Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions

Shao, Shiying; Xu, Qinqin; Yu, Xuefeng; Pan, Ruping; Chen, Yong

doi:10.1016/j.pharmthera.2020.107503

Cited by 141 publications

(120 citation statements)

References 184 publications

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“…Future studies are warranted to evaluate the use of Fig. 1 Mechanistic effects of DPP4 inhibition in lung injury ( modified from Shao et al 2020) [13] gliptins in modulating the inflammatory response of distal respiratory tract, with the aim of improving prognosis and reducing mortality of respiratory infections in patients with COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…This trans-membrane glycoprotein, known also as CD26 lymphocyte cell surface protein, is expressed in different types of immune cells, and it is supposed to influence their function: CD4 + , CD8 + T cells, B cells, NK cells, dendritic cells, and macrophages. In principle, therefore, DPP4 is capable to modulate many cytokines, chemokines, and peptide hormones [13]. As noted, DPP4/CD26 is directly involved in various immune or inflammatory diseases.…”

Section: Dipeptidyl Peptidase-4 and Pulmonary Inflammationmentioning

confidence: 99%

“…DPP4is, commonly called gliptins, have been initially developed and are currently widely used as effective oral hypoglycemic drugs in the treatment of type-2 diabetes mellitus (T2DM). However, DPP4 inhibition has the potential to exert a positive pleiotropic effect on vascular and inflammatory diseases [14,15], or even direct anti-inflammatory effect on various cell types: T cells, macrophages, and adipocytes [13,16,17]. With specific respect to lung diseases, Kawasaki et al demonstrated the direct anti-inflammatory effects of DPP4 inhibition on LPS-induced lung injury in mice and in human lung epithelial cells.…”

Section: Dipeptidyl Peptidase-4 Inhibition and Pulmonary Inflammationmentioning

confidence: 99%

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Potential role of incretins in diabetes and COVID-19 infection: a hypothesis worth exploring

2020

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Patients with diabetes mellitus have been reported to be at a high risk of complications from SARS-CoV2 virus infection (COVID-19). In type 2 diabetes, there is a change in immune system cells, which shift from an anti-inflammatory to a predominantly pro-inflammatory pattern. This altered immune profile may induce important clinical consequences, including increased susceptibility to lung infections; and enhanced local inflammatory response. Furthermore, dipeptidyl peptidase 4 (DPP4) enzyme is highly expressed in the lung, and that it may have additional actions besides its effects on glucose metabolism, which might exert profound pro-inflammatory effects. We briefly review the impact on the inflammatory system of DPP4 for its possible detrimental effect on COVID-19 syndrome, and of DPP4 inhibitors (gliptins), currently used as glucose lowering agents, which may have the potential to exert positive pleiotropic effect on inflammatory diseases, in addition to their effects on glucose metabolism. Thanks to these ancillary effects, gliptins could potentially be "repurposed" as salutary drugs against COVID-19 syndrome, even in non-diabetic subjects. Clinical studies should be designed to investigate this possibility.

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Section: Discussionmentioning

confidence: 99%

Section: Dipeptidyl Peptidase-4 and Pulmonary Inflammationmentioning

confidence: 99%

Section: Dipeptidyl Peptidase-4 Inhibition and Pulmonary Inflammationmentioning

confidence: 99%

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Potential role of incretins in diabetes and COVID-19 infection: a hypothesis worth exploring

2020

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“…Sireesh et al 41 reported that IFN-γ and related cytokine levels were increased while Th2 response cytokines, having homeostatic effects on oxidative stress and antioxidant status were decreased in T2DM patients. Metformin and DPP4 inhibitors such as vildagliptin have immunomodulatory effects, and they are both reported to decrease IFN-γ production, modulate T lymphocyte activation and decrease Th1 type immune response by diverse mechanisms [42][43][44][45][46] . Serum and urinary neopterin levels in T2DM patients were found higher than T1DM patients (p = 0.029 and p = 0.158, respectively; Table 2).…”

