A new study shows that a particular type of enterovirus can trigger a MODY4-like diabetes in affected patients.
A research team from the Growth Factors, Nutrients, and Cancer Group, led by Dr. Nabil Djouder at the Spanish National Cancer Research Centre (CNIO), demonstrated how the enterovirus, Coxsackievirus B Type 4 (CVB4), could induce diabetes in affected patients. Their findings, which were published in the scientific journal Cell Reports Medicine, showed that the CBV4 infection in mice induced downregulation of URI, a protein that controls various cellular functions. This downregulation caused a cascade of molecular events, including the Pdx1 gene’s silencing, which could eventually trigger diabetes in patients who have the enterovirus.
According to the World Health Organization (WHO), approximately 1.6 million people died due to diabetes in 2016 globally. Moreover, it is estimated that 425 million people live with diabetes worldwide, and by 2045, that number is projected to skyrocket to 629 million if the current trend continues.
Dr. Djouder and his researchers stated that their findings could be especially relevant during the COVID-19 pandemic, since there seems to exist a possible relationship between SARS-COV-2 viral infection and diabetes. They suggested that since the SARS-COV-2 receptor is expressed in the pancreas, it could operate and lead to the development of diabetes in a similar way that CBV4 does, irrespective of immune reactions.
Coxsackievirus belongs to the Enteroviruses family, which causes various diseases with neurologic, respiratory, skin, and gastrointestinal symptoms. It also includes the poliovirus and the echovirus, and has a range of effects from mild flu-like symptoms to more serious and debilitating ones such as pancreatitis, meningitis, pericarditis, and myocarditis. Initially, it was suspected that these viruses could cause diabetes in humans, but their specific mechanism has not been known.
Hence, the CNIO research team aims to find and describe the specific mechanism by which CBV4 infection causes diabetes. They worked on animal models grafted with human pancreatic cells infected with CVB4 and human and mouse insulin-producing cells with the virus. They observed that CBV4 infection induces the deregulation of URI, which results in the silencing of the gene Pdx1. The Pdx1 gene is critical for the identity and function of beta cells present in the endocrine pancreas. They are responsible for the production and secretion of insulin, a hormone that decreases blood glucose levels. As Dr. Djouder explains, “Pdx1 gene silencing causes the loss of the identity and function of beta cells in the Islets of Langerhans, which become more like alpha cells, in charge of increasing blood glucose levels, and hence leading to hyperglycemia and subsequent diabetes.”
Moreover, the researchers also observed that mice with diabetes, which overexpressed the URI protein in beta cells, were more tolerant of blood glucose changes. The researchers also noted a correlation between URI expression, Pdx1 gene, and viral particles in the pancreas from people with diabetes. Thus, there seems to be a possible causal relationship between enterovirus infection and diabetes in humans.
The CNIO study results could help pave the way for using antiviral therapies alongside drugs that inhibit the silencing of the gene Pxd1 from preventing and treating diabetes. Drugs such as DNA methyltransferase inhibitors, which inhibit a protein involved in Pdx1 silencing, could reinstate Pdx1 expression and glucose tolerance in diabetic mice models; hence, they could be used in clinical trials for future studies.
Indeed, Dr. Djouder and his team believe that their study has potential implications for the COVID-19 pandemic. As he stated, “since the receptor of SARS-COV-2 is present in beta cells, it would be interesting to study if this virus also alters URI function and silences the expression of Pdx1 to affect beta-cell function, promoting diabetes.”
- The enterovirus, Coxsackievirus B Type 4 (CVB4), could induce diabetes in affected patients through the downregulation of URI, a protein that controls various cellular functions.
- Coxsackievirus belongs to the Enteroviruses family, which causes multiple diseases with neurologic, respiratory, skin, and gastrointestinal symptoms.
- There seems to be a possible relationship between COVID-19 and diabetes since the SARS-COV-2 receptor is expressed in the pancreas; it could operate and lead to the development of diabetes in a similar way that CBV4 does.
Djouder, Nabil et al. “Coxsackievirus B type 4 infection in beta cells downregulates the chaperone prefoldin URI to induce a MODY4-like diabetes via pdx1 silencing.” Cell reports medicine vol.1,100125 (2020): 1-18. doi:10.1016/j.xcrm.2020.100125
Nekoua, Magloire Pandoua et al. “Salivary anti-coxsackievirus-B4 neutralizing activity and pattern of immune parameters in patients with type 1 diabetes: a pilot study.” Acta diabetologica vol. 55,8 (2018): 827-834. doi:10.1007/s00592-018-1158-3
Arjay Mendoza, PharmD Candidate, University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences