Does diabetes risk after SARS-CoV-2 infection depend on the viral variant?

SARS-CoV-2 infection is associated with an elevated risk of new-onset diabetes. With infections forecast to rise in the coming months, this may exacerbate an existing public health crisis by increasing rates of diabetes worldwide. Much remains to be learned about a causal link between SARS-CoV-2 and incident diabetes. This is complicated by the rapid evolution of new SARS-CoV-2 variants that may have differential effects on development of diabetes. It is possible that some variants confer an increased risk, while others carry little to no risk. Distinguishing between these possibilities could be key in preventing or screening for new-onset diabetes, and could inform care of at-risk individuals with recent SARS-CoV-2 infection.

Going viral in the islet: mediators of SARS-CoV-2 entry beyond ACE2.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Following initial infection of airway epithelia, SARS-CoV-2 invades a wide range of cells in multiple organs, including pancreatic islet cells. Diabetes is now recognised as a risk factor for severe COVID-19 outcomes, including hospitalisation and death. Additionally, COVID-19 is associated with a higher risk of new-onset diabetes and metabolic complications of diabetes. One mechanism by which these deleterious outcomes may occur is via the destruction of insulin-producing islet ß cells, either directly by SARS-CoV-2 entry into ß cells or indirectly due to inflammation and fibrosis in the surrounding microenvironment. While the canonical pathway of viral entry via angiotensin-converting enzyme 2 (ACE2) has been established as a major route of SARS-CoV-2 infection in the lung, it may not be solely responsible for viral entry into the endocrine pancreas. This is likely due to the divergent expression of viral entry factors among different tissues. For example, expression of ACE2 has not been unequivocally demonstrated in ß cells. Thus, it is important to understand how other proteins known to be highly expressed in pancreatic endocrine cells may be involved in SARS-CoV-2 entry, with the view that these could be targeted to prevent the demise of the ß cell in COVID-19. To that end, this review discusses alternate receptors of SARS-CoV-2 (CD147 and GRP78), as well as mediators (furin, TMPRSS2, cathepsin L, ADAM17, neuropilin-1, and heparan sulphate) that may facilitate SARS-CoV-2 entry into pancreatic islets independent of or in conjunction with ACE2.