COVID-19 may trigger the onset of diabetes in normally healthy people and higher the mortality in diabetic patients

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An international review involving Monash University has found elderly people with diabetes who contract COVID-19 are at a much higher risk of dying from the disease – and the virus may actually trigger the onset of diabetes in normally healthy people.

The study, published in The Lancet Diabetes & Endocrinology, found that depending on the global region, 20 to 50 percent of patients diagnosed with COVID-19 during the pandemic had diabetes.

It also noted the risk of dying from COVID-19 was up to 50 percent higher in people with diabetes, particularly elderly type 2 diabetes cases.

In Australia, one third of the 46 people who had died from COVID-19 by April 12 had diabetes, while 20 percent of the 752 people hospitalised with the virus had diabetes.

The Lancet report was done by an international panel of experts in the field of diabetes.

They came together to provide guidance and practical recommendations for the management of diabetes for clinicians in both developed and developing countries.

It was co-authored by Monash University Professor Paul Zimmet AO, from the Department of Diabetes. He is also an Honorary President of the International Diabetes Federation and co-chair of a group that has been advising the Federal Minister for Health on the Government’s National Diabetes Strategy, independent of the COVID-19 crisis

Professor Zimmet says the data highlights the real dangers COVID-19 poses to people with diabetes, as they are more susceptible to developing severe pneumonia and a septic course.

He says the study is important because it draws together what is currently known across the world about the impact of COVID-19 on people with diabetes and the increased risks they face given that this pandemic is very recent.

“Evidence from epidemiological observations in regions heavily affected by COVID-19and reports from the Centres for Disease Control (CDC) and other national health centres and hospitals showed the risk of a fatal outcome from COVID-19 is up to 50 percent higher in patients with diabetes than in those who do not have diabetes,” the study says.

Professor Zimmet said that most of the emphasis on this review focussed on people with type 2 diabetes. Most of the current information so far focusses on this older group.

He noted the risk from COVID-19 in young people with type 1 diabetes appears to be much less. Providing they have access to satisfactory health care and good control of their diabetes, he said that parents of children and adolescents with type 1 diabetes should be reassured on this issue.

The report noted that “damage to pancreatic β cells (the cells that make insulin) may lead to direct damage to the function of the pancreas.”

“Although this has not been verified in humans, they suggest that diabetes might not only be a risk factor for a severe form of COVID-19 disease, but also that infection could result in causing new onset diabetes,” the review says.

“Potential pancreas β cell damage caused by the virus leading to insulin deficiency is supported by the observation of Italian colleagues and the co-authors of these recommendations who have reported frequent cases of severe diabetic ketoacidosis (DKA) at the time of hospital admission.”

Professor Zimmet said the review proposed implementing testing for diabetes in people with the COVID-19 infection to identify if previously healthy individuals have developed diabetes as a result of contracting the virus.

“We should consider everyone who gets sick with COVID-19 is also tested for diabetes. They should be tested at the time they become ill as it clearly will influence their medical management and health outcome,” he said.

According to the study, patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multiple organ failure, including lung, heart and kidney.

Professor Zimmet said there should also be a warning to health professionals with diabetes who are engaged in care of COVID-19 patients to ensure they have the protection they need to prevent contracting the virus.

He said the consensus group noted some sub-groups of people with diabetes may also require specific attention. They include:

  • Persons with poor metabolic (blood sugar) control of their diabetes.
  • Diabetes with complications, and overall, there is a high risk of kidney failure in those critically ill with COVID-19 infection.
  • A significant number of persons with type 2 diabetes are obese and this may cauise problems in management.
  • Management of persons with diabetes who have had bariatric surgery for obesity will require special attention.
  • Persons who have had transplantations of the pancreas and kidneys, or are on regular dialysis.
  • Those on immunosuppressive therapy for other disorders, and/or on cortisone.
  • Those on certain diabetes medications which may affect progress if they are very ill.
  • Most patients with type 2 diabetes have other components of the metabolic syndrome including hypertension and high blood lipid (fats). Therefore, continuation with an appropriate antihypertensive and lipid-lowering regimen in all these patients is of crucial importance.

