SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Abstract

Initially, the pandemic COVID-19, caused by SARS-CoV-2, was considered to be an exclusive lung disease, eventually leading to serious respiratory symptoms 1 . In the meantime, accumulating experimental and clinical studies have suggested that SARS-CoV-2 may also cause lesions in the kidneys, heart, brain, and gastrointestinal and endocrine organs [2][3][4][5][6][7] . SARS-CoV-2 tropism towards distinct tissues is governed by cellular factors expressed on target cells such as the viral entry receptor angiotensin-converting enzyme 2 (ACE2) 8 and the transmembrane serine protease 2 (TMPRSS2) 8 . ACE2 messenger RNA 9-13 and protein 12-14 expression within the islets of Langerhans has been reported, but not yet been shown, to allow SARS-CoV-2 entry 9,12,15 . Diabetes mellitus presents Janus like in 16 ): first, pre-existing diabetes is a highly prevalent comorbidity observed in 11-22% of patients and as such increases the risk of a severe disease, requiring more intense interventions and increasing mortality [17][18][19][20][21][22] . Second, SARS-CoV-2 infection seems to affect the exocrine pancreas, manifesting as pancreatitis in 32.5% of critically ill patients 23 , and pancreatic enlargement and abnormal amylase or lipase levels in 7.5-17% of patients 9,22 . Third, metabolic dysregulation has been observed in patients with COVID-19 as:(1) increased hyperglycaemia in patients with type 2 diabetes 24 ; (2) ketoacidosis in 2-6.4% of diabetic and non-diabetic patients 18,25 ; and (3), in case studies reporting ketoacidosis on SARS-CoV-2 infection, accompanied by (4) new-onset type 1 diabetes mellitus (T1DM) in the absence of autoantibodies [26][27][28] . In a cohort study of patients with diabetes, hyperglycaemia was reported in more than 50% of all cases, and almost a third experienced diabetic ketoacidosis 29 . Finally, a multicentre study found an 80% increase of new-onset T1DM in children during the COVID-19 pandemic 30 . In accordance, a recent meta-analysis summarizes that severe SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Not so sweet and simple: impacts of SARS-CoV-2 on the β cell

“…32 The potential for direct infection of human islets ex vivo has recently been demonstrated. 31 Here, isolated human islets exposed to SARS-CoV-2 exhibited detectable expression of viral spike and nucleocapsid protein by d 3 postexposure. Interestingly, most of the SARS-CoV-2-infected cells appeared to lack mature hormone expression, but were still positive for PDX1 or NKX6.1, raising the possibility that endocrine cells lose hormone positivity upon infection.…”

“…36 Another group recently reported positive immunofluorescent staining for both ACE2 and TMPRSS2 in islets in 5/5 pancreas sections tested. 31 Strong ACE2 expression was also detected in endothelial cells and a subpopulation of ductal cells, with ACE2 only faintly expressed in acinar cells. TMPRSS2 was also detected in endocrine cells and in some ducts, with insulin-positive cells more likely to show costaining for ACE2 and TMPRSS2 than glucagon or somatostatinpositive cells.…”

Post-COVID Syndrome: An Insight on Its Pathogenesis

“…Post-viral infection destruction of β-pancreatic cells can occur and trigger the onset of diabetes mellitus. It has been shown that SARS-CoV-2 can infect and replicate in human pancreatic islets, in association with reduced insulin-secreting granules in pancreatic β-cells and impaired glucose-stimulated insulin secretion [ 65 ], which may explain the deterioration of glycemic control observed in diabetic patients with COVID-19 necessitating exceptionally high doses of insulin [ 66 ], but also increase the risk for onset of diabetes after COVID-19 [ 67 ]. Potential pathways of injury of pancreatic β-cells include a profound proinflammatory cytokine response, leading to a chronic low-grade inflammationactivation of the renin-angiotensin-aldosterone system, through the SARS-CoV-2 target ACE2 receptor, which is abundant in pancreatic β-cells, and enhances autoimmunity in genetically predisposed individuals [ 67 ].…”

Intestinal SGLT1 as a therapeutic target in COVID‐19‐related diabetes: A “two‐edged sword” hypothesis

“…In line with what is already known from studies conducted with other coronaviruses, it has been demonstrated that SARS-CoV-2 exerts cytotoxic effects that cause islet cell injury and impair insulin production. 5 Moreover, downregulation of ACE2 following the endocytosis of the virus complex results in increased angiotensin II concentrations, which are known to impede insulin secretion. 6,7 Similar to what happens with other viral infections, an immune-mediated beta-cell destruction triggered by the SARS-CoV-2 infection has been also suggested.…”