Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM)

Abstract

Aims: Dipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) has been identified as the most important risk factor for SARS-CoV-2, and that gliptins (DPP4 inhibitors) are a prescribed diabetic treatment, this study aims to unravel the impact of DPP4 in the intersection of T2DM/COVID-19.

Materials and methods: We analyzed 189 serum human samples, divided into six clinical groups (controls, T2DM, T2DM + gliptins, COVID-19, COVID-19 + T2DM, and COVID-19 + T2DM + gliptins), measuring DPP4 protein concentration and activity by Western blot, ELISA, and commercial activity kits. The obtained results were verified in Huh-7 cellular models.

Key findings: Both DPP4 concentration and activity were decreased in COVID-19 patients, and as in T2DM patients, compared to controls. Despite these lower levels, the ratio of DPP4 activity/concentration in COVID-19 sera was the highest (0.782 ± 0.289 μU/ng vs. 0.547 ± 0.050 μU/ng in controls, p < 0.0001), suggesting a compensating mechanism in these patients. Supernatants of Huh-7 cells incubated with COVID-19 serum showed a consistent and significantly lower DPP4 concentration and activity. Furthermore, COVID-19 + T2DM + gliptins patients showed a higher serum DPP4 concentration and activity than T2DM + gliptin subjects (p < 0.05), indicating that sera from COVID-19 convalescents interfere with gliptins.

Significance: Either SARS-CoV-2 or some metabolites present in the sera of COVID-19-convalescent patients interact with soluble DPP4 or even gliptins themselves since the inhibitory effect of gliptins on DPP4 activity is being prevented. The interactions between DPP4, gliptins, and SARS-CoV-2 should be further elucidated to reveal the mechanism of action for these interesting observations.

Keywords: COVID-19; DPP4; Enzymatic activity; Gliptins; Type 2 diabetes.