Association between COVID-19 and Diabetes

Diabetes and Infection: General Considerations and Potential Mechanisms

Diabetes is one of the leading causes of morbidity and mortality throughout the world. The condition is associated with several macrovascular and microvascular complications, that ultimately impact the overall patient’s survival [30]. A relationship between diabetes and infection has long been clinically recognized [31].

Infections, particularly influenza and pneumonia, are often common and more serious in older people with type 2 diabetes mellitus (T2DM) [32], [33]. Nevertheless, the evidence remains controversial regarding whether diabetes itself indeed increases susceptibility and impacts outcomes from infections, or the cardiovascular and renal comorbidities that are frequently associated with diabetes are the main factors involved [34].

Diabetes and uncontrolled glycaemia were reported as significant predictors of severity and deaths in patients infected with different viruses, including the 2009 pandemic influenza A (H1N1) [35], SARS-CoV [36] and MERS-CoV [37]. In the current SARS-CoV-2 pandemic, some studies did not find a clear association between diabetes and severe disease [19], [38]. However, other reports from China [7], [20] and Italy [29] showed that older patients with chronic diseases, including diabetes, were at higher risk for severe COVID-19 and mortality.

Scarce data exist regarding glucose metabolism and development of acute complications of diabetes (e.g., ketoacidosis) in patients with COVID-19. Infection of SARS-CoV-2 in those with diabetes possibly triggers higher stress conditions, with greater release of hyperglycemic hormones, e.g., glucocorticoids and catecholamines, leading to increased blood glucose levels and abnormal glucose variability [39].

On the other hand, 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) [40]. Hypoglycemia has been shown to mobilize pro-inflammatory monocytes and increase platelet reactivity, contributing to a higher cardiovascular mortality in patients with diabetes [41].

Yet it remains largely unknown how exactly the inflammatory and immune response occurs in these patients, as well as whether hyper- or hypoglycemia may alter the SARS-CoV-2 virulence, or the virus itself interferes with insulin secretion or glycemic control. Furthermore, the impact of usual diabetes drug treatment on COVID-19 outcomes, as well as therapeutic approaches for COVID-19 on glucose regulation remains unspecified.

Diabetes is a chronic inflammatory condition characterized by multiple metabolic and vascular abnormalities that can affect our response to pathogens [34]. Hyperglycemia and insulin resistance promote increased synthesis of glycosylation end products (AGEs) and pro-inflammatory cytokines, oxidative stress, in addition to stimulating the production of adhesion molecules that mediate tissue inflammation [34], [42]. This inflammatory process may compose the underlying mechanism that leads to a higher propensity to infections, with worse outcomes thereof in patients with diabetes [34].

Several defects in immunity have been associated with hyperglycemia, even though the clinical relevance of some in vitro disturbances are still not fully understood [43]. Poorly controlled diabetes has been linked to inhibited lymphocyte proliferative response to different kinds of stimuli [44], as well as impaired monocyte/macrophage and neutrophil functions [34].

Abnormal delayed type hypersensitivity reaction [43] and complement activation dysfunction [45] have also been described in patients with diabetes. In vitro studies have shown that pulmonary epithelial cells exposure to high glucose concentrations significantly increases influenza virus infection and replication, indicating that hyperglycemia may enhance viral replication in vivo [46].

In animal models, structural lung changes have been related to diabetes, such as augmented vasculature permeability and collapsed alveolar epithelium [47]. On the other hand, patients with diabetes generally present a significant reduction in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), which is associated with raised plasma glucose levels [48].

Aspects of SARS-CoV-2 Pathogenesis and Potential Implications for Clinical Management of Patients with COVID-19 and Diabetes

Patients with COVID-19 commonly show on admission lymphocytopenia, and to a lesser extent thrombocytopenia and leukopenia, which are more prominent among those with severe disease [7].

Further, elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and C-reactive protein, as well as increased coagulation activity, marked by higher d-dimer concentrations, were also associated with severity [7], [26]. In T2DM, besides the marked inflammatory process previously discussed, an imbalance between coagulation and fibrinolysis takes place, with increased levels of clotting factors and relative inhibition of the fibrinolytic system.

