• References

    Chee YJ et al. (2020). Diabetic ketoacidosis precipitated by COVID-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin 164, 108,166.

    Ferri G et al. (2020). Metabolic response of Insulinoma 1E cells to glucose stimulation studied by fluorescence lifetime imaging. FASEB Bioadv 2, 409-418.

    Haythorne E et al. (2019). Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nat Comm 10, 2,474.

    Mallapaty S (2020). Mounting clues suggest the coronavirus might trigger diabetes. Nature Briefing. Accessed February 02, 2021.

    Rubino F (2020). New-onset diabetes in COVID-19. N Eng J Med 383, 789-790.

    Yang L et al. (2020). A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 27, 125-136.

    Zhu L et al. (2020). Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab 31, 1068-1077.

Can COVID-19 Trigger New-Onset Diabetes?

10 March, 2021

 

Can COVID-19 Trigger New-Onset Diabetes?

When looking into the pancreas, you will find clusters of cells called islets containing endocrine cells responsible for synthesizing and secreting hormones for glucose homeostasis and nutrient metabolism. Within the endocrine cells, beta cells are the ones responsible for producing, storing, and releasing insulin. In normal conditions, secreted insulin travels to cells with insulin receptors throughout the body to enable the cell to take in glucose for energy. However, in diabetic conditions, beta cells become dysfunctional, unable to secrete or secreting too much insulin, which eventually leads to hyperglycemia. Type 1 diabetes (T1D) is insulin-dependent diabetes, while type 2 diabetes (T2D) is insulin-independent.

Diabetes is a key risk factor for severe COVID-19 (Zhu et al. 2020) and worsens outcomes for COVID-19 patients, as they often require more medical interventions and have substantially higher mortality rates. Preliminary research suggests that diabetes may also be an outcome of SARS-CoV-2 infection (Rubino et al. 2020, Chee et al. 2020). In this guest blog, Janielle Cuala, a graduate student in the field of diabetes based at the Senta Georgia’s lab at the Children’s Hospital Los Angeles, tells us about this interesting link and the research her lab is doing in this area.

An Interesting Case Study

A popular case study and often referred to is that of Finn Gnadt, an 18-year-old student from Germany. In mid-April, Gnadt tested positive for SARS-CoV-2 antibodies. He hadn't felt unwell himself, but his parents started feeling sick after going on a river cruise in Austria, so the whole family were tested for virus antibodies. Although asymptomatic for COVID-19, not long after, Gnadt started having other symptoms including fatigue and excessive thirst, prompting a visit to his physician. He was diagnosed with T1D. Most people with T1D have immune cells destroying their insulin secreting beta cells within the pancreas. However, in Gnadt’s case, these immune cells were not present, and his doctor suggested that the virus itself may have destroyed his beta cells, leading to the onset of diabetes (Mallapaty 2020).

Additional cases similar to Gnadt’s have since emerged, adding support to the possibility that diabetes may be triggered by SARS-CoV-2 infection. To further investigate this, a group of scientists started an initiative to keep track of these cases by establishing a global database, called COVIDIAB. This database collects data on COVID-19 patients, presenting with high blood-sugar levels, and no preexisting diabetic condition. With this registry, they hope to determine the extent of and characterize COVID-19 related diabetes.

Could Beta Cells Be Key to This?

Pancreatic beta cells are responsible for sensing increases in blood sugar and releasing glucose to maintain normal blood sugar levels. One of the driving forces behind both T1D and T2D is the loss of a functional number of beta cells. Once beta cell function is lost, either by autoimmune mediated beta cell destruction in T1D or beta cell exhaustion and dedifferentiation in T2D, blood sugar increases and people become diabetic. Clinical reports, database studies, and anecdotal clinician’s reports raise the question: does SARS-Cov2 infection cause beta cell dysfunction and lead to diabetes?

While this is an interesting question, data from patients is limited due to the novelty of COVID-19, and reports on the subject have been conflicting. However, the entry receptor for SARS-CoV-2, the ACE-2 receptor, is expressed on many human cells, including beta cells. It is therefore plausible that beta cells are directly infected by SARS-CoV-2, leading to their death and the onset of T1D. Evidence supporting this, came from a stem cell-based platform, used to study SARS-CoV-2 infection in human cells and different organoids, which highlighted that it is possible for SARS-CoV-2 to infect pancreatic beta cells and primary human islets (Yang et al. 2020).

