Researchers have found that patients infected with COVID-19 suffer from many diseases, disabilities and symptoms. New research published on March 16, 2022, in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]), suggests a possible association between mild COVID-19 cases and subsequently diagnosed type 2 diabetes.

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Impact of COVID-19 on the pancreas

COVID-19 can have an adverse impact on all organs. For instance, pancreas cells become a target of severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2). Following SARS-CoV-2 infections, researchers have observed reduced numbers of insulin secretory granules in beta cells and impaired glucose-stimulated insulin secretion. SARS-CoV-2 may trigger pro-inflammatory cytokines and damage beta cells.

Researchers noted that pro-inflammatory pathways leading to chronic low-grade inflammation in adipose tissue play an important role in causing insulin resistance and type 2 diabetes. Previous studies confirm that inflammation caused by SARS-CoV‑2 may damage insulin-producing beta cells, causing them to die or change how they work, resulting in acute hyperglycaemia (high blood glucose).

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Tissues less reactive to insulin

The researchers clarified:

"Tissues becoming less reactive to insulin due to inflammation in the body is also thought to be a possible cause. Sedentary lifestyles brought on by lockdowns could also be playing a role. This may explain why new-onset hyperglycaemia and insulin resistance have been reported in COVID-19 patients with no prior history of diabetes." 

In the present study, the researchers investigated diabetes incidence after COVID-19 in individuals with the most mild disease treated in primary care. They selected individuals with Acute Upper Respiratory tract Infections (AURI), which are also frequently caused by viruses (e.g. rhinoviruses), as a non-exposed control group.

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Methods

In order to gather more evidence, the researchers analysed electronic health records from the Disease Analyzer (DA) database, which included information on 8.8 million adults who visited 1,171 general and internal medicine practices across Germany between March 2020 and January 2021. This included 35,865 patients who were diagnosed with COVID-19.

1. The Disease Analyzer(DA) is a computerised healthcare database that comprises a representative panel of physicians’ practices in Germany.
2. The DA assembles drug prescriptions, diagnoses, and basic medical and demographic data directly obtained from the practices’ computer systems.
3. The researchers have shown that the database gives valid estimates of the incidence and prevalence of type 2 diabetes, as well as for other chronic diseases.
4. The researchers knew that earlier studies have observed reduced numbers of insulin secretory granules in beta cells and impaired glucose-stimulated insulin secretion after COVID-19 virus infection. However, there was a lack of studies on the incidence of diabetes after recovery from COVID-19 in mild cases.

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Findings

Researchers concluded this (verbatim):

1. Individuals with COVID-19 showed an increased Type 2 diabetes incidence compared with patients with AURI.
2. An incidence rate ratio for type 2 diabetes of 1.28 (95% CI of 1.05,1.57) was estimated after COVID-19 compared with individuals with AURI.
3. There was no increased rate ratio for other forms of unspecified diabetes.

The researchers recommended that if confirmed, these results support active monitoring of dysregulation after recovery from a mild form of SARS-CoV-2 infection.

According to the lead author, Professor Wolfgang Rathmann, COVID-19 infection may lead to diabetes by up-regulation of the immune system after remission, which may induce pancreatic beta-cell dysfunction and insulin resistance, or patients may have been at risk for developing diabetes due to having obesity or pre-diabetes, and the stress COVID-19 put on their bodies speeded it up.

The co-author Professor Oliver Kuss, added:

“The risk of abnormally high blood sugar in individuals with COVID-19 is most likely a continuum, depending on risk factors such as injury to beta cells, an exaggerated inflammatory response, and changes in pandemic-related weight gain and decreased physical activity.”

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Short follow up

Prof Rathmann revealed that since the COVID-19 patients were only followed for about three months, further follow-up is needed to understand whether type 2 diabetes after mild COVID-19 is just temporary and can be reversed after they have fully recovered, or whether it leads to a chronic condition.

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Experts' comments

In a press release from Science Media Centre, London, published on 16 March, Dr Betty Raman, senior clinical research fellow in the Radcliffe Department of Medicine, University of Oxford agreed that this is an important paper and is in keeping with other evidence suggesting a rising incidence of diabetes and cardiovascular disease after COVID-19. According to her, the strengths of the study are that the researchers included large numbers of patients and the use of a viral infection control group.

Dr Betty Raman clarified:

"The limitations are the retrospective nature that uses electronic medical health records. There is a potential for increased vigilance and testing due to a heightened awareness of the risks associated with COVID-19 and hence an associated tendency for increased diagnosis. Also as the author states, the persistent inflammatory state may have unmasked an inherent tendency in some people to develop diabetes and whether this will improve over time is currently unknown."

She confirmed that the press release accurately reflects the science; it is good quality research and the conclusions are backed up by solid data.

She revealed that the researchers used propensity score matching and so both groups are reasonably well matched, but it is possible that there is residual confounding which was not captured by electronic health records. It is unclear if this risk will still be seen in a vaccinated population infected with newer variants as the researchers conducted this study on data collected from March 2020-Jan 2021

Dr Betty Raman noted that these are important findings with huge implications given that nearly half a billion people globally have been affected by SARS-CoV-2 infection.

There are some caveats. This analysis was carried out for patients with a diagnosis of COVID-19 from March 2020 to Jan 2021 (so Wuhan and Kent variant) and pre-vaccine. It is hard to know if these results can be extrapolated to patients infected with milder variants and those who have been vaccinated.

To the question, does this study convincingly suggest there are higher rates of newly diagnosed type 2 diabetes after infection with mild COVID-19? She cautioned:

“There is a strong signal seen, but further validation of these findings in an external cohort is needed.”

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Critical remarks

While accepting that this study is interesting Prof Naveed Sattar, Professor of Metabolic Medicine, University of Glasgow cautioned that it is perhaps too premature to say that it is robust science as the study is still quite small and the findings remain marginal. This means any unaccounted for factor could have led to the results rather than there being a true link between COVID-19 and diabetes risk.

“For example, we know that people who developed more severe COVID-19 disease were heavier than those who would normally be admitted with pneumonia and whilst the authors appear to have adjusted for obesity rather than continuously measured BMI, there may be things still unaccounted for that could have impacted the results. The authors themselves realise their work is preliminary. Larger datasets are needed to test this important question.” he warned.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in some of its Technical and Advisory Committees.