Molecular Analysis of Long COVID and New-onset Diabetes Mellitus: Pathobiological Relationships and Current Mechanistic Views

Getasew Shitaye^1,2*Muluabay Getie³Zewdie Mekonnen^2,4Gianluca D'Abrosca⁵Roberto Fattorusso⁶Carla Isernia⁶Asmare Amuamuta⁷Gaetano Malgieri⁶

• ¹1Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania “Luigi Vanvitelli”, via Vivaldi 43, 81100, Caserta, Italy
• ²2Department of Biomedical sciences, College of Medicine and Health Sciences, Bahir Dar University, 79, Bahir Dar, Ethiopia
• ³Department of Biomedical sciences, College of Medicine and Health Sciences, Bahir Dar University, 79 Bahir Dar, Ethiopia, Bahir Dar University College of Medical and Health Sciences, Bahir Dar, Ethiopia
• ⁴4Department of Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, P. O. Box 9086,, Addis Ababa, Ethiopia
• ⁵Link Campus, Department of Human Science, Via del Casale di S. Pio V 44, Roma, Italy
• ⁶Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania “Luigi Vanvitelli”, via Vivaldi 43, 81100, Caserta, Italy
• ⁷Department of Biomedical sciences, College of Medicine and Health Sciences, Bahir Dar University, 79, Bahir Dar, Ethiopia

Abstract Long COVID or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) refers to the association of SARS-CoV-2 infection with a range of persistent health effects. Long COVID, as a complex and multisystem disorder, can affect nearly every organ system that strongly links with the incidence of diabetes and other chronic conditions. Likewise, persistent SARS-CoV-2 infection has been increasingly connected to the development of new-onset diabetes and other metabolic disorders. Thus, in this review, we opted to assess the current evidences and discuss the incidence of new-onset diabetes and the patho-biological mechanisms by which SARS‐CoV‐2 might lead to progression of both new-onset type 1 and 2 diabetes mellitus (T1DM and T2DM). We summarize our latest understanding of the molecular and cellular mechanisms underlying SARS-CoV-2 infection-associated new-onset diabetes. The potential mechanisms of new-onset DM, including direct damage to pancreatic beta cells, inflammation, insulin resistance, and autoimmune responses, among others, are explored. Dysregulated ACE2/RAS pathway has been connected to multiple inter-organ pathogenesis; increased inflammatory cytokines and dysregulation of interferon regulatory factors (IRFs) (such as overexpression of IRF1) seem to be main cellular/molecular mechanistic link to such multitude of inter-organ damages and metabolic alterations. Moreover, the presence of viral RNA or fragments could directly damage different islets of the pancreas, contributing to insulin resistance and beta-cell dysfunction that, in turn, could lead to the progression of new-onset diabetes. In light of these notions, the review further assessed the evidences supporting the persistence of SARS-CoV-2 RNA in PASC reservoir tissues such as the pancreas, along with its potential association with the development of new-onset DM.