SARS-CoV-2 Directly Infects The Pancreatic Islets And Causes Pancreatic Inflammation

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Italian researchers from Universitá di Milano, have in a new study found that the SARS-CoV-2 coronavirus is able to directly and also indirectly affect the pancreatic islets of the host and cause pancreatic inflammation that can lead to Post COVID Hyperglycemia and other health conditions and issues.

The study findings were published in the peer reviewed journal: Diabetes. 

https://diabetesjournals.org/diabetes/article/doi/10.2337/db21-0926/146863/Indirect-and-Direct-Effects-of-SARS-CoV-2-on-Human
 

Several emerging clinical reports have described an increased incidence of patients with new-onset hyperglycemia associated with acute COVID-19 20 or onset within a few weeks from recovery of the disease 21.

In this study, we observed impaired function and survival of human pancreatic islets induced upon challenge with serum from patients with COVID-19 but also with sera from patients with T2D and the triggered lethality may be due to the presence of some circulating inflammatory factors as reported in literature 22.

We would like to point out that the lethality of T2D sera on human islets was largely described in cross-sectional and prospective studies, where elevated circulating inflammatory factors including acute-phase proteins and pro-inflammatory cytokines have driven the inflammatory process during T2D pathogenesis and led to islet inflammation and consequently beta-cell death 23.

This may confirm the high rate of cell death and the drastic decrease in insulin secretion that we observed upon challenge of human islets with sera from T2D patients. Importantly, IL-1β was retrieved within the several circulating pro- inflammatory cytokines found in the sera of patients with T2D, possess a pleiotropic effect on human islet survival and homeostasis.

Extended exposure or high levels of IL-1β may trigger a pro-inflammatory cascade prominent in T2D pathogenesis and disease progression 23,24. That been said, when applying a more rigorous one-way ANOVA with Bonferroni correction for multiple comparisons analysis, the effect of IL-1β was not statistically different anymore.

Another important observation is related to the absence of the autoantibodies in our samples obtained from patients with COVID-19 and from those who recovered from COVID-19. This may be also due to the short study follow-up since their diagnosis of SARS-CoV- 2 infection.

We acknowledge that this limited endured time frame may not be enough to allow us to see any defined aspects of the autoimmune process including the generation of anti-islet autoantibodies. Notably, pathological examination of pancreatic sections retrieved from newly hyperglycemic patients with COVID-19 revealed mild lymphocytic infiltration, which combined with the detection of SARS- CoV-2-specific viral RNA, was suggestive of a direct tropism of SARS-CoV-2 for β-cells that in turn may contribute to their dysfunction or death, as suggested by other recent studies 3,25.

The expression of several cytokine receptors on human pancreatic islets is also indicative of islet susceptibility to COVID-19- associated cytokine-induced death. Interestingly, the detection of histopathological alterations such as features of pancreatic inflammation and activation of pancreatic lymph nodes as well as altered pancreatic ultrastructure suggests broad and potentially long-term effects in patients with COVID-19.

Surprisingly, we also were able to detect SARS-CoV-2 viral RNA in pancreatic samples from some hyperglycemic patients with COVID-19, which confirms the extrapulmonary tropism of SARS-CoV-226-28. The ultrastructural finding of numerous cytoplasmic vacuoles in some β-cells, as well as in capillary endothelial cells, in pericytes and in histiocytes, is suggestive of the presence of virus, even if viral particles have not been identified.

In sum, this may suggest that the diabetogenic effect induced by SARS-CoV-2 infection also can be mediated by a possible direct viral cytotoxicity against human pancreatic islets. Evidence of SARS-CoV-2 viral particles within the pancreas have been reported recently 29-33, as has the expression of the SARS-CoV-2 cell entry receptor ACE2 in pancreatic ductal epithelium and microvasculature, while minor expression of ACE2 mRNA transcript was observed in the endocrine pancreas34.

Other recent reports demonstrated the presence of the canonical SARS-CoV-2 cell entry machinery such as ACE2, TMPRSS2 and DPP4, in addition to direct evidence of SARS-CoV-2 infection, within pancreatic ducts, acinar cells, endothelial cells, and in close proximity to the islets of Langerhans, within the islets, and within insulin-producing β-cells 25,30.