Section: Discussionmentioning

confidence: 99%

Neopterin and biopterin levels and tryptophan degradation in patients with diabetes

Gürcü

Girgin

Yorulmaz

et al. 2020

Sci Rep

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This study aimed to evaluate the possible changes of neopterin, biopterin levels and tryptophan degradation in diabetes and to compare the results within diabetes groups and with healthy subjects. Diabetes mellitus patients and healthy controls were recruited the study. Patients were further subgrouped according to their drug therapy. Serum neopterin concentrations were detected by ELISA. Urinary neopterin, biopterin, serum tryptophan (Trp) and kynurenine (Kyn) levels were detected by HPLC. There was no difference between controls and diabetes patients in serum neopterin, urinary neopterin and biopterin levels (p > 0.05, all). Serum Trp and Kyn levels were significantly different in type 1 diabetes (T1DM) patients compared to controls (p < 0.05, both). Serum neopterin levels were significantly higher in type 2 diabetes patients (T2DM) compared to T1DM (p < 0.05). Urinary biopterin levels of T2DM patients using both metformin and vildagliptin were significantly higher than T1DM patients (p < 0.05). The correlations between serum neopterin and urinary neopterin, Kyn and Kyn/Trp were statistically significant in control and patient groups (p < 0.05, all). The study showed that Kyn/Trp was altered in diabetes patients due to immune modulation. On the other hand, although xenobiotic exposure may change pteridine levels, metformin and/or vildagliptin use in T2DM patients did not have any effect on the measured parameters.

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“…DPP4 immunomodulatory function raises the question whether DPP4i might alter the immune response in diabetic patients ( Shao et al, 2020 ). The pharmakokinetic and pharmacodynamic properties of DPP4i allow that DPP4 enzymatic activity in tissues and circulation is not completey blocked ( Drucker, 2020 ).…”

Section: Therapeutic Potential Of Targeting Dpp4 In Diabetic Patientsmentioning

confidence: 99%

DPP4 and ACE2 in Diabetes and COVID-19: Therapeutic Targets for Cardiovascular Complications?

et al. 2020

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COVID-19 outbreak, caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus has become an urgent health and economic challenge. Diabetes is a risk factor for severity and mortality of COVID-19. Recent studies support that COVID-19 has effects beyond the respiratory tract, with vascular complications arising as relevant factors worsening its prognosis, then making patients with previous vascular disease more prone to severity or fatal outcome. Angiotensin-II converting enzime-2 (ACE2) has been proposed as preferred receptor for SARS-CoV-2 host infection, yet specific proteins participating in the virus entry are not fully known. SARS-CoV-2 might use other co-receptor or auxiliary proteins allowing virus infection. In silico experiments proposed that SARS-CoV-2 might bind dipeptidyl peptidase 4 (DPP4/CD26), which was established previously as receptor for MERS-CoV. The renin–angiotensin–aldosterone system (RAAS) component ACE2 and DPP4 are proteins dysregulated in diabetes. Imbalance of the RAAS and direct effect of soluble DPP4 exert deleterious vascular effects. We hypothesize that diabetic patients might be more affected by COVID-19 due to increased presence ACE2 and DPP4 mediating infection and contributing to a compromised vasculature. Here, we discuss the role of ACE2 and DPP4 as relevant factors linking the risk of SARS-CoV-2 infection and severity of COVID-19 in diabetic patients and present an outlook on therapeutic potential of current drugs targeted against RAAS and DPP4 to treat or prevent COVID-19-derived vascular complications. Diabetes affects more than 400 million people worldwide, thus better understanding of how they are affected by COVID-19 holds an important benefit to fight against this disease with pandemic proportions.

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Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions

Cited by 141 publications

References 184 publications

Potential role of incretins in diabetes and COVID-19 infection: a hypothesis worth exploring

Potential role of incretins in diabetes and COVID-19 infection: a hypothesis worth exploring

Neopterin and biopterin levels and tryptophan degradation in patients with diabetes

DPP4 and ACE2 in Diabetes and COVID-19: Therapeutic Targets for Cardiovascular Complications?

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