Type 2 diabetes mellitus and hypertension are the most common comorbidities in patients with coronavirus infections. Emerging evidence demonstrates an important direct metabolic and endocrine mechanistic link to the viral disease process.
Clinicians should ensure early and complete metabolic control for all patients affected by COVID-19.
Type 2 diabetes mellitus (T2DM) appears to be a risk factor for contracting the new coronavirus infection. In fact, T2DM and high blood pressure have been identified as the most common comorbidities for other coronavirus infections, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS-CoV) 1.
According to several reports, including those from the Centers for Disease Control and Prevention (CDC), patients with T2DM and metabolic syndrome could have up to a tenfold increased risk of death when they contract COVID-19 (coronavirus reports from the CDC). Although T2DM and metabolic syndrome increase the risk of more severe symptoms and mortality in many infectious diseases, there are some additional specific mechanistic aspects in coronavirus infections that require separate consideration, which will have clinical consequences for better management of patients. seriously affected.
Hyperglycemia and the diagnosis of DM2 are independent predictors of mortality and morbidity in patients with SARS1. This finding could be due to the fact that these patients have a state of metabolic inflammation that predisposes them to increased cytokine release. For COVID-19, a cytokine storm (i.e., very elevated levels of inflammatory cytokines) has been implicated in multiple organ failure in patients with severe disease3.
Metabolic inflammation will also compromise the immune system, reducing the body’s ability to fight infection, impairing the healing process and prolonging recovery.
An animal model demonstrated that comorbid T2DM results in immune dysregulation and increases disease severity after MERS-CoV2 infection. In this work, diabetic mice expressing human DPP4 (resulting in susceptibility to MERS-CoV) exhibited an altered cytokine profile, with increased expression of IL-17α after infection.
| These data support the hypothesis that the combination of coronavirus infection and T2DM triggers a dysregulated immune response, resulting in more aggravated and prolonged lung pathology2. |
A direct endocrine link
The SARS-CoV-2 coronavirus (which causes COVID-19) enters human cells through the envelope spike glycoprotein, which is also responsible for host-to-host transmission4. This glycoprotein, found on the surface of the virus, binds to angiotensin-converting enzyme 2 (ACE2; located in human cells) to enter the cell. Furthermore, the cellular serine protease TMPRSS2 is required to prime viral entry through ACE24.
In the respiratory system, ACE2 has the function of degrading angiotensin II to angiotensin 1–7 and acts as a key regulatory point for the angiotensin system. When ACE1 activity is increased and ACE2 is inhibited, intact angiotensin II acts through the angiotensin 1 receptor (AT1R) or AT2R to exert proinflammatory responses and stimulate aldosterone secretion; These effects not only increase blood pressure and potentially cause hypokalemia , but also increase vascular permeability locally, increasing the risk of respiratory distress syndrome.
On the contrary, angiotensin 1-7 acts on the Mas receptor pathway, leading to anti-inflammatory and antifibrotic responses that would be favorable for the recovery of patients with COVID-195. It could be postulated that people with more severe COVID-19 have an imbalance in the activation of these pathways, with increased activation of AT1R and AT2R, which could be the case in T2DM, hypertension, and insulin-resistant states.
A direct metabolic link
In addition to a link between coronavirus infection and high blood pressure, there appears to be a direct link to type 2 diabetes
In the pancreas, binding of the SARS coronavirus (SARS-CoV, which causes SARS) to its receptor, ACE2, damages islets and reduces insulin release6.
In one study, patients with SARS who had no history of T2DM and did not receive steroid treatment were compared with their healthy siblings over a 3-year follow-up period. More than 50% of patients in the study became diabetic during hospitalization for SARS-CoV infection. After 3 years of recovery from the viral infection, only 5% of patients remained diabetic6.
As the human endocrine pancreas expresses ACE2, the coronavirus can enter the islets and cause acute β-cell dysfunction , leading to acute hyperglycemia and transient T2DM6.
More importantly, evidence in diabetic mice demonstrated that ACE2 activity levels were increased in the pancreas7. This finding suggests that patients with T2DM could be particularly vulnerable to coronavirus infection. Similarly, T2DM induces the expression of angiotensin-converting enzymes in other tissues, including the lung, liver, and heart,7 explaining why T2DM may mechanistically contribute to multiorgan failure in SARS-CoV infections.
Immediate clinical consequences
Based on the data discussed here, it is evident that optimal metabolic control of T2DM and associated metabolic parameters in COVID-19 patients is mandatory.
This is not only relevant because of the obvious danger and increased risk of complications for patients with T2DM and severe infectious disease, but also because this approach could help the treatment of all COVID-19 patients.
Antidiabetic drugs , such as GLP1 agonists, that improve metabolic function and induce the activity of protective ACE2 receptor pathways could have the advantage of improving glucose metabolism and blood pressure, and also prevent coronaviruses from entering cells as a result of competitive binding to ACE2. This effect could help protect and restore lung function 5.
Similarly, early treatment with angiotensin II receptor blockers (such as losartan or telmisartan) or, more directly, recombinant ACE2 , could be useful to improve the ACE2 and Mas system in preference to angiotensin receptor-mediated pathways. . This approach would allow the combination of an antidiabetic, anti-inflammatory and antiviral effect. Finally, the synthetic protease inhibitor camustat , which blocks the serine protease TMPRSS2 required for ACE2-mediated coronavirus entry into cells4, also reverses dyslipidemia and hyperglycemia8. The intriguing link between coronavirus infections and these endocrine and metabolic pathways will have an important effect on the general medical treatment of severe COVID-19. |
Glucocorticoids that have been useful in the treatment of acute respiratory distress syndrome may not be indicated in patients with coronavirus infection.
Glucocorticoids not only aggravate metabolic control, but also attenuate angiotensin 1-7 and Mas receptor expression (9). Therefore, they might have a limited role in treating COVID-19 patients.
In contrast, the antirheumatic drug hydroxychloroquine , which is now widely used in many centers around the world treating patients with COVID-19, has also attracted interest as a potential therapeutic intervention for patients with T2DM10. At this point, it is unclear whether hydroxychloroquine in addition to anti-inflammatory and antidiabetic medications will also directly interfere with the coronavirus-ACE2 pathways.
Conclusions
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