First COVID, then diabetes?
Ulm study shows that SARS-CoV-2 also infects the pancreas

Ulm University

SARS-CoV-2 infects multiple organs. Severe presentations of COVID-19 not only affect the respiratory tract, the digestive tract and the cardiovascular and nervous system, but also glucose metabolism. Researchers at Ulm University Medical Center have now discovered that SARS-CoV-2 infects the insulin-producing beta cells of the pancreas in severe courses of the disease. This may explain the occurrence of diabetes-like symptoms in COVID-19 patients and the impairment of glucose metabolism in diabetic patients with COVID-19. The findings were published in the high-ranking journal Nature Metabolism.

In COVID-19 patients, “dysregulation of blood glucose levels has been frequently observed,” explains Professor Martin Wagner, Senior Physician and Head of Endocrinology in the Department of Internal Medicine 1 at Ulm University Medical Center. In severe courses of the disease, symptoms typically found in type 1 diabetes mellitus caused by insulin deficiency are more frequently observed. The symptoms range from severe hyperglycaemia – high blood glucose levels – to increased acidity of the blood, called ketoacidosis. “Current studies report exacerbations of known diabetes mellitus upon infection, but also cases of new-onset diabetes after COVID-19,” said Heisenberg Professor Alexander Kleger, one of the heads of the study, whose research group is doing in-depth work on pancreatic diseases.

The Ulm study, a joint project of the Department of Internal Medicine 1, the Institute of Molecular Virology and the Institute of Pathology, investigated how these typical diabetes symptoms could occur in COVID-19 patients.

The scientists exposed pancreatic tissue to SARS-CoV-2 and discovered that the islets of Langerhans can be infected with the coronavirus. These small, spherically arranged structures are home to insulin-producing beta cells. “These beta cells express certain protein molecules, viral entry proteins, without which SARS-CoV-2 cannot infect the cells. The human proteins TMPRSS2 and ACE2 are, so to speak, the lock that coronaviruses open with their key spike protein to enter the cells. The viral components are then replicated, releasing numerous new infectious viral particles. This is exactly what we observed in the islets of Langerhans,” explains Professor Jan Münch, head of the study at the Institute of Molecular Virology. With their experiments, the scientists were also able to show that infected insulin-producing tissue undergoes decisive changes in form and function. “We noticed that the number of insulin granules, in which the beta cells store insulin, was reduced. Thus it is no wonder that in these cases the secretion of this vital hormone that regulates blood sugar levels was disturbed” emphasize Dr Janis Müller and Dr Sandra Heller, who were both also instrumental in the study.

Another revealing finding in autopsies performed on deceased COVID-19 patients in close collaboration with Heidelberg University Hospital revealed SARS-CoV-2 infection of the pancreas. “It is striking that even after viral proteins were no longer observed in the lungs, they could still be detected in the pancreas, and this was the case independent of the duration of the disease,” says Professor Thomas Barth, who was involved in the study as a pathologist at Ulm University Medical Center. This possibly indicates that the novel coronavirus not only infects other organs than the lungs, but that these infections are more frequent and persistent than previously assumed.

Inflammation of the pancreas also occurs in COVID-19

The pancreas not only produces the hormone insulin, it also releases digestive juices in the duodenum that break down fats, carbohydrates, and proteins from food. The research team’s investigations during the study have now also shown that the pancreatic tissue that produces these digestive enzymes was also infected with coronaviruses. The relevance of this finding for the clinical progression of the disease is still unclear. “What is known so far is that inflammation of the pancreas occurs in active COVID-19 cases,” explains Professor Kleger, who heads the pancreas outpatient clinic at Ulm University Medical Center.

Another unresolved question is whether the acute impairment of insulin production in COVID-19 patients can lead to diabetes in the long term. “We definitely need further studies here as well,” the research team is convinced.

In addition to the pancreas specialists, virologists and pathologists from Ulm University; physiologists, microbiologists and electron microscopists from Ulm University and other scientists from Germany and abroad were also involved in the large-scale research project. Funding for the study was provided by the German Research Foundation (Focus Funding on COVID-19), the European Union (EU Horizon 2020 “Fight-nCoV”), the German federal government, the state government and other funding agencies and foundations.

Literature reference:

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas: Janis A. Müller, Rüdiger Groß, Carina Conzelmann, Jana Krüger, Uta Merle, Johannes Steinhart, Tatjana Weil, Lennart Koepke, Caterina Prelli Bozzo, Clarissa Read, Giorgio Fois, Tim Eiseler, Julia Gehrmann, Joanne van Vuuren, Isabel M. Wessbecher, Manfred Frick, Ivan G. Costa, Markus Breunig, Beate Grüner, Lynn Peters, Michael Schuster, Stefan Liebau, Thomas Seufferlein, Steffen Stenger, Albrecht Stenzinger, Patrick E. MacDonald, Frank Kirchhoff, Konstantin M. J. Sparrer, Paul Walther, Heiko Lickert, Thomas F. E. Barth, Martin Wagner, Jan Münch, Sandra Heller and Alexander Kleger ✉, in: Nature Metabolism ( doi 10.1038/s42255-021-00347-1

Media contact: Andrea Weber-Tuckermann
Translation: Robin Limmeroth

Group picture Pancreas COVID Study
The team in Ulm includes researchers from the Department of Internal Medicine 1 and the Institute of Molecular Virology at Ulm University Medical Center. Pictured (from left): Rüdiger Groß, Carina Conzelmann, Professor Martin Wagner, Jana Krüger, Professor Alexander Kleger, Dr Sandra Heller, Professor Jan Münch and Dr Janis Müller (photo: Elvira Eberhardt/Ulm University)
Tissue section from the pancreas of a COVID-19 deceased
Tissue section from the pancreas of a COVID-19 deceased, two areas were enlarged (right): insulin was stained in brown, thus showing the beta cells located in the islets of Langerhans. In pink, a SARS-CoV-2 protein was stained. This shows that in this patient, the islets of Langerhans are infected with SARS-CoV-2 (Figure: J. Müller et al., Nature Metabolism, 2021).
Fluorescence micrographs (merge) of SARS-CoV-2-infected beta cells
Fluorescence micrographs (merge) of SARS-CoV-2-infected beta cells from the islets of Langerhans of the pancreas (Figure: J. Müller et al., Nature Metabolism, 2021)