Type 1 diabetes is often referred to as juvenile or childhood diabetes, but this is misleading. Many people only develop type 1 diabetes after decade of normal pancreas function. A growing body of evidence indicates that viral infection is a potential culprit. If doctors can identify these vulnerable people, vaccines or antiviral treatments might be able to save them before they develop type 1 diabetes before it is too late.
An estimated 9 million people worldwide have type 1 diabetes, a chronic and potentially fatal disease that occurs when the pancreas cannot produce enough insulin to regulate blood glucose. Although scientists have identified genes associated with an increased likelihood of developing type 1 diabetes, heredity does not fully explain who develops diabetes and who does not.
“In Norway, about 85% of patients developing type 1 diabetes are the first case in the family,” says Lars Krogvold, a physician and paediatrician at Oslo University Hospital who researches diabetes. Type 1 diabetes is often referred to as juvenile or childhood diabetes, but Krogvold says that this is misleading. Some people develop type 1 suddenly after decades of apparently normal pancreas function. “There has to be something in the environment causing the disease to develop,” Krogvold adds.
New research, published in July in Frontiers in Endocrinology, adds to a growing body of evidence indicating that viral infection is a potential culprit. By examining samples taken from the pancreas of people newly diagnosed with type 1 diabetes, researchers found genetic evidence of immune systems in overdrive.
The functional decline of the pancreas “starts months, potentially years before we ever see evidence of it in the clinic,” says Pia Leete, a researcher at the University of Exeter Medical School and a co-author. The authors think that they are now one step closer to understanding how the process may begin – with implications for early-intervention treatment.
Islets of Langerhans and enteroviruses
The pancreas contains the fancifully named islets of Langerhans: tiny clusters of cells that reside in the pancreatic organ and secrete insulin and other key hormones that work to balance blood glucose. “You can fit 10 on the top of a pinhead, and each islet is a micro-organ in its own right,” Leete explains. “It has its own vasculature and its own innervation, and each islet appears to work independently of the others to maintain a healthy balance of sugars in the blood.”
The islets of Langerhans seem to be a prime target for enteroviruses, a class of pathogens that includes the viruses causing hand, foot and mouth disease, poliovirus and a slew of garden-variety bugs that children pick up from day care. Autopsy studies have shown that people with type 1 diabetes have more evidence of enteroviruses in their pancreas than people without diabetes.
Generally, enteroviruses are mild and should not cause systemic issues, says Sarah Richardson, another University of Exeter Medical School researcher and co-author. “If you have young kids, you will encounter one or two of these a year,” she says. Enteroviruses are inevitable, but for some, they seem to provoke the immune system in the pancreas to attack and destroy the islets of Langerhans. “It is not whether you get an enterovirus; it is what you do with it when you get it that might determine whether you set off an autoimmune reaction.”
To investigate what goes wrong in the immune response to enteroviruses among people with type 1 diabetes, the interdisciplinary research team behind the article turned to samples from the Diabetes Virus Detection Study (DiViD) conducted in the early 2010s in which six people recently diagnosed with type 1 diabetes volunteered to undergo invasive surgery so that scientists could biopsy their pancreas.
Krogvold emphasises that the DiViD volunteers participated totally “altruistically” – it was unrelated to their course of treatment and carried some risk to them. “It has been 100 years now since insulin was discovered. That is very important, of course – now people with type 1 diabetes live and become old, many hopefully with no complications, but still we do not have any cure,” he explains. “That may very much be because actually examining the organ is so difficult.”
The pancreas is nestled between many vital organs and, in addition to the islets of Langerhans, also contains cells that produce digestive enzymes for the stomach. Any damage to the organ, during surgery or otherwise, can release these destructive proteins into the abdominal cavity, where they can damage other organs, which means that researchers largely rely on studying autopsy samples.
“DiViD allowed us to explore the pancreas from healthy, living, active, coping patients,” Leete says.
A flurry of activity
For this study, the team compared the activity of a range of genes involved in cellular stress and immune response in the DiViD patients’ islets of Langerhans with those of healthy controls of the same age.
The researchers found a flurry of changes that paint a picture of an immune system under siege. The islets from DiViD patients contained significantly more RNA encoding MDA5, a protein that can recognise genetic material from invading viruses and sound the cellular alarm.
MDA5 works by triggering the creation of interferons, proteins that coordinate the cell’s defence by activating genes that can stymie a virus’s reproduction. Mutations to MDA5 are associated with an increased risk for type 1 diabetes.
Downstream in the immune response, the team also found striking differences in the rates of two of the proteins summoned by interferons. The first, MxA, is an antiviral response protein that is effective against several diverse viruses, including the Coxsackieviruses most often linked with type 1 diabetes. It is thought that MxA might disrupt viral activity by forming complex shapes with other MxA proteins, creating rings and tubes to physically cordon off the virus and potentially wrench pieces of it apart.
The second, protein kinase R, was found specifically in holdout cells in the DiViD patients’ islets that still contained insulin and show evidence of previous infections, which is rarely, if ever, found in the pancreas of people without diabetes. All these results “add grist to the mill” that viruses may be involved in developing type 1 diabetes, Richardson explains.
What does it mean?
Further study is required and ongoing to tease out whether any of these immune processes are appropriate targets for intervention.
Part of the problem, Leete explains, is that “we still don’t know quite when it starts”. Scientists are not certain what percentage of the islets of Langerhans need to be knocked out before the pancreas cannot do its job and type 1 diabetes begins, and this may not be the same for every individual.
“It may be that the viruses have a role right at the beginning, setting the process off in the first place,” Richardson says. “It may also speed up people developing the clinical symptoms, and it may also be involved in the persisting autoimmunity we see after diagnosis.”
“So there is this balance between having genetic risk, having an immune component in which your body can turn against itself and some environmental trigger such as an enterovirus that sets off these things,” she adds.
If doctors can identify these vulnerable people before they develop type 1 diabetes, vaccines for enteroviruses or antiviral treatments might be able to save their islets of Langerhans before it is too late.
Krogvold’s team at the Oslo Diabetes Research Centre is currently wrapping up an experiment testing the effects of 6-month antiviral treatments on children recently diagnosed with type 1 diabetes. “This particular treatment is too late to prevent the disease at onset,” Krogvold says, but in combination with the lessons learned through the generosity of the DiViD patients, we may one day achieve this extraordinary goal.