facilitating viral entry by cleaving the S1 and S2 domain of the spike protein, are elevated in patients with DM. These studies support the hypothesis that patients with DM are susceptible to SARS-CoV-2 infection. Indeed, a recent study reported that clearance of SARS-CoV-2 was delayed in patients with DM, a finding that needs to be confirmed in larger studies.
ACE catalyzes the conversion of the prohormone, angiotensin (Ang) I to the octapeptide, AngII), whereas ACE2 converts AngII to Ang1–7. AngII, through the activation of Ang II type 1a receptors induces vasoconstriction and proliferation, whereas Ang1–7 stimulates vasodilatation and suppresses cell growth. Increased ratio of pulmonary ACE/ACE2 activity as observed in patients with ARDS favors AngII generation. Once bound to ACE2, SARS-CoV downregulates cellular expression of ACE2, and the unopposed action of AngII contributes to acute lung injury. Binding to ACE2 alone does not lead to severe lung injury as is observed with other CoVs (NL63). Whether SARS-CoV-2 causes downregulation of pulmonary ACE2 is unknown. Nevertheless, there exists a potential for salutary, if not therapeutic, effects of Ang II receptor blockers, ACE inhibitors, TZDs, GLP-1 agonists, and statins in the setting of low ACE2 expression. Lacking further evidence of risk or benefit, the American College of Cardiology, the American Heart Association, and the American Society of Hypertension have recommended that patients should continue treatment with their usual antihypertensive therapy.
DM inhibits neutrophil chemotaxis, phagocytosis, and intracellular killing of microbes. Impairments in adaptive immunity characterized by an initial delay in the activation of Th1 cell-mediated immunity and a late hyperinflammatory response is often observed in patients with diabetes. In an elegant study, examined the effects of DM in a humanized mouse model of MERS-CoV infection on a high-fat diet. Following MERS-CoV infection, the disease was more severe and prolonged in diabetic male mice and was characterized by alterations in CD4+ T cell counts and abnormal cytokine responses (such as elevated IL17a). Consistent with this finding, in patients with COVID-19, peripheral counts of CD4+ and CD8+ T cells are low, but with a higher proportion of highly proinflammatory Th17 CD4+ T cells, as well as elevated cytokine levels. Thus, it is likely that patients with DM may have blunted anti-viral IFN responses, and the delayed activation of Th1/Th17 may contribute to accentuated inflammatory responses
There is a paucity of data in the United States regarding comorbidities and COVID-19 outcomes and mechanisms that modulate viral pathogenesis. Certain racial groups such as African Americans, Hispanics, Asians, and Native Americans are highly prone to develop DM, and disparities in health care make these groups more vulnerable. Identification of clinical and biochemical parameters using multi-omics approaches that predict severity of the COVID-19 in DM using large data sets is urgently needed. Studies in humanized ACE2 (hACE2) mice and non-human primates aimed at understanding how hyperglycemia, hyperinsulinemia, and hypoglycemic agents affect pathogenesis of COVID-19 and how DM affects the efficacy of vaccines and antiviral investigational agents currently in trials are warranted. Finally, we need to develop novel ways to deliver care to our patients with DM using telehealth, remote patient monitoring, and wearable technologies. As the global pandemic unfolds and rapidly spreads across the United States, social isolation measures will enable the transition, but there is an urgent need for basic and clinical investigations to address the many important and unanswered questions
Reference & Source information: https://journals.physiology.org/
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