Posted on by Dr. Francis Collins
Along with the pneumonia, blood clots, and other serious health concerns caused by SARS-CoV-2, the COVID-19 virus, some studies have also identified another troubling connection. Some people can develop diabetes after an acute COVID-19 infection.
What’s going on? Two new NIH-supported studies, now available as pre-proofs in the journal Cell Metabolism [1,2], help to answer this important question, confirming that SARS-CoV-2 can target and impair the body’s insulin-producing cells.
Type 1 diabetes occurs when beta cells in the pancreas don’t secrete enough insulin to allow the body to metabolize food optimally after a meal. As a result of this insulin insufficiency, blood glucose levels go up, the hallmark of diabetes.
Earlier lab studies had suggested that SARS-CoV-2 can infect human beta cells . They also showed that this dangerous virus can replicate in these insulin-producing beta cells, to make more copies of itself and spread to other cells .
The latest work builds on these earlier studies to discover more about the connection between COVID-19 and diabetes. The work involved two independent NIH-funded teams, one led by Peter Jackson, Stanford University School of Medicine, Palo Alto, CA, and the other by Shuibing Chen, Weill Cornell Medicine, New York. I’m actually among the co-authors on the study by the Chen team, as some of the studies were conducted in my lab at NIH’s National Human Genome Research Institute, Bethesda, MD.
Both studies confirmed infection of pancreatic beta cells in autopsy samples from people who died of COVID-19. Additional studies by the Jackson team suggest that the coronavirus may preferentially infect the insulin-producing beta cells.
This also makes biological sense. Beta cells and other cell types in the pancreas express the ACE2 receptor protein, the TMPRSS2 enzyme protein, and neuropilin 1 (NRP1), all of which SARS-CoV-2 depends upon to enter and infect human cells. Indeed, the Chen team saw signs of the coronavirus in both insulin-producing beta cells and several other pancreatic cell types in the studies of autopsied pancreatic tissue.
The new findings also show that the coronavirus infection changes the function of islets—the pancreatic tissue that contains beta cells. Both teams report evidence that infection with SARS-CoV-2 leads to reduced production and release of insulin from pancreatic islet tissue. The Jackson team also found that the infection leads directly to the death of some of those all-important beta cells. Encouragingly, they showed this could avoided by blocking NRP1.
In addition to the loss of beta cells, the infection also appears to change the fate of the surviving cells. Chen’s team performed single-cell analysis to get a careful look at changes in the gene activity within pancreatic cells following SARS-CoV-2 infection. These studies showed that beta cells go through a process of transdifferentiation, in which they appeared to get reprogrammed.
In this process, the cells begin producing less insulin and more glucagon, a hormone that encourages glycogen in the liver to be broken down into glucose. They also began producing higher levels of a digestive enzyme called trypsin 1. Importantly, they also showed that this transdifferentiation process could be reversed by a chemical (called trans-ISRIB) known to reduce an important cellular response to stress.
The consequences of this transdifferentiation of beta cells aren’t yet clear, but would be predicted to worsen insulin deficiency and raise blood glucose levels. More study is needed to understand how SARS-CoV-2 reaches the pancreas and what role the immune system might play in the resulting damage. Above all, this work provides yet another reminder of the importance of protecting yourself, your family members, and your community from COVID-19 by getting vaccinated if you haven’t already—and encouraging your loved ones to do the same.
 SARS-CoV-2 infection induces beta cell transdifferentiation. Tang et al. Cell Metab 2021 May 19;S1550-4131(21)00232-1.
 SARS-CoV-2 infects human pancreatic beta cells and elicits beta cell impairment. Wu et al. Cell Metab. 2021 May 18;S1550-4131(21)00230-8.
 A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Yang L, Han Y, Nilsson-Payant BE, Evans T, Schwartz RE, Chen S, et al. Cell Stem Cell. 2020 Jul 2;27(1):125-136.e7.
 SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Müller JA, Groß R, Conzelmann C, Münch J, Heller S, Kleger A, et al. Nat Metab. 2021 Feb;3(2):149-165.
