Abstract
Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2), is a necessary step for SARS-CoV-2 infection permissiveness. In the light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyse ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies.
Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing β-cells. ACE2 is also is highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. By using different ACE2 antibodies we showed that a recently described short-ACE2 isoform is also prevalently expressed in human β-cells.
Finally, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, but not palmitate, increases ACE2 expression in the β-cell line EndoC-βH1 and in primary human pancreatic islets.
Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes through putative infection of pancreatic microvasculature and/or ductal cells and/or through direct β-cell virus tropism.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Joint first co-authorship
↵# Share last co-authorship
In the present manuscript, following the increasing evidence of: a) an association between COVID-19 infection and diabetes mellitus, both in terms of acute hyperglycaemia observed at admission in a substantial percentage of SARS-CoV-2 infected subjects, regardless of the past medical history of diabetes, and of the association between impaired glycaemic control and increased risk of severe COVID-19 clinical manifestations; b) the demonstration that expression of Angiotensin I-Converting Enzyme type 2 (ACE2) on target cells is a necessary step for SARS-CoV-2 infection permissiveness; we aimed at analyzing ACE2 expression in human pancreas with a particular focus on the islet endocrine cell subsets. To this end, we took advantage of the access to precious pancreatic tissue samples from multiorgan donors obtained through the EU-funded INNODIA network EUnPOD biobank to thoroughly analyze ACE2, both at mRNA and protein level. An additional set of experiments was performed on the human β-cell line EndoC-βH1, in order to gain insight into the potential mechanisms involved in the regulation of ACE2 expression. Specifically, we demonstrated that: - Human pancreatic islets express SARS-CoV-2 receptor ACE2. - In human pancreatic islets, ACE2 is preferentially expressed by insulin secreting β-cells. - In human β-cells, ACE2 expression is increased upon cytokine-induced inflammatory stress, thus putatively suggesting an enhancement of β-cell sensitivity to SARS-CoV-2 in the presence of proinflammatory conditions. Taken together, our data uncover a link between SARS-CoV-2 infection, inflammation and diabetes mellitus, through direct β-cell virus tropism via ACE2.
