What is the association between diabetes and SARS-CoV-2 infections?

In a recent review published in Nature Metabolism, researchers explored whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can expedite or trigger the development of diabetes mellitus (DM).

Study: COVID-19 and diabetes — where are we now? Image Credit: Andrey_Popov/Shutterstock
Study: COVID-19 and diabetes — where are we now? Image Credit: Andrey_Popov/Shutterstock

Recent studies have reported an elevated risk of incident DM after coronavirus disease 2019 (COVID-19); however, a causal association and the underlying biological mechanisms have not been well-characterized. The continuation of elevated glucose levels after COVID-19 has regressed, and probable non-pancreatic tissue SARS-CoV-2 infections have added a new dimension to the complexity of deciphering the true link between diabetes and COVID-19.

About the review

In the present review, researchers assessed the association between COVID-19 and diabetes.

Epidemiological and clinical evidence of diabetes and COVID-19

Multiple studies have reported an elevated risk of incident DM of type 1 (T1D) and (T2D) following SARS-CoV-2 infections. However, for T1D, epidemiological studies have reported controversial findings.

On the contrary, surveys utilizing electronic health records have documented a heightened risk of incident DM ≤12 weeks after SARS-CoV-2 infection, and the affected individuals were more likely to receive insulin prescriptions in <91 days of being diagnosed with SARS-CoV-2 infections with an excess health burden of new-onset DM and hyperglycemia (wherein >77% of patients had T2D) after a year of follow-up.

Among a few cohorts, glycaemic control was reported to improve in 63% to 79% of COVID-19 patients six months post-recovery and in 41% to 79% of COVID-19 patients 10.0 months post-recovery. In contrast, high sugar levels persisted in ≤56% of patients. Hospitalized SARS-CoV-2-positive patients having dysregulated glucose levels in acute COVID-19 have shown glycaemic control reversion to physiologically permitted levels seven months after the acute COVID-19 period.

Thus, dysglycaemia might represent a probable aspect of PASC (post-acute sequelae of COVID-19). However, the diabetogenic effects of COVID-19 may not be direct results since hyperglycemia has been reported post-non-COVID ARDS (acute respiratory distress syndrome), probably due to generalized inflammation. Nevertheless, the development of incident T2D and insulin resistance in the PASC phase indicates that COVID-19 could potentiate β cell exhaustion in high-risk individuals.  

Of note, breakthrough infections post-COVID-19 vaccinations did not significantly reduce DM incidence; however, a lesser risk of insulin usage indicates amelioration of COVID-19 severity and of metabolic dysfunction by pre-existing anti-SARS-CoV-2 immunity.

SARS-CoV-2 infection of pancreatic beta (β)-cells

Multiple studies have documented the presence of the classical viral entry factors, ACE2 and TMPRSS2, in pancreatic β cells. In addition, Neurolipin-1 (ACE2-potentiating factor) expression is indicative of additional routes for viral entry in pancreatic β cells. Susceptibility of the pancreatic microvasculature and exocrine pancreatic cells for viral infections could assist in disseminating the virus to pancreatic endocrine cells. Still, the virus may cause pancreatic inflammation-associated metabolic changes.

Studies have documented β cell infection among deceased COVID-19 individuals, resulting in lowered expression of insulin production- and release-associated genes. Specifically, COVID-19 has been associated with degranulation, impairments in the glucose-stimulated secretion of insulin, trans- or de-differentiation, and cell death. Moreover, findings of a recent study showed that a sizeable fraction of islet cells transform into exocrine-like cells during T2D progression, which indicates that pathological islet plasticity may be the underlying reason for β-cell failure among T2D patients.

Mechanisms of glucose metabolism dysregulation in organs other than the pancreas

Direct infection of β cells of the pancreas could result in lower insulin granularity, lesser endocrinal functionality, and lower in de- or trans-differentiation. Adipocyte tissue infection with SARS-CoV-2 decreases adiponectin release, thereby lowering insulin sensitivity. Infection of hepatocytes promotes glucogenic GP73 secretion, therefore, stimulating gluconeogenesis. β-cell exhaustion also occurs due to insulin desensitization, gluconeogenesis, and direct β cell injury.

Studies have reported that mature adipocytes supported SARS-CoV-2 replication, and the viral proteins have been identified in adipocytes among 56.0% of COVID-19 deceased male individuals. Of note, SARS-CoV-2 material has only been identified among males who were obese. Adiponectin has demonstrated insulin-sensitizing features, and therefore, lack of adiponectin could increase generalized resistance to insulin, per the findings of SARS-CoV-2-positive patients with elevated and reduced concentrations of C-peptides and adiponectin, respectively.

Hepatocyte infection with SARS-CoV-2 has been reported to increase glucogenic GP73 activity and promote gluconeogenesis. Conversely, SARS-CoV-2-positive patients have reported high serum GP73 levels in correlation with the glucose levels in the blood.

The review findings highlighted the bidirectional relationship between COVID-19 and diabetes mellitus. DM is a common comorbidity linked to COVID-19 severity but may be a direct consequence of the SARS-CoV-2 infection. It is essential to completely understand the biological pathways and conduct population-level and long-term studies to facilitate the development and use of targeted COVID-19 interventions and decrease the associated health burden during the pandemic.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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