COVID-19 and diabetes: is this association driven by the DPP4 receptor? Potential clinical and therapeutic implications

Recently, Iacobellis [1] commented on the high prevalence of type 2 diabetes mellitus (T2DM) among individuals affected by the coronavirus disease COVID-19, especially in those with severe SARS-COV-2 infection needing intensive care for acute respiratory complications. The author reports observations that show that human dipeptidyl peptidase 4 (DPP4) was identified as a functional receptor for the spike protein of the MERS-Co-V [2]. MERS-CoV binds to the receptor-binding domain and interacts with T cells and nuclear factors, activating an inflammatory response. Antibodies directed against DPP4 inhibit human coronavirus-Erasmus Medical Center (hCoV-EMC) infection of primary human bronchial epithelial cells. Furthermore, transgenic mice were made susceptible to MERS-CoV by expressing human DPP4 [3], and these knock-in mice had a lethal form of lung disease, characterized by a strong inflammatory response [3], [4]. Based on these observations, Iacobellis suggest that DPP4 may represent a potential target for DPP4 inhibitors for preventing and/or reducing the risk and progression of the acute respiratory complications that T2DM may add to the COVID-19 infection. However, there are some points to consider carefully before claiming possible novel therapeutic approaches to COVID-19. The potential interaction between SARS-CoV-2 spike glycoproteins and DPP4 has been predicted by structural studies [5], but needs confirmation in human cells. Moreover, Iacobellis does not take into account that the same authors that demonstrated human DPP4 as a functional receptor for the spike protein of the MERS-Co-V [2] showed that hCoV-EMC infection could not be blocked by the DPP4 inhibitors sitagliptin, vildagliptin and saxagliptin, probably because these inhibitors do not target the binding interface between the S1 domain of hCoV and the receptor. So, the potential role for DPP4 inhibition may not be as important as suggested. There is, however, a point worth taking from Iacobellis’ remarks. We have shown that higher plasma DPP4 is evident in obesity, metabolic syndrome and type 2 diabetes [6] and increases with aging [7], all representing significant risk factors for unfavourable COVID-19 outcomes [8]. Thus, increased plasma DPP4 may represent a driver for clinical severity in SARS-COV2 infection. On one side, the broad DPP4 distribution could contribute to explain the large number of SARS-COV2 target organs, which are more than those expressing ACE2 receptors, identified as the main SARS-COV2 receptor so far [9]. On the other, DPP4 levels may, at least in part, determine COVID-19 severity, reflecting the accessibility of SARS-COV2 to target cells, tissues and organs, and may explain the high incidence of mortality in severe COVID-19. Therefore, it may be warranted to further investigating the utility of DDP4 measurement. Plasma DPP4 measurement could represent an easy tool for risk stratification in SARS-COV2 infected patients, particularly in highly susceptible populations as those with Diabetes or other metabolic conditions, and a marker of disease progression and response to treatment in COVID-19.