We did not find increased levels of unmethylated, beta cell-derived INS DNA but the timing of killing may have been well before the samples were collected and there was a dramatic increase in INS DNA derived from non-beta cells which may have obscured this sign of beta cell killing.

Albeit data from the literature supported/considered that the increased frequency of unmethylated INS CpG sites in β-cells and the ratio of unmethylated-to-methylated INS DNA released into the circulation upon cell death is a reflection of β-cell death 35, there have been several limitations regarding the use unmethylated INS DNA as a reliable marker of in vivo β-cell death.

Particularly, the limited inter-lab validation of the indicated methodology and also the fact that stressed β- cells may methylate insulin DNA and die without releasing demethylated insulin 36.

Several other caveats are related to the findings from the literature that other cell types were reported to contain limited/lower levels of circulating unmethylated INS and raised the concern that unmethylated INS DNA may not be exclusively restricted to β-cells and therefore may not solely reflect on β-cell death 37,38.

To our knowledge this is the first report showing the coexistence of an exaggerated peripheral inflammation and a direct tropism of SARS-CoV-2 virus, which together may drive β-cell dysfunction/damage. Our data suggest that a dysregulation of cytokines and a proinflammatory environment may synergistically act in concert with pancreatic localization of SARS-CoV-2 to promote abnormal glycometabolic control (Supplementary Fig. S4).

In conclusion, in the present study we suggest that new-onset hyperglycemia in patients with COVID-19 may be due to the proinflammatory milieu initiated by a cytokine storm in combination with a direct localization of SARS-CoV-2 within pancreatic β-cells.


Initially, the pandemic COVID-19, caused by SARS-CoV-2, was considered to be an exclusive lung disease, eventually leading to serious respiratory symptoms1. 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 organs2,3,4,5,6,7.

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 9,10,11,12,13 and protein 12,13,14 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 COVID-19 (refs. 3,16): 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 patients23, 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;
  • (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 COVID-19 is associated with increased blood glucose levels 31.

However, the formal proof of SARS-CoV-2 as a β-cell tropic virus, potentially leading to diabetes, is still missing, and the only correlative evidence stands in the light of conflicting experimental and clinical findings 13,22,32,33,34. Prospectively collected acute and long-term outcomes on new-onset diabetes cases, together with thoughtful interpretations of emerging data up to final clarification of this debate, are warranted 33.

Accordingly, it is unclear whether and how SARS-CoV-2 might trigger β-cell injury, but it may occur via either immune-mediated β-cell ablation or direct perturbation of β-cell function, both eventually leading to so-called infection-related diabetes according to the current World Health Organization (WHO) classification35.

Recent evidence suggests that SARS-CoV-2 can infect human endocrine cells in vitro 12,36. However, this finding was obtained with stem-cell-derived, immature human β-cells that express ACE2 and TMPRSS2, and viral replication or impact on β-cell function has not been analysed in detail 36.

ACE2 or TMPRSS2 expression was also detected in exocrine and endocrine cells in human pancreatic tissue; however, varying expression patterns across distinct pancreatic cell types were reported 9,10,12,13,14,15,34,36,37,38. Thus, it is imperative to clarify whether human pancreatic endocrine cells organized within an islet of Langerhans are permissive for and affected by SARS-CoV-2 infection, and to elucidate the mechanisms underlying a potential endocrine dysfunction associated with COVID-19 (refs. 16,21,22,36).

In the present study, we (1) defined ACE2 and TMPRSS2 expression patterns in human pancreatic endocrine and exocrine cell types, (2) employed human pancreatic islet cultures to demonstrate susceptibility to SARS-CoV-2 infection and viral replication in β-cells and (3) showed that SARS-CoV-2 infection affects glucose-stimulated insulin secretion (GSIS).

In addition, we (4) visualized viral particles replicating in endocrine pancreatic cells and defined their subcellular localization patterns and finally (5) presented examples of multiorgan infection patterns including the pancreata of patients who died from COVID-19.

reference link : https://www.nature.com/articles/s42255-021-00347-1

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