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

In a recent review published in Metabolism of natureresearchers investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can accelerate or initiate the development of diabetes mellitus (DM).

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

Recent studies have reported an increased risk of DM after coronary disease 2019 (COVID-19); however, the causal relationship and underlying biological mechanisms have not been well characterized. Persistence of elevated glucose levels after COVID-19 has receded, and probable SARS-CoV-2 infections in non-pancreatic tissues have added a new dimension to the complexity of deciphering the true relationship between diabetes and COVID-19.

About the review

In this review, researchers assessed the relationship between COVID-19 and diabetes.

Epidemiological and clinical evidence of diabetes and COVID-19

Many studies have reported an increased risk of DM type 1 (T1D) and (T2D) after SARS-CoV-2 infections. However, for T1D, epidemiological studies have reported controversial results.

On the contrary, surveys using electronic medical records have shown an increased risk of DM ≤12 weeks after SARS-CoV-2 infection, and affected subjects were more likely to receive insulin prescriptions <91 degi eftir að þeir greindust með SARS-CoV -2 sýkingar með of mikilli heilsubyrði af nýkominni DM og blóðsykurshækkun (þar sem >77% of patients had T2D) after one year of follow-up.

Among small cohorts, glycemic control was reported to improve in 63% to 79% of COVID-19 patients at six months after recovery and in 41% to 79% of COVID-19 patients at 10.0 months after recovery. Conversely, high sugar levels remained in ≤56% of patients. Hospitalized SARS-CoV-2-positive patients with dysregulated glucose levels during acute COVID-19 have shown glycemic control back to physiologically acceptable levels seven months after the acute COVID-19 episode.

Thus, hypoglycemia could be a likely factor in PASC (post-acute sequelae of COVID-19). However, the diabetogenic effect of COVID-19 may not be a direct result as hyperglycemia has been reported after non-COVID ARDS (acute respiratory distress syndrome), likely due to systemic inflammation. Nevertheless, the development of incident T2D and insulin resistance in the PASC phase suggests that COVID-19 may exacerbate β-cell exhaustion in high-risk individuals.

Of note, breakthrough infections after COVID-19 vaccination did not significantly reduce the incidence of DM; However, the reduced risk of insulin use suggests amelioration of COVID-19 severity and metabolic dysfunction by the presence of SARS-CoV-2 immunity.

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

Many studies have confirmed the presence of classical viral entry factors, ACE2 and TMPRSS2, in pancreatic β-cells. Moreover, Neurolipin-1 (ACE2-enhancing factor) expression is indicative of additional pathways for viral entry in pancreatic β-cells. Susceptibility of the pancreatic microvasculature and pancreatic pancreatic cells to viral infection may aid in the spread of the virus to the pancreatic endocrine cells. However, the virus can cause pancreatitis-related metabolic changes.

Studies have confirmed β-cell infection among deceased COVID-19 individuals, resulting in reduced expression of insulin production and release-related genes. Specifically, COVID-19 has been associated with degranulation, impairment of glucose-stimulated insulin secretion, trans- or de-differentiation, and apoptosis. In addition, the results of a recent study showed that a significant fraction of islet cells transform into apoptotic-like cells during the progression of T2D, suggesting that pathological islet plasticity may be an underlying reason for β-cell failure among T2D patients.

The mechanism of action of glucose metabolism disorders in organs other than the pancreas

Direct infection of pancreatic β-cells could result in reduced insulin granules, reduced endocrine activity, and reduced de- or trans-differentiation. Adipose tissue infection with SARS-CoV-2 reduces adiponectin release and thereby decreases insulin sensitivity. Infection of hepatocytes promotes glucogenic secretion of GP73 and therefore stimulates gluconeogenesis. β-cell exhaustion also occurs due to insulin resistance, gluconeogenesis, and direct β-cell damage.

Studies have reported that mature adipocytes supported the replication of SARS-CoV-2, and the viral proteins have been identified in adipocytes among 56.0% of COVID-19 deceased male subjects. It is noteworthy that SARS-CoV-2 material has only been detected among men who were obese. Adiponectin has shown insulin-sensitizing properties, and therefore adiponectin deficiency could increase generalized insulin resistance, according to the results of SARS-CoV-2-positive patients with elevated and decreased levels of C-peptide and adiponectin, respectively.

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

The review’s findings highlighted the bidirectional relationship between COVID-19 and diabetes. DM is a common comorbidity associated with the severity of COVID-19 but may be a direct consequence of the SARS-CoV-2 infection. It is necessary to fully understand the biological pathways and conduct population-level and longitudinal studies to facilitate the development and use of targeted COVID-19 interventions and reduce the associated health burden during the pandemic.

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