SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature

Fignani, Daniela; Licata, Giada; Brusco, Noemi; Nigi, Laura; Grieco, Giuseppina Emanuela; Marselli, Lorella; Overbergh, Lut; Gysemans, Conny; Colli, Máikel Luís; Marchetti, Piero; Mathieu, Chantal; Eizirik, Décio L.; Sebastiani, Guido; Dotta, Francesco

doi:10.3389/fendo.2020.596898

Cited by 170 publications

(167 citation statements)

References 84 publications

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“…Evidence from single-cell RNA surveys available at the outset of the pandemic indicated that the SARS-CoV-2 co-receptor ACE2 is not present in β-cells, whereas the receptor TMPRSS and the newly discovered NRP1 co-receptor are expressed at low levels 13 . Some surveys of pancreatic islets by immunohistochemistry have yielded results consistent with these findings 14,15 , whereas others have found SARS-CoV-2 receptors in β-cells 16 . Could the receptors be induced in β-cells as part of the syndrome?…”

Section: Pancreatic β-Cells and Sars-cov-2mentioning

confidence: 63%

Can COVID-19 cause diabetes?

2021

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Section: Pancreatic β-Cells and Sars-cov-2mentioning

confidence: 63%

Can COVID-19 cause diabetes?

2021

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“…As DKA occurs as a result of insulin deficiency and increased counterregulatory responses, which favor the production of ketones, the unique interactions between SARS-CoV-2 and the RAAS might provide yet another mechanism in the pathophysiology of DKA firstly by direct entry of SARSCoV-2 into pancreatic islet cells that might worsen b-cell injury and secondly by downregulation of ACE2 after viral entry that can lead to unopposed angiotensin II and subsequent insulin secretion impedance [86]. It has been proposed that direct cytopathic effects of SARS-CoV-2 on pancreatic b-cell populations may contribute to this high prevalence of severe COVID-19-associated DKA in T2DM; ACE2 expression at both the mRNA and protein is increased substantially in human beta cells in response to inflammatory cytokines, presumably rendering these cells more susceptible to infection [90]. Both SARS and COVID-19 have been reported to trigger transient insulin resistance and hyperglycaemia.…”

Section: Discussionmentioning

confidence: 99%

Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports

Papadopoulos¹,

Koutroulos²,

Zikoudi³

et al. 2021

Preprint

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BackgroundCOVID-19 is associated with DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and EDKA (Euglycaemic DKA). High mortality has been observed in COVID-19-related diabetic ketoacidosis; however, evidence is scarce.MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January to December 2020 to identify all case reports describing DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment. Univariate and multivariate analysis assessed correlations of study origin, combined DKA/HHS, age, BMI, HbA1c, administered antidiabetics, comorbidities, symptoms onset, disease status (DS), CRP, ferritin, d-dimers, glucose, osmolarity, pH, bicarbonates, ketones, lactates, β-hydroxybutyric acid, anion gap, and acute kidney injury (AKI) with outcome. The relevant protocol was submitted to PROSPERO database (ID: 229356).ResultsFrom 312 identified publications, 41 including 71 cases analyzed qualitatively and quantitatively. The types of acute metabolic emergencies observed were DKA (45/71, 63.4%), EDKA (6/71, 8.5%), combined DKA/HHS (19/71, 26.8%), and HHS (1/71, 1.4%). Overall mortality was 32.4% (22/68 patients; 3 missing). Multivariate analysis by classical regression demonstrated that COVID-19 DS4 (P=3•10−8), presence of DKA/HHS (P=0.021), and development of AKI (P=0.037) were all independently correlated with death. Increased DS (P=0.003), elevated lactates (P<0.001), augmented anion gap (P<0.001), and presence of AKI (P=0.002) were associated with DKA/HHS. SGLT-2i administration was linked with EDKA (P=0.004); however, a negative association with AKI was noted (P=0.023).ConclusionCOVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality. Key determinants are critical COVID-19 illness, coexistence of DKA/HHS and AKI. Awareness of clinicians to timely assess them might enable early detection and immediate treatment commencing. As previous treatment with was negatively associated with AKI, thus implying a prophylactic effect on renal function, the issue of discontinuation of SGLT-2i in COVID-19 patients remains to be further evaluated.Key messagesWhat is already known on this subject▸Diabetes mellitus (DM) is a risk factor for poor outcomes in COVID-19 patients.▸Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) are not rare in COVID-19 diabetic and non-diabetic patients; key determinants of outcome remain unknown.What this study adds▸COVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality; key determinants are critical COVID-19 illness, coexistence of DKA and HHS as well as development of acute kidney injury.▸SGLT2-i administration is linked with euglycaemic DKA in patients with COVID-19, though preserving renal function.

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“…ACE2 mRNA transcripts were detected by qPCR in RNA from collagenase-isolated human islet preps from 4 different non-diabetic donors, as well as in islet RNA isolated by laser capture microdissection from 5 different non-diabetic donors. Exposure of human EndoC-βH1 cells or human islets to a pro-inflammatory cytokine cocktail markedly upregulated ACE2 RNA and protein expression, whereas relative ACE2 expression was not different in human islets exposed to palmitate, or in islet RNA isolated from diabetic donors ( Fignani et al., 2020 ).…”

Section: Localization Of Ace2 and Accessory Proteins Mediating Suscepmentioning

confidence: 98%

“…Similarly, ACE2 expression was reported at the lower limit of detection, whereas TMPRSS2 mRNA transcripts were more readily detectable by RNA-seq in RNA from fluorescence-activated cell sorting (FACS)-sorted human α, β, and exocrine cells ( Bramswig et al., 2013 ). ACE2 localization was assessed by IHC using multiple antibodies in human pancreatic tissue obtained from 7 non-diabetic donors, demonstrating ACE2 immunopositivity, in ductal, endothelial, and endocrine cells, preferentially in ~57% of INS+ β cells ( Fignani et al., 2020 ). A short form of ACE2 protein was preferentially localized to β cells.…”

Section: Localization Of Ace2 and Accessory Proteins Mediating Suscepmentioning

confidence: 99%

Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

2021

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SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature

Cited by 170 publications

References 84 publications

Can COVID-19 cause diabetes?

Can COVID-19 cause diabetes?

Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports

Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

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