This study also investigated the induction of chemokine and cytokine production due to infection, which triggered an immune response that could also lead to beta cell death. Transcript profiles comparing the infected pancreatic human pluripotent stem cell derived islet organoids to COVID-19+ human lung autopsy samples (as it is challenging to obtain pancreatic samples from patients) showed an upregulation of chemokines such as CCL2, CXCL5, and CXCL6 that attract cytotoxic immune cells. This suggests the potential of an immune storm that could trigger beta cell death.

What's Happening to the Beta Cells?

With all this in mind, Senta Georgia’s lab at the Children’s Hospital Los Angeles has hypothesized that SARS-CoV2 infection acutely compromises beta cell function, replication, and survival by reprogramming cellular metabolism, thus leaving the host susceptible to disease during, or after, infection. To answer these questions, the Georgia lab studies infected beta cells using an in-situ hybridization method that tracks target RNA in intact cells (RNAscope), to determine viral load over time. In addition, we are using immunohistochemistry to determine the distribution of the ACE2 receptor and TMPRSS2 in insulin-positive cells. Cells are also stained/tagged with both proliferation and apoptotic markers to visualize whether beta cells are dying or replicating. We are going to also quantify cytokine expression within the cell to figure out if there is any suggestion of an autoimmune mediated cell death.

Whether SARS-CoV2 is directly infecting beta cells or eliciting an immune response within the beta cells, indirectly causing damage, the Georgia lab also hypothesizes some sort of metabolic dysfunction is happening within the cells causing a rise in cases of COVID-19 related new onset diabetes.

In normal glucose conditions (euglycemic), beta cells primarily use oxidative phosphorylation as the primary means of cellular metabolism. In a diabetic condition, cellular metabolism shifts to a glycolytic profile. This switch in gene and protein regulation indicates that there is shift in metabolism from oxidative phosphorylation to glycolysis in the context of diabetes (Haythorne et al. 2019). An imaging technique called Fluorescence Lifetime Imaging (FLIM) uses the inherent autofluorescence of NADH overlaid on a mitochondrial stain to enable subcellular analysis of the metabolic conditions in beta cells. Bound NADH (oxidative phosphorylation state) and unbound NADH (glycolytic state) have specific FLIM signatures that can be plotted to determine whether a metabolic shift has occurred in different cellular context. It has been shown that within glucolipotoxic insulinoma, 1E cells, the standard cell line for studying pancreatic beta cells, there is a shift towards a glycolytic profile (Ferri 2020). Therefore, the Georgia lab plans to utilize FLIM imaging to determine if SARS-CoV2 infected beta cells follow a similar trend.

In conclusion, while there appears to be an association between COVID-19 and some cases of sudden onset diabetes, it is still not clear whether it is the result of a direct infection of beta cells, or an immune storm triggering T1D onset. Tying clinical observations and molecular phenotypes together should provide important information to those managing COVID-19 and diabetic patients, hopefully improving future patient outcomes. It is possible that this type of research will provide insight into the cellular pathways involved to help develop therapies to save beta cells before, during, and after SARS-CoV-2 infection.

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References

Chee YJ et al. (2020). Diabetic ketoacidosis precipitated by COVID-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin 164, 108,166.

Ferri G et al. (2020). Metabolic response of Insulinoma 1E cells to glucose stimulation studied by fluorescence lifetime imaging. FASEB Bioadv 2, 409-418.

Haythorne E et al. (2019). Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nat Comm 10, 2,474.

Mallapaty S (2020). Mounting clues suggest the coronavirus might trigger diabetes. Nature Briefing. Accessed February 02, 2021.

Rubino F (2020). New-onset diabetes in COVID-19. N Eng J Med 383, 789-790.

Yang L et al. (2020). A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 27, 125-136.

Zhu L et al. (2020). Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab 31, 1068-1077.

 

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