Subject(s)
COVID-19/complications , COVID-19/virology , Glucose Metabolism Disorders/etiology , Glucose Metabolism Disorders/metabolism , Host-Pathogen Interactions , Membrane Proteins/metabolism , SARS-CoV-2 , Biomarkers , Blood Glucose , Disease Susceptibility , Glucose/metabolism , Glucose Metabolism Disorders/diagnosis , Humans , Liver/metabolism , Liver/pathology , Membrane Proteins/geneticsABSTRACT
Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet ß cells. This would require binding and entry of SARS-CoV-2 into ß cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single ß cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in ß cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects ß cells in vivo through ACE2 and TMPRSS2.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Diabetes Mellitus/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/complications , COVID-19/genetics , Cells, Cultured , Diabetes Complications/genetics , Diabetes Complications/metabolism , Diabetes Mellitus/genetics , Gene Expression , Humans , Insulin-Secreting Cells/metabolism , Mice , Microvessels/metabolism , Pancreas/metabolism , RNA, Messenger/analysis , RNA, Messenger/genetics , Serine Endopeptidases/analysis , Serine Endopeptidases/geneticsABSTRACT
Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet ß cells. This would require binding and entry of SARS-CoV-2 into host ß cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or ß cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet ß cells through these cell entry proteins.