COVID-19 Research (NIH)
Type 1 Diabetes (National Institute of Diabetes, Digestive and Kidney Disorders/NIH)
Jackson Lab (Stanford Medicine, Palo Alto, CA)
Shuibing Chen Laboratory (Weill Cornell Medicine, New York City)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Human Genome Research Institute; National Institute of General Medical Sciences; National Cancer Institute; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development
Posted on by Dr. Francis Collins
COVID-19 is primarily considered a respiratory illness that affects the lungs, upper airways, and nasal cavity. But COVID-19 can also affect other parts of the body, including the digestive system, blood vessels, and kidneys. Now, a new study has added something else: the mouth.
The study, published in the journal Nature Medicine, shows that SARS-CoV-2, which is the coronavirus that causes COVID-19, can actively infect cells that line the mouth and salivary glands. The new findings may help explain why COVID-19 can be detected by saliva tests, and why about half of COVID-19 cases include oral symptoms, such as loss of taste, dry mouth, and oral ulcers. These results also suggest that the mouth and its saliva may play an important—and underappreciated—role in spreading SARS-CoV-2 throughout the body and, perhaps, transmitting it from person to person.
The latest work comes from Blake Warner of NIH’s National Institute of Dental and Craniofacial Research; Kevin Byrd, Adams School of Dentistry at the University of North Carolina, Chapel Hill; and their international colleagues. The researchers were curious about whether the mouth played a role in transmitting SARS-CoV-2. They were already aware that transmission is more likely when people speak, cough, and even sing. They also knew from diagnostic testing that the saliva of people with COVID-19 can contain high levels of SARS-CoV-2. But did that virus in the mouth and saliva come from elsewhere? Or, was SARS-CoV-2 infecting and replicating in cells within the mouth as well?
To find out, the research team surveyed oral tissue from healthy people in search of cells that express the ACE2 receptor protein and the TMPRSS2 enzyme protein, both of which SARS-CoV-2 depends upon to enter and infect human cells. They found the proteins may be expressed individually in the primary cells of all types of salivary glands and in tissues lining the oral cavity. Indeed, a small portion of salivary gland and gingival (gum) cells around our teeth, simultaneously expressed the genes encoding ACE2 and TMPRSS2.
Next, the team detected signs of SARS-CoV-2 in just over half of the salivary gland tissue samples that it examined from people with COVID-19. The samples included salivary gland tissue from one person who had died from COVID-19 and another with acute illness.
The researchers also found evidence that the coronavirus was actively replicating to make more copies of itself. In people with mild or asymptomatic COVID-19, oral cells that shed into the saliva bathing the mouth were found to contain RNA for SARS-CoV-2, as well its proteins that it uses to enter human cells.
The researchers then collected saliva from another group of 35 volunteers, including 27 with mild COVID-19 symptoms and another eight who were asymptomatic. Of the 27 people with symptoms, those with virus in their saliva were more likely to report loss of taste and smell, suggesting that oral infection might contribute to those symptoms of COVID-19, though the primary cause may be infection of the olfactory tissues in the nose.
Another important question is whether SARS-CoV-2, while suspended in saliva, can infect other healthy cells. To get the answer, the researchers exposed saliva from eight people with asymptomatic COVID-19 to healthy cells grown in a lab dish. Saliva from two of the infected volunteers led to infection of the healthy cells. These findings raise the unfortunate possibility that even people with asymptomatic COVID-19 might unknowingly transmit SARS-CoV-2 to other people through their saliva.
Overall, the findings suggest that the mouth plays a greater role in COVID-19 infection and transmission than previously thought. The researchers suggest that virus-laden saliva, when swallowed or inhaled, may spread virus into the throat, lungs, or digestive system. Knowing this raises the hope that a better understanding of how SARS-CoV-2 infects the mouth could help in pointing to new ways to prevent the spread of this devastating virus.
 SARS-CoV-2 infection of the oral cavity and saliva. Huang N, Pérez P, Kato T, Mikami Y, Chiorini JA, Kleiner DE, Pittaluga S, Hewitt SM, Burbelo PD, Chertow D; NIH COVID-19 Autopsy Consortium; HCA Oral and Craniofacial Biological Network, Frank K, Lee J, Boucher RC, Teichmann SA, Warner BM, Byrd KM, et. al Nat Med. 2021 Mar 25.
COVID-19 Research (NIH)
Saliva & Salivary Gland Disorders (National Institute of Dental and Craniofacial Research/NIH)
Blake Warner (National Institute of Dental and Craniofacial Research/NIH)
Kevin Byrd (Adams School of Dentistry at University of North Carolina, Chapel Hill)
NIH Support: National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences