key: cord-0981098-fe8f7tk1
authors: Pal, Rimesh; Bhadada, Sanjay K.
title: COVID-19 and diabetes mellitus: An unholy interaction of two pandemics
date: 2020-05-06
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2020.04.049
sha: fa2c01daf3bc750129ccf6ce5829407c647cae3a
doc_id: 981098
cord_uid: fe8f7tk1

Abstract Background and aims Diabetes mellitus is associated with poor prognosis in patients with COVID-19. On the other hand, COVID-19 contributes to worsening of dysglycemia in people with diabetes mellitus over and above that contributed by stress hyperglycemia. Herein, we have reviewed the two-way interactions between COVID-19 and diabetes mellitus. Methods We have performed an extensive literature search for articles in PubMed, EMBASE and Google Scholar databases till April 25, 2020, with the following keywords: “COVID-19”, “SARS-CoV-2”, “diabetes”, “diabetes mellitus”, “SARS”, “infection” and “management of diabetes mellitus” with interposition of the Boolean operator “AND”. Results Compromised innate immunity, pro-inflammatory cytokine milieu, reduced expression of ACE2 and use of renin-angiotensin-aldosterone system antagonists in people with DM contribute to poor prognosis in COVID-19. On the contrary, direct β-cell damage, cytokine-induced insulin resistance, hypokalemia and drugs used in the treatment of COVID-19 (like corticosteroids, lopinavir/ritonavir) can contribute to worsening of glucose control in people with diabetes mellitus. Conclusions The two-way interaction between COVID-19 and diabetes mellitus sets up a vicious cycle wherein COVID-19 leads to worsening of dysglycemia and diabetes mellitus, in turn, exacerbates the severity of COVID-19. Thus, it is imperative that people with DM take all necessary precautions and ensure good glycemic control amid the ongoing pandemic.

Ever since its outbreak in Wuhan, China, the novel coronavirus disease 2019 , caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 2.8 million people, claiming more than 198000 lives in over 200 nations all over the globe (1) . The overall mortality rate of COVID-19 is variable, ranging from as low as 0.7% in Germany to as high as 10.8% in Italy (2); nevertheless, older adults and people with underlying comorbidities invariably have a poor prognosis (3) . Accordingly, diabetes mellitus (DM) has emerged as a distinct comorbidity that is associated with severe disease, acute respiratory distress syndrome (ARDS) and increased mortality in COVID-19 (4) (5) (6) . In the largest series reported from China comprising of 72,314 cases, patients with DM had higher mortality (7.3% in DM vs. 2.3% overall) (7) . DM was present in 20.3% of the patients with COVID-19 who died in Italy (8) .

Coexistence of DM and COVID-19 is an unholy situation wherein one disease entity tends to compliment the other. Herein, we have summarized the possible interactions between the two raging pandemics.

Available evidence does not support the notion that people with DM are at an increased risk of COVID-19 (9) . However, diabetes mellitus has been found to be an independent predictor of admission to intensive care unit or invasive ventilation or death in COVID-19 (Hazard Ratio 1.59, 95% CI: 1.03-2.45) (10) . No clear distinction has however been made between type 1 diabetes mellitus (T1DM) and type 2 diabetes 6 6 mellitus (T2DM), but it is likely that both T1DM and T2DM are predictors of poor prognosis in COVID-19 (11) .

Multiple pathophysiological explanations can be put forward supporting the association between DM and COVID-19 severity. Innate immune system, the first line of defense against SARS-CoV-2, is compromised in patients with uncontrolled DM (12) . Moreover, DM is a pro-inflammatory state characterized by inappropriate and exaggerated cytokine response; this has been depicted in COVID-19 patients wherein serum levels of interleukin-6 (IL-6), C-reactive protein and ferritin were significantly higher in patients with DM than those without DM (13) . This suggests that people with diabetes are more susceptible to an inflammatory cytokine storm eventually leading to ARDS, shock and rapid deterioration of COVID-19. In addition, the aforementioned study also showed that COVID-19 patients with DM had higher D-dimer levels than those without DM (13); perhaps signifying over-activation of the hemostatic system. Amid an already underlying pro-thrombotic hypercoagulable state predisposed by the mere presence of DM (14) , over-activation of the coagulation cascade in COVID-19 can lead to fatal thromboembolic complications and eventual mortality (15) .

Diabetes mellitus is associated with reduced expression of angiotensin-converting enzyme 2 (ACE2), an enzyme widely expressed in the lungs (specially type II pneumocytes), kidney, intestine and vascular endothelium. Under normal physiological conditions, ACE2 degrades angiotensin-II and to a little extent angiotensin-I to smaller peptides, namely angiotensin (1-7) and angiotensin (1-9), respectively. The pulmonary ACE2/Ang (1-7) system plays a potent antiinflammatory and anti-oxidant role and ACE2 is known to be protective against lethal avian influenza A H5N1 infection (16) . Accordingly, low ACE2 expression in DM 7 might explain the increased incidence of severe lung injury and ARDS with COVID-19 (4, 17) .

One needs to keep in mind the confounding role of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB). ACEi/ARBs are commonly used in people with DM as anti-hypertensive and renoprotective drugs.

The use of ACEi/ARBs is associated with increased expression of ACE2 as an adaptive response to counteract the elevated levels of angiotensin-II (4, 18) .

Unfortunately, SARS-CoV-2 uses ACE2 as a receptor for entry into the host pneumocytes, thus, ACE2 upregulation would facilitate entry and subsequent proliferation of the coronavirus. However, once the virus uses the enzyme to gain entry into the host tissue, ACE2 get downregulated and it is unable protect against lung injury (4).

A recent study (although presently in pre-print stage) has shown that non-structural proteins of SARS-CoV-2 attacks the β1-chain of hemoglobin leading to dissociation of iron from porphyrin, thereby impairing the ability of hemoglobin to carry oxygen (19) . Although just a hypothesis, SARS-CoV-2 might have a higher affinity to bind to glycated hemoglobin than non-glycated hemoglobin.

Preclinical data and data derived from studies based on the prior SARS outbreak (2003) suggest that COVID-19 can lead to worsening of glycemic control in people with pre-existing DM over and above that caused by the stress of a critical illness (i.e., stress hyperglycemia). Yang et al. had reported that patients with SARS (caused by SARS-CoV, the 'cousin' of SARS-CoV-2) who had never received glucocorticoids had significantly higher fasting plasma glucose levels as compared to 8 8 patients with non-SARS pneumonia (20) . This was explained on the basis of SARS-CoV mediated damage of the pancreatic β-cells as ACE2 is also expressed on the pancreatic islets (21) . Infact, immunohistochemistry and in-situ hybridization have identified SARS-CoV in the pancreas of patients who died of SARS (22) . This could partly explain the worsening of glucose control in people with T2DM who do have some functional β-cells in reserve.

In addition, COVID-19 can lead to worsening of insulin resistance in people with T2DM and T1DM (specially those who are obese and have some component of insulin resistance apart from an absolute insulin deficiency). Even mild COVID-19

can induce a pro-inflammatory milieu, as evident by high amounts of IL-6, IL-1β, tumor-necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and

inducible protein-10 that can further lead to lowering of insulin sensitivity. Moreover, obesity, commonly associated with T2DM is likely to further aggravate the cytokine response, thereby further worsening insulin resistance (23) . In addition, SARS-CoV increases serum levels of fetuin A, an α2-Heremans-Schmid glycoprotein that has been linked to impaired insulin sensitivity (24) ; whether SARS-CoV-2 can lead to elevation of fetuin A needs exploration. Lastly, COVID-19 is often associated with hypokalemia; this has been attributed to downregulation of pulmonary ACE2, reduced angiotension-II degradation and subsequent increased aldosterone secretion (4).

Hypokalemia, in turn, can worsen glucose control in patients with T1DM and T2DM (25) .

Amid the prevailing nationwide lockdowns, restriction in outdoor movements would limit the sunlight exposure leading to vitamin D deficiency (26) . Hypovitaminosis D has long been regarded as a risk factor for insulin resistance and vitamin D supplementation improves insulin sensitivity (27) . Thus, vitamin D deficiency can The indirect role played by drugs used in the management of COVID-19 on worsening of glucose control also needs to be considered. Corticosteroids, used in patients with co-existing ARDS and sepsis can lead to glycemic excursions.

