Emerging evidence indicates that the relationship between coronavirus disease 2019 (COVID-19) and diabetes is 2-fold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have an increased risk of developing new-onset diabetes. However, the mechanisms underlying this association are mostly unknown, and there are no reliable biomarkers to predict the development of new-onset diabetes. In the present study, we demonstrate that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells reliably predicts the risk of developing new-onset diabetes in COVID-19. This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer.

SIGNIFICANCE STATEMENT We demonstrate for the first time that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells is able to reliably predict the risk of developing diabetes after having contracted coronavirus disease 2019 (COVID-19). This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. Our findings are also relevant when considering the emerging importance of post-acute sequelae of COVID-19, with systemic manifestations observed even months after viral negativization (long COVID).

Santulli’s Laboratory is supported in part by National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL159062], [Grant R01-HL146691], and [Grant T32-HL144456] and National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK123259] and [Grant R01-DK033823] (to G.S.), by the Diabetes Action Research and Education Foundation (to G.S.), by the Samuel Waxman Foundation (to G.S.), and by the Monique Weill-Caulier and Irma T. Hirschl Trusts (to G.S.). This publication was also produced with the cofunding of the European Union – Next Generation EU, in the context of The National Recovery and Resilience Plan, PE8 Investment, Project Age-It (Ageing Well in an Ageing Society) (to P.M.). S.S.J., J.G., U.K., and F.V. are supported in part by postdoctoral fellowships of the American Heart Association (AHA-836407, AHA-35211151, AHA-1026190, and AHA-241195524).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

↵1P.M., S.S.J., and M.V.M. share the first authorship.

dx.doi.org/10.1124/jpet.122.001253.