The link between severe COVID-19 and diabetes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has spread to almost every country in the world since it emerged in December 2019.

To study: Interrelation between DPP4 2019-nCov receptor and diabetes mellitus targets based on protein interaction network. Image Credit: UGREEN S /

While restrictions on social gatherings and other methods to help reduce the transmission of SARS-CoV-2 have been enacted by most governments, healthcare workers have continued to be frustrated by the lack of information and the availability of effective treatments. As a result, patients with severe COVID-19 have had to rely on mechanical ventilation or supplemental oxygen to improve their condition, rather than treating the infection itself.

Several COVID-19 vaccines have received emergency use authorization from various government agencies around the world. These vaccination regimens, in addition to the development of several specific treatments for COVID-19, have rapidly reduced the number of patients suffering from serious illness. However, due to the novelty of COVID-19, little information remains on how specific comorbidities, such as diabetes, interact with this disease. In general, diabetic patients seem more likely to contract SARS-CoV-2 and succumb to severe forms of this disease than non-diabetic patients.


Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a serine exopeptidase present in dimeric form on the surface of cells. DPP4 is associated with a wide variety of functions in mammals, some of which include regulating the activity of hormones, neuropeptides and cytokines, as well as mediating interactions between cells and the matrix, as well as between cells.

DPP4 is expressed on the surface of various cells and plays an important role in glucose metabolism. Accordingly, DPP4 inhibitors have been widely used to treat patients with diabetes. Specifically, these hypoglycemic drugs antagonize insulin secretion by preventing DPP4 from breaking down glucagon-like peptide-1 (GLP-1), thereby controlling blood sugar and improving both glucose tolerance and resistance to glucose. insulin.

Due to the increased risk of infection and severe consequences of COVID-19 in patients with a history of diabetes, researchers have turned to DPP4 inhibitors for their utility in treating this patient population. In a recent Nature Science Reports study, researchers are further exploring the relationship between DPP4 and diabetes targets in the management of COVID-19.

About the study

In the present study, researchers identified targets by searching the GeneCards database for “diabetes mellitus” and included all targets with a relevance score greater than 20. These targets were then imported into the tool. Search for Interacting Gene/Protein Retrieval (STRING) database to obtain protein-protein interaction map, with all targets directly related to DPP4 reviewed for further research.

STRING was used to perform the gene ontology (GO) function enrichment analysis. Comparatively, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to predict its mechanism of action and construct the network diagram.

Module 1, where DPP4 is located, was used as the internal network, while the inter-module association of the internal network is eliminated to better assess the impact of DPP4 on the network and possible pathways.

Study results

A total of 1031 diabetes mellitus targets and 43 targets directly related to DPP4 were obtained. Three functional modules were obtained by cluster analysis, including 17 nodes in the first module, 14 nodes in the second and 13 nodes in the third module.

Through GO and KEGG analysis, the researchers found that the target of module 1 was mainly enriched in insulin secretion and glucagon signal transfection pathway. Comparatively, the targets of modules 2 and 3 were mainly enriched in binding to signaling receptors.

It was also found that module 1 contained 190 inter-module associations, which accounted for 33% of all observed network associations. In module 1, the LEP and apoB proteins were found to have the highest scores, indicating their likely ability to have cross-module effects. Moreover, INS, IL-6 and ALB in module 1 obtained the highest scores, supporting the hypothesis that this module has an impact on the aforementioned protein interactions.


Several studies have demonstrated that soluble CD26 levels are reduced in the serum of diabetic patients. Therefore, the researchers here hypothesized that higher levels of DPP4 might provide protection against SARS-CoV-2 infection by preventing entry of this virus through DPP4 receptors.

Previous observations have also shown that unregulated glucose metabolism and inflammation may increase mortality risk with COVID-19. Since DPP4 plays an important role in glucose metabolism, the use of DPP4 inhibitors could help reduce the severity of COVID-19 through this pathway, as well as through their proven use in preventing lung inflammation. and reduce lung damage.

By analyzing the functional modules and targets of diabetes associated with DPP4, the researchers concluded that their findings support the hypothesis that COVID-19 alters the expression of DPP4 in diabetic patients through its interactions with the INS, leptin, IL-6 and other proteins. . As a result, disturbances in glucose metabolism and inflammation may occur, thereby increasing the risk of mortality in diabetic patients with COVID-19.

Taken together, the findings from the current study support future study of DPP4 inhibitors in the treatment of COVID-19 in animal models of diabetes. These studies could later serve as the basis for clinical trials of DPP4 inhibitors for the treatment of COVID-19 in diabetics.

Journal reference:

  • Gao, Q., Zhang, W., Li, T. et al. (2022). Interrelation between DPP4 2019-nCov receptor and diabetes mellitus targets based on protein interaction network. Scientific reports. doi: 10.1038/s41598-021-03912-6.
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