Lopinavir-ritonavir could lead to lipodystrophy and subsequent insulin resistance, although short-term exposure as under the present clinical scenario might not be clinically significant. More importantly, ritonavir, being a potent enzyme inhibitor, can prolong the half-life of glucocorticoids and indirectly contribute to poor glucose profile (28) . Type 1 interferons (interferon-β1) have also been investigated as a potential treatment against COVID-19 (29) and interferon therapy has been associated with β-cell damage as well (30) . Azithromycin has also been used in combination with hydroxychloroquine in COVID-19 (31); the macrolide antibiotic can increase the risk of dysglycemia in people with diabetes mellitus (32) .

Apart from worsening of hyperglycemia, a retrospective study from Wuhan reported that around 10% of the patients with T2DM and COVID-19 suffered at least one episode of hypoglycemia (<3.9 mmol/L) (33) . Hypoglycemia, in turn, contributes to higher number of cardiovascular events in patients with DM by undue activation of the sympathetic nervous system and by mobilizing pro-inflammatory mononuclear cells and increasing platelet reactivity (34) .

Thus, COVID-19 in patients with underlying DM leads to worsening of glycemic profile that further compromises the innate immune response and promotes generation of pro-inflammatory cytokines, thereby setting up a vicious cycle (figure 1).

Considering the gravity of the pandemic and in the absence of a definitive therapy against COVID-19, it is imperative that people with DM be extra cautious and take all necessary precautions (3, 4) . Stringent social distancing and hand hygiene should be the norm. Good glycemic control should be targeted as it would help boost the innate immune system (4, 35) . However, widespread nationwide lockdowns would curtail their routine in-clinic visits, limit their physical activity, alter their food habits and adversely affect their psychological health; all these would ultimately lead to poor glycemic control (36) . Infact, a recent study from China had shown that elderly subjects with type 2 diabetes mellitus had higher fasting blood glucose during the COVID-19 pandemic (37) . Teleconsultations with registered medical practitioners would help people with DM circumvent a lot of problems imposed by lockdowns (38) . Although certain anti-diabetic drugs like pioglitazone and liraglutide have been shown to upregulate ACE2 in animal models, the current evidence does not support any change in the ongoing medications (39) . Similarly, international organizations recommend patients on ACEi/ARBs to carry on with their medications. Although used rarely, hydroxychloroquine can be good anti-diabetic medication in the present scenario as the drug has also been shown to inhibit SARS-CoV-2 infection in-vitro as well as reduce the viral load in COVID-19 patients. The drug has also been approved for prophylaxis against COVID-19 in many countries (40) . Considering the low-cost, widespread availability, modest HbA1c reduction, once-daily dosing and relatively good tolerability, hydroxychloroquine may be a good add-on drug during this outbreak for patients with poor glucose control, provided contraindications like diabetic retinopathy and cardiomyopathy has been ruled out (39) . Similarly, tocilizumab, a monoclonal antibody against IL-6, is being tried in patients with 11 COVID-19. Tocilizumab is known to improve insulin resistance and reduce HbA1c in patients with rheumatoid arthritis and diabetes mellitus (42) . In addition, camostat mesilate has been used as anti-viral drug against COVID-19; the drug was earlier pursued as an anti-diabetic drug as it was shown to lower blood glucose levels in insulin-treated patients with diabetes mellitus (44) . In addition, remdesivir, an adenosine analogue that inhibits viral replication, does not affect blood glucose and lipids when compared to placebo (45) . Convalescent plasma has been used in the management of COVID-19 and seems to be a safe alternative (46) . The effect of drugs being tried in the management of COVID-19 on glucose and lipid profiles has been summarized in table 1.

The complex interaction between COVID-19 and diabetes mellitus places an individual at an extraordinarily high-risk of severe disease, acute respiratory distress syndrome and eventual mortality. In addition, the concurrent COVID-19 is likely to make glucose control difficult in people with diabetes mellitus. Nevertheless, people with DM need to be extra cautious and ensure strict social distancing, proper hand hygiene and good glycemic control amid the ongoing pandemic. 

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