The piece last week titled “Diabetes And COVID-19” generated a number of feedbacks. As a result, I am inclined to do a follow up on some issues raised. Again, I have looked at articles published in this area. For the purposes of this piece I will dwell on two of these papers. One is by Antonio Ceriello titled “Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory” published inDiabetes Research and Clinical Practice (2020). Another is by Cristelo et al titled “SARS-CoV-2 and diabetes: New challenges for the disease” published in Diabetes Research & Clinical Practice 164 (2020).In this particular piece I will be responding to enquiries raised by health workers as well.

Evidence in the COVID-19 pandemic shows that hyperglycemia (high blood glucose), not only in people with diabetes, worsens the prognosis and increases the risk to die. It is, moreover, emerging that particularly the hyperglycemia at the admission in the hospital is a very bad prognostic factor. High blood glucose in the very early phase of the disease plays a particular role in determining the seriousness of the prognosis.

There are at least two reasons why high blood glucose, particularly an acute one, can be very dangerous during the SARS-CoV-2 infection. One is that an acute increase of blood glucose accompanied by a huge increase of inflammatory mediators. Overreaction of the immune system (“cytokine storm”) has been cited as one of the consequences for the complications and multi-organ failure in COVID-19 infections. Clearly, knowing the role of the “cytokines storm” in the COVID-19 means all efforts must be made to manage high blood glucose at the outset of COVID-19 infection.  Another reason seems to be very specific for COVID-19 and it is related to the binding of SARS-CoV-2 to ACE2.  The glycosylation, a reaction that can be induced by hyperglycemia, of the ACE2 is needed for the linkage of the virus to this cellular receptor. Therefore, high and aberrantly glycosylated ACE2 in the tissue in uncontrolled hyperglycemia could favor the cellular intrusion of SARS-CoV2, thus leading to a higher propensity to COVID-19 infection and a higher disease severity. It is well known, however that the hyperglycemia-related process of glycosylation is at the beginning a reversible process-hence the need for early intervention in controlling high blood glucose. 

The fast normalization of hyperglycemia during COVID-19  results in a decrease of inflammatory cytokines release and in a lower ACE2 binding capacity for the virus, two facts which consistently help in improving the prognosis in people affected by SARS-CoV- 2.

Studies show that angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS-CoV virus. The novel SARS-CoV-2 (COVID-19) also binds to ACE2 with 10 to 20 times higher affinity than SARS-CoV does.ACE2 is a naturally occurring enzyme abundantly present in humans, mainly in the cell membrane of lung alveolar epithelial cells, enterocytes of the small intestine, which provide as entry routes for COVID-19 infection. Additionally, ACE2 is also expressed by arterial and venous endothelial cells and arterial smooth muscle cells, cholangiocytes], testis, pancreas, in cardiovascular, renal, urothelial, mucosal and gastrointestinal tissues. 

ACE2 is homologous to the firstly discovered ACE1, and both enzymes are part of the renin-angiotensin system(RAS), which has a crucial role in regulating blood pressure, maintaining electrolyte and fluid homeostasis for its potent vasoconstrictor/vasodepressor actions. RAS is an enzymatic cascade starting with the cleavage of angiotensinogen by renin to form angiotensin (Ang) I. This peptide is then further metabolized by ACE1to form the potent vasopressor (vasoconstrictor) peptide Ang II. Ang II levels are endogenously regulated by the ACE2, which forms Ang 1-9 and Ang 1-7 from Ang I and Ang II. Ang 1–7 exerts a potent vasodilator, anti-fibrotic, anti-proliferation and anti-inflammatory effect. The effects of ACE2 counterbalance the ACE1-Ang II-ATR1 (Angiotensin II receptor type 1) system.

Many antihypertensives have been developed to target the ACE1-Ang II-ATR1 system. What are known as the Angiotensin converting inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are notable antihypertensives with substantially lower the risk of death, heart failure and stroke. Their use is a compelling indication in persons with diabetes and high blood pressure. Patients with hypertension and diabetes benefit from the use of these drugs, since not only ACE2 is insensitive to blockade by ACE1 inhibitors, but also, the use of these inhibitor drugs increases the ACE2 gene expression and activity. Specifically, in diabetes, ACE2 has a protective role in the progression of cardiovascular and renal complications- hence being a target site by COVID-19 virus invasion should be of concern to all.

Overall, the immune response, which is vital to fight against COVID-19 infection, is impaired, especially in diabetic patients with poor blood glucose control. Several studies have shown that diabetic patients have a significant decrease in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), which are important indicators of lung function. This impaired pulmonary function is significantly associated with poorly controlled diabetes and consequently hyperglycemic levels. Therefore, this reduced pulmonary capacity may also increase susceptibility to respiratory infections.

European Medicines Agency (EMA) recommend that treatment with ARBs and ACEIs should be maintained in patients with diabetes and hypertension. Patients who stop taking them may face more complications regarding kidney failure and increased mortality. Commonly, and according to standard procedure, very sick patients should stop taking metformin and sodium-glucose transporter 2 inhibitors, due to their adverse side effects. In addition, the glucagonlike peptide receptor–1 analogues can also be stopped, since they may cause nausea, vomiting. The same goes for pioglitazone. Insulin should be the only one used in acutely sick patients or with severe breathing disorders. Only when recovered or stabilized, can noninsulin therapy can be introduced.

The Endocrine Society clinical practice guidelines for inpatient management of hyperglycemia recommend that all hospitalized patients regardless of the diagnosis of diabetes undergo laboratory blood glucose (BG) testing on admission. Patients without known diabetes and BG > 7.8 mmol/L (140 mg/dL) should undergo bedside testing by a point-of-care device for the next 24–48 h. Appropriate treatment should be initiated in those with persistently high BG (>7.8 mmol/L or 140 mg/dL). Measurement of glycated hemoglobin (HbA1c) is also recommended in such individuals to distinguish stress hyperglycemia (HbA1c <6.5%) from previously unrecognized diabetes (HbA1c ≥ 6.5%). The American Diabetes Association (ADA) guidelines suggest BG testing at admission in all hospitalized patients, HbA1c in those with BG greater than 7.8 mmol/L (140 mg/dL), and initiation of treatment in cases with persistent hyperglycemia (≥10.0 mmol/L or 180 mg/dL).

Until then, regularly/daily consume polyphenol-rich cocoa to reduce blood glucose, reduce blood pressure and strengthen your immune system, among others.




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