It is clear that Diabetes Mellitus, more commonly known as Diabetes, is a risk factor for severe Covid-19 illness, but can the SARS-CoV-2 virus lead to new onset Diabetes? Clinicians are increasingly observing a link between Covid-19 and a rise in Diabetes diagnosis and are keen to understand this relationship. In order to do so, the COVIDIAB Registry has been established by an international group of leading Diabetes researchers to explore the extent and characteristics of new-onset, Covid-19-related diabetes. But what is the evidence and how can it happen?
What is Diabetes Mellitus?
Metabolism is the set of chemical reactions in the body’s cells that change food into energy. Diabetes Mellitus is a disorder of metabolism that causes the body to have too much glucose (sugar) in the bloodstream.
There are a few types of Diabetes, but the two main ones are Type 1 and Type 2. More than 95% of people with Diabetes have Type 2.
There is also a condition now known as ‘pre-Diabetes’ or Borderline Diabetes in which a person’s blood sugar is higher than normal, but not high enough to be diagnosed with Type 2. A person with pre-Diabetes is often asymptomatic, but this condition often leads to developing Type 2 Diabetes, especially if it persists undetected.
Insulin is the main hormone in our bodies that controls the levels of glucose in our blood. It does this by increasing the uptake of glucose into our muscles and adipose (‘fat’) tissues and converting it into a storage form. When insulin is lacking, blood sugar increases above a normal level (Hyperglycaemia), which can lead to tissue damage and dysfunction of the immune and vascular system. Illnesses associated with Diabetes include Coronary Vascular Disease, Hypertension, Chronic Kidney Disease and Infections. Sometimes, Hyperglycaemia can lead to an acute emergency called Diabetic Ketoacidosis, whereby the high level of blood sugar is converted to toxic chemicals called ketones and acids, a build-up of which can be lethal.
Inflammatory Processes in Diabetes
The relationship between the immune system and metabolism is a two-way street in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and Diabetes), and metabolic factors (eg. Insulin and Hyperglycaemia) work to regulate immune cell functions. This relationship is very complex and recently, a new branch of science, Immunometabolism, has evolved out of the need to understand the mechanisms of these systems in disease.
Insulin and glucose can have direct effects on immune cells such as T-cells and Macrophages and immune messengers (cytokines). Cytokines in turn can affect the cells that produce insulin. The effects can be pro-inflammatory or anti-inflammatory, depending on the signalling sequences.
In Diabetes, it is observed that insulin resistance can affect these signals and make it difficult for the correct message to get through. For example, Macrophages are key to initiating an inflammatory response to invading pathogens. However, they have also been shown to develop resistance when they are chronically exposed to high insulin levels. This resistance results in a less effective type of cell, less able to respond to infection. Indeed, patients with Diabetes are known to be more susceptible to particular types of infection, and respiratory tract infections are responsible for a significant number of medical appointments by persons with Diabetes compared to those without. Further, people with Diabetes are six times more likely to need hospitalisation during influenza epidemics than non-diabetic patients, so it stands to reason that the Sars-CoV-2 virus might cause complications for diabetic patients.
To date, it appears that the primary risk of infection with SARS-CoV-2 is not increased in diabetics. However, given the severity of the effects of Covid-19 on diabetic patients, this cohort of people may behave differently (wearing masks, social distancing and isolating more frequently) and hence affect incidence rates. Therefore, this does not necessarily mean that diabetics are less likely to be infected, it just appears that way thus far, and may be down to different behaviour rather than a physiological effect.
Conversely, it is also known that infections can lead to insulin resistance and Diabetes. Infection was initially recognised as a cause for increased insulin resistance almost 80 years ago. It is only recently that studies have emerged to confirm this and to attempt to identify mechanisms.
Can SARS-CoV Infection Cause Diabetes?
It is true that some viral infections can trigger Diabetes, but the mechanisms of this are still not fully understood and there are many other factors that contribute to its development (genetic predisposition, gut health, obesity, viral load, etc.) as well as viral status of the patient.
In terms of Covid-19, investigators have observed links between infection and newly diagnosed Diabetes. The type remains to be determined (Type 1, 2, or some other rarer or unidentified type), as do the mechanisms involved and whether the Hyperglycaemia/Diabetes is transient or permanent. Furthermore, many clinical observations and studies of Covid-19 patients are emerging, demonstrating that Hyperglycaemia and/or Diabetic Ketoacidosis occurs in non-diabetic as well as diabetic hospitalised patients, increasing the incidence of the lack of glucose control in patients, regardless of their diabetic status.