Both insulin resistance and T2DM are associated with endothelial dysfunction, and enhanced platelet aggregation and activation. These abnormalities favor the development of a hypercoagulable pro-thrombotic state [49]. Additionally, atherosclerosis, vascular inflammation and endothelial dysfunction are also part of the pathogenesis of other chronic conditions, e.g., hypertension and CVDs [42].

Animal studies involving SARS-CoV reported that older age was related to defects in T-cell and B-cell function and excess inflammation markers. Thus, T2DM alone or in association with older age, hypertension and/or CVDs might contribute to a deficient control of SARS-CoV-2 replication and more prolonged proinflammatory response, potentially leading to poor outcomes [26].

Viral entry into the host cells is a fundamental component of cross-species transmission, particularly for the coronaviruses (CoVs). Upon exposure of the host to the virus, all CoVs, through a Spike protein, bind to cells that express specific receptors. After binding to the target cells, the host-cell protease cleaves the spike, which allows the virus to enter and replicate [50].

The angiotensin-converting enzyme 2 (ACE2) has been identified as one of the main receptors for both SARS-CoV [51] and SARS-CoV-2 [50]. ACE2 is widely expressed on the respiratory tract, heart, kidneys, intestines, cerebral neurons, endothelium of arteries and veins, immune cells and pancreas [2].

A Chinese study compared 39 SARS-CoV patients without previous diabetes, who did not receive steroid treatment, with 39 matched healthy siblings and showed that 20 of the 39 SARS-CoV patients developed diabetes during hospitalization. Since immunostaining for ACE2 was strong in the pancreatic islets, it was suggested that SARS-CoV might have damaged islets and caused acute insulin dependent diabetes mellitus [52]. Therefore, although further evidence is needed, pancreatic damage may also be present in COVID-19 patients, possibly contributing to worse outcomes in subjects with diabetes.

Previous studies have reported decreased mortality and endotracheal intubation in patients with viral pneumonia who were in continued use of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [53], [54]. These medications are postulated to have significant immunomodulatory effects [55] and reduce pulmonary and systemic inflammatory response by decreasing cytokines [53], [54].

They are commonly used by those with diabetes and hypertension [56], therefore, their impact on the clinical course of COVID-19 has been widely debated. Considering that ACE2 is a functional receptor for SARS-CoV-2 and its levels can be increased by ACE inhibitors and ARBs, it has been argued that these drugs might affect negatively the outcome of COVID-19 patients [57].

On the contrary, some have advocated that ACEIs and ARBs might rather be beneficial [58]. SARS-CoV infection and the virus Spike protein reduce ACE2 expression. Mice injected with SARS-CoV Spike presented worsened acute lung failure, which could be attenuated by blocking the renin-angiotensin pathway [59].

Nevertheless, a retrospective analysis performed on 112 patients with COVID-19 and CVD did not show a significant difference in the proportion of ACEI/ARB medication between survivors and non-survivors [60]. Similar to ACEIs and ARBs, ibuprofen [61] and thiazolidinediones [62] can also result in increased levels of ACE2, thus generating questions regarding the safety of these drugs in patients with COVID-19.

Although diabetes has been associated with worse outcomes in COVID-19 patients, the susceptibility to SARS-CoV-2 infection may not be higher in people with diabetes. According to several studies, the prevalence of diabetes in people infected with the virus is about the same as in the general population, even slightly lower [28], [63].

A meta-analysis of 12 studies describing data from 2,108 Chinese patients with COVID-19 reported a diabetes prevalence of 10.3% [63], which was similar to the national prevalence of 10.9% reported in 2013 [64]. An Italian study conducted among 146 patients with confirmed SARS-CoV-2 infection at the University Hospital of Padova found an equivalent pattern.

The prevalence of diabetes in these patients was 8.9% (mean age 65.3 years), while it was 11.0% among people aged 55-75 years (mean age 65 years) from the same region in 2018 [65]. Although underreporting may be an issue to consider, potential biological mechanisms should not be disregarded.

It has been shown that dipeptidyl peptidase-4 (DPP-4) is the primary receptor of MERS-CoV [2]. Since DPP-4 inhibitors are commonly applied in the treatment of diabetes worldwide, future research should explore whether DPP-4 may also act as receptor for SARS-CoV-2, thus contributing to a potential protective effect of these drugs against COVID-19 [63], [66].

