By sorting the correlation scores of DPP4 related proteins, we found that GCG, INS and GLP1R had the highest correlation scores, which were more than 0.8, and GCG and INS were more than 0.9, which meant that DPP4 was most closely related to the above diabetes related proteins. By cluster analysis, three functional modules were found. Module 1 was mainly involved in insulin secretion and glucagon signal transduction pathway including DPP4, while module 2 and module 3 were involved in signaling receptor binding. The binding of S protein of COVID-19 with DPP4 is the starting point of the course of the disease. In order to evaluate the possible influence and pathway of the virus after entering the human body, DPP4 is taken as the starting point of the whole network for in-depth analysis. Because there are a lot of low values in the correlation scores of DPP4 cross module associated proteins, the mean and median are used as the standard to filter the data, and the sum of the correlation scores is used as the score. It was found that LEP and apoB were the highest in module 1. The scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. It is worth noting that DPP4 cross module correlation scores are less than 0.6, so it does not shown. Therefore, the abnormal changes of DPP4 may not play an effect by directly interacting with module associated proteins, but may be that module 1 magnifies its effect, and this effect is transmitted to module 2 and module 3 through the close relationship between module 1 and INS, IL6 and ALB, resulting in the disorder of glucose metabolism and inflammatory regulation.
The data of clinical trials related to COVID-19 show that diabetic patients are more likely to be infected with SAR-COV-2, while the prognosis of patients with diabetes mellitus is worse and the risk of death is higher.[9–10] So, what is the mechanism of susceptibility to SAR-COV-2 in diabetic patients? What is the mechanism of higher risk of death and worse prognosis in patients with diabetes mellitus? How to guide the medication of diabetic patients infected with SAR-COV-2 in clinic? DPP4 as a type II transmembrane protein is also known to be cleaved from the cell membrane involving different metalloproteases in a cell-type-specific manner. Circulating, soluble DPP4 has been identified as a new adipokine, which exerts both para- and endocrine effects. Recently, studies have found that sCD26 serum protein levels are reduced in diabetes. High serum sCD26 level could protect from viral infection by blocking the receptor from virus entry, whereas low sCD26 level may be associated with a higher risk of infection which may be one of the mechanisms of susceptibility to SARS-COV-2 in diabetic patients. The high mortality of patients with COVID-19 are closely related to the disorder of glucose metabolism and inflammation regulation.  The S protein of SARS-COV-2 can invade T, NK and other immune cells through binding receptor DPP4, and activate nuclear factor - κ B (NF - κ b) pathway, resulting in the secretion of a series of pro-inflammatory cytokines, including interleukin-6 (IL-6).  IL-6 can promote the differentiation of T helper cell 17 (Th17) and other lymphocyte changes. Circulating IL-6 and soluble IL-6 receptor complexes indirectly activate many types of cells, including endothelial cells, leading to the proliferation of a series of cytokines, leading to decreased blood pressure and acute respiratory distress syndrome (ARDS). IL-6 plays a key role in this cascade. It suggests that people should evaluate the possibility of IL-6 antagonists (such as tocilizumab, sarilumab and siluximab) in the treatment of severe COVID-19 disease. DPP4 also degrades GLP-1 and GIP and plays an important role in glucose metabolism. Studies have shown that GLP-1-based therapy can reduce the activation of immune cells, inhibit the release of pro-inflammatory cytokines, and reduce organ dysfunction and mortality.  DPP4 inhibitor can increase the half-life of GLP-1 and play an indirect role. DPP4 inhibitors can also resist lung inflammation and reduce lung injury.  These studies suggest that DPP4 inhibitors may play an active role in the treatment of diabetic patients with COVID-19. However, the issue remains controversial. Males believes that DPP4 inhibitors inhibit the immune system and may increase the risk of infection.  However,There are also studies that show that the use of DPP4 inhibitors does not have a negative impact.  Previous retrospective studies have found that DPP4 inhibitors have serious heterogeneity in the treatment effect of COVID-19. [22–28] However, these studies are not randomized controlled double-blind studies. At present, three randomized controlled trials (NCT 04341935、NCT 04371978、NCT04365517)(Retrieved from: https://clinicaltrials.gov/) are ongoing to study the effect of DPP4 inhibitors on the prognosis of COVID-19 and the clinical results are expected to be obtained as soon as possible.
Leptin was the protein with the highest cross module effect in module 1, with a score of 16.071. Leptin is a hormone secreted by adipose tissue. When the body fat is reduced or in a low-energy state (such as starvation), leptin will decrease significantly, thus stimulating the food seeking behavior and reducing its own energy consumption. On the contrary, when the body fat increases, leptin increases, which inhibits eating and accelerates metabolism.  Leptin not only regulates body weight, but also is associated with monocyte activation and severe illness in patients with COVID-19. Overweight patients with COVID-19 tend to have higher leptin levels, which further activates monocytes, leading to amplification or imbalance of immune response, which may also be the mechanism of overweight patients more prone to serious diseases.  CRS is one of the important causes of death in patients with COVID − 19. However, the changes of cytokine profile and the underlying mechanism are still unknown. Using the cytokine array containing 174 cytokines related to inflammation found that the cytokine spectrum of severe patients with COVID-19 was significantly different from that of mild patients or healthy controls. Leptin, CXCL-10, IL-6, IL-10, IL-12, TNF and other cytokines, indicating that these inflammatory factors can predict the severity of COVID − 19 disease. The cluster analysis showed that leptin in module 1 and IL-6, IL-10, TNF in module 2 had a cross model effect, and the highest score of IL-6 was 6.163, which further suggested the possibility of IL-6 antagonists in the treatment of severe COVID-19 disease.
In this paper, we screened out the diabetes related proteins and functional modules closely related to DPP4 through protein interaction network, and analyzed the influence of DPP4 module 1 on the whole protein network and the possible pathway. It was proposed that the influence of COVID-19 infection was amplified by DPP4 in diabetic patients, and through its interaction with INS, leptin, IL-6 and other proteins. Increased glucose metabolism disorder and excessive inflammatory reaction lead to the high mortality in diabetic patients with COVID-19. At present, the data of retrospective observational studies show that the therapeutic effect of DPP4 inhibitors has serious heterogeneity, but the strength of the above studies is low. We look forward to further randomized controlled trials to verify our inference.