More recently, some studies have compared the onset of Diabetes from Covid-19 against onset of Diabetes from flu (USA) or acute upper respiratory tract infections (AURI)(Germany). Both of these studies demonstrated an increased risk of new onset Diabetes in both mild and moderate-to-severe Covid-19 when compared to their control groups (flu or AURI). Further, in the USA study, the risk was greater for the moderate-to-severe Covid-19 group. In the German study, patients were observed for one year for detecting Diabetes. However, neither study looked at whether these diagnoses were transient or permanent.
In a study conducted during the first SARS outbreak, it was observed that diabetes (no specific type designated) occurred of in 20 of 39 hospitalised patients, but after 3 years of follow-up, only 2 patients had Diabetes, while the other 18 had returned to normal glucose and insulin levels. In a recent study of 594 individuals admitted to hospital with Covid-19 and diabetes, 77 patients (13%) were deemed to have truly new onset diabetes (no known history of pre-diabetes), and follow up of these patients a year later revealed that 40% of these patients reverted back to pre-diabetes or normal glycaemic state. This demonstrates that many patients appear to revert back to normal glucose (or pre-diabetic) levels at some point after Covid-19 illness.
What's the cause?
One way that SARS-CoV-2 infection may lead to DM is through a direct effect on pancreatic ß-cells; the cells in our bodies that produce insulin. Certain receptors occur on pancreatic ß-cells to which SARS-CoV-2 could bind. Once the virus binds to these cells, they can cause cell death either directly, or by causing immune cells to attack the cells containing SARS-CoV-2, thus resulting in a loss of insulin production and ultimately leading to Diabetes. Initial evidence for this possibility comes from a study during the first outbreak where clinicians observed an abundance of ACE2 expression (the main receptor for SARS-CoV) in the pancreatic the ß-cells of patients who died of Covid-19, suggesting that SARS-CoV may bind to the ACE2 receptor, causing damage to ß-cells, potentially leading to Diabetes. Although there is still much debate about the presence and role of the ACE2 receptor in the pancreatic ß-cells, recent autopsy studies demonstrate the presence of ACE2 receptors and SARS-CoV-2 genetic material in pancreatic ß-cells of Covid-19 deceased patients, supporting the theory that SARS-CoV-2 damages these cells, partly through the ACE2 receptor. More work needs to be done to confirm this finding.
Steroid induced Diabetes
Systemic steroid (Dexamethasone, Prednisolone, etc.) use in treating seriously ill Covid-19 patients may also lead to diagnosis with Diabetes. Steroid-induced Hyperglycaemia is common in hospitalised patients, and approximately 40% of patients go on to develop Diabetes. The RECOVERY trial and the UK Government guidelines recommend systemic steroid use for treating only hospitalised patients with severe Covid-19 as a life-saving treatment, and it is possible that this may lead to an uptick in Diabetes diagnoses.
Previously undiagnosed Diabetes
It is certainly possible that many of the patients entering hospital with Covid-19 illness have had previously undiagnosed hyperglycaemia or pre-diabetes. Pre-diabetes glucose levels tend to be asymptomatic and hence individuals with it would be unlikely to visit a doctor for diagnosis, especially during the pandemic as lockdown limited preventative and service-level clinical visits.
Changes in lifestyle during lockdowns (less exercise, poor diets, poor mental health) may have also pushed borderline blood glucose levels over the limit into Diabetes territory. However, this is highly debatable as some studies show improved glycaemic control during lockdown, particularly for Type 1 Diabetes whereas the data for Type 2 Diabetes is more variable.
So, can Covid-19 cause Diabetes?
Well, sort of, but there are also other factors, like genetic pre-disposition and viral loads, that will affect its ability to do so. And this is not novel. Clinicians have known for a long time that other viruses can do this, too. Is it worse than the other viruses at inducing Diabetes? We just don’t know that yet. Very recent data suggests maybe, but if so, only in moderate-to-severe illness. Is the Diabetes permanent? Again, we just don’t know. Data from both SARS CoV-1 and SARS CoV-2 studies suggest that the Hyperglycaemia/Diabetes observed now may ultimately resolve, but only time and continuous observation will tell. The ongoing COVIDIAB Study, taking place at King’s College London, UK and Monash University, Australia should yield some eagerly awaited data. Until then, if you’ve had Covid-19, it might be good to become familiar with the signs of Diabetes, and if you have any concerns, see your doctor.