So far, no anti-SARS-CoV-2 drug or vaccine has been officially approved for COVID-19 treatment [67]. Several clinical trials are in progress to assess the safety and efficacy of potential treatment alternatives, including remdesivir, tocilizumab, lopinavir/ritonavir, ribavirin, interferon, chloroquine phosphate, arbidol, among others [68].

One promising pharmacological option of relevance for patients with diabetes is chloroquine and its hydroxy-analogue hydroxychloroquine. Widely used for malaria and autoimmune diseases, chloroquine has also been reported as a potential broad-spectrum antiviral drug. Although the efficacy and safety of chloroquine for COVID-19 treatment remain unclear, a recent study showed that the drug was highly effective in controlling SARS-CoV-2 infection in vitro.

In addition to its immunomodulant and anti-inflammatory effect, chloroquine increases endosomal pH and interferes with the glycosylation of cellular receptors of SARS-CoV, thereby blocking viral infection [69].

Preliminary results from more than 100 patients included in a Chinese clinical trial showed that chloroquine was superior to the control group in shortening the disease course, inhibiting pneumonia exacerbation, promoting a virus negative conversion and radiological improvement without severe side effects [70].

On the other hand, several studies have reported that hydroxychloroquine improves glycemic control in decompensated, treatment-refractory patients with diabetes [71], [72]. It has even been approved to treat T2DM in India as an add-on therapy for patients who do not achieve glycemic targets with two other oral glucose-lowering drugs [73].

Although inflammation is associated with impaired glucose control, the underlying mechanism of hydroxychloroquine’s hypoglycemic effect remains unclear [71].

It has been described that chloroquine increases the C peptide response, potentially reflecting an improved pancreatic β-cell function [72]. Reduced intracellular insulin degradation and increased insulin accumulation have also been identified as possible effects of hydroxychloroquine in animals models [74].

Given the previously reported impact of chloroquine/hydroxychloroquine on glucose metabolism, caution should be taken when the drug is administered to patients with diabetes and COVID-19. A dose adjustment of the oral antidiabetic drugs and/or insulin might be necessary in order to prevent potential hypoglycemic events.

The effect of corticosteroids on COVID-19 is also under investigation [68]. Acute lung damage and ARDS are partly due to the host immune response. While corticosteroids suppress lung inflammation, they also inhibit immunity and pathogen clearance [75]. In SARS-CoV and MERS-CoV infections, pulmonary histology showed inflammation and diffuse alveolar damage [76].

Therefore, corticosteroids were broadly applied [77], [78]. However, evidence did not show benefits, rather it was reported delayed viral RNA clearance or increased mortality and rate of complications, including diabetes, psychosis, and avascular necrosis [75]. The interim guidance from the WHO on clinical management of severe acute respiratory infection when SARS-CoV-2 infection is suspected advises against the use of corticosteroids outside clinical trials [79].

Considering the hyperglycemic effect [80] and the impact of these drugs on the immune response [75], special caution should be taken in patients with diabetes included in trials assessing the safety and efficacy of corticosteroids for COVID-19 [80].

No data is available regarding the most appropriate management of patients with diabetes infected by SARS-CoV-2, as well as patients with COVID-19 who develop glycemic decompensation. Rigorous glucose monitoring and careful consideration of drug interactions might attenuate worsening of symptoms and adverse outcomes.

Although hyperglycemia is usually the main concern in this context, one should not disregard the possibility of hypoglycemic episodes as a result of the interplay between drug treatment, viral pathogenesis and typical metabolic disturbances of diabetes.

Patient tailored therapeutic strategies and optimal glucose control goals should be formulated based on disease severity, presence of comorbidities and diabetes-related complications, age and other factors. A multidisciplinary team approach, including infectologists, endocrinologists, pulmonologists, psychologists, nutritionists and exercise rehabilitation specialists may be necessary during the prolonged hospitalization periods and recovery.

Special attention should be paid to those with diabetic nephropathy, or diabetes-related heart complications, since they are also at higher risk for severe COVID-19 and death [7], [19]. Finally, increased vigilance and testing in outpatient diabetes clinics for COVID-19, as well as lower thresholds for hospitalization of these patients may have a positive impact on their outcomes.

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Monash University

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