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Why are diabetics at high risk of suffering particularly severe responses to viruses such as SARS-CoV-2 which causes COVID-19?

What is Type 2 Diabetes mellitus?

Diabetes is a chronic disease that affects more than 415 million people worldwide which represents 1 in 11 adults aged 20–79 years (1,2). 90% of these individuals have ‘type 2’ diabetes. The main driver of this type of diabetes is a persistent uncontrolled rise of glucose (sugar) concentration in the blood as a result of energy-dense diets (high fat, high sugar diet), lack of exercise as well as genetic and other environmental factors.

In non-diabetic individuals, the hyperglycaemia (high concentration of glucose in the blood) is detected by cells in the pancreas which release a hormone called insulin that allows the excess glucose to be stored in cells. However in diabetes, the high blood sugar levels becomes habitual, the cells are desensitized to insulin and are no longer able to store the excess glucose. This leads to a persistent hyperglycaemic condition which can have wide-ranging and severe consequences. Indeed, compared with people who do not have diabetes, patients with type 2 diabetes have a 15% increased risk of all-cause mortality, with many deaths occurring in individuals under the age of 70 years (1,2).

What are the consequences of hyperglycaemia?

Chronic diabetes and the hyperglycaemia, or high blood sugar, that this causes mostly affects the cardiovascular system which includes the heart and blood vessels that are responsible for distributing blood, oxygen and nutrients throughout the body. Therefore, diabetic people often have a high risk of developing heart disease, stroke and microvascular damage of the eyes, kidney, brain and limbs (2,3). Hyperglycaemia also affects the defence mechanism of the body (immune system) and highly increases the risk of contracting bacterial infections (4), but we don’t fully understand why yet.

Since the H1N1 swine flu epidemic in 2009, people with diabetes have been highlighted as a particularly susceptible group for severe viral infections. This means that in many studies, people with diabetes had a higher risk of being hospitalised, admitted to an intensive care unit and even having a fatal outcome after viral infections than non-diabetic people (4). Several studies have now also highlighted diabetic people as a major risk group for having severe COVID-19 disease which is caused by the virus SARS-CoV-2. Severe COVID-19 can require ventilation which can lead to multiple organ failure and death (5).

How does hyperglycaemia impact responses to viruses?

It is however sometimes challenging to draw conclusions from such statistical studies. This is in part because many diabetic patients also have other conditions such as cardiovascular diseases and obesity which are independently described as risk factors for suffering severe viral infections. Therefore we need to supplement these statistical community-based studies by performing experiments under very controlled conditions in the laboratory to directly assess how glucose concentrations can impact responses to viruses. This is exactly what one group did in 2013 when they showed that increasing glucose concentrations directly enhanced the multiplication of the Influenza A (flu) virus (viral replication) in the infected lung cells (6). These results suggest that hyperglycaemia can directly affect levels of infection which may explain why people with diabetes have this increased risk of severe responses to infections.

Given the ongoing COVID-19 pandemic and need to expand upon existing studies to better understand the impact of diabetes and hyperglycaemia on the ability of the body to fight infections, SARS-CoV2 virus is a good model to choose.

A new study suggesting that high sugar levels may increase SARS-CoV-2 viral replication and drive detrimental inflammation

If we can understand why patients with uncontrolled diabetes are at a greater risk of particularly severe COVID-19, then we can hopefully develop new drugs to improve the prognosis for these individuals. In a study recently published online but not yet reviewed by independent experts in the field, the lab of Moraes-Vieira in Brazil investigated the link between glucose and SARS-CoV-2 infection (7).

The authors focused on a specific type of an immune cell called a monocyte because it is known to be enriched in the lungs of patients with COVID-19. They isolated these immune cells from the blood of healthy volunteers and infected these cells with the SARS-CoV-2 virus in the laboratory. To artificially mimic hyperglycaemia they added glucose to the monocytes and observed that the amount of virus detected was increased, suggesting that glucose is encouraging viral replication. The authors suggest that monocytes activated by a high amount of sugar might be responsible for the subsequent damage and killing of cells in the lung. Specifically, the authors found that the more active monocytes could damage the cells that line the lung and diminish the immune response. This could explain why diabetic patients with COVID-19 present with severe lung damage that requires ventilation and intensive care. Finally, the authors describe the mechanism by which glucose impacts monocyte activation and propose that the use of drugs to block this process may help treat severe COVID-19 in both individuals with and without diabetes.

In summary, this recent publication suggests that high glucose levels such as those found in diabetic patients may drive higher viral replication and increased inflammation (termed “cytokine storm”), which worsens COVID-19. Greater insight into which specific molecules are involved in this process will hopefully aid the development of new targeted treatments. Further research is however needed to confirm these findings using cells isolated from the lungs rather than the blood, and to look more broadly at the impact of any proposed drugs and potentially side effects.

Original paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3606770

Oximmuno summary for researchers: https://www.nature.com/articles/s41577-020-0368-4

These summaries were created by the OxImmuno Literature initiative and are simplified views which are meant to help to explain the concept/ideas behind the research papers and not every single detail.  They should not be considered as an endorsement or otherwise of the research.  For more information on the initiative and its work please see our first blog post 

 

Key references:

  1. https://www.who.int/news-room/fact-sheets/detail/diabetes  
  2. https://doi.org/10.1016/S0140-6736(17)30058-2
  3. https://www.nature.com/articles/nrendo.2017.151
  4. https://www.frontiersin.org/articles/10.3389/fmicb.2017.00861/full
  5. https://www.sciencedirect.com/science/article/pii/S1550413120302382
  6. https://doi.org/10.1016/j.virol.2013.06.026
  7. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3606770