By: Lucija Kavčič
We talked with Prof. Dr Tadej Battelino about his work at the Paediatric Clinic and the Medical Faculty in Ljubljana, the new-born screening system, and the successes he and his team have achieved in managing diabetes using continuous subcutaneous tissue glucose measurement systems.
DEMOKRACIJA: You have been accepted in SAZU as an extraordinary member, for which we sincerely congratulate you! At the same time, we wonder what this means for you?
Battelino: I am extremely grateful to the Slovenian Academy of Sciences and Arts and to my teachers who nominated and elected me. I see this as a kind of duty to do something else in life and justify the honour bestowed on me. I believe that everyone has got their talents and in this short period, we call life, we need to use and develop them as much as possible. Sometimes we fail, but only by developing talents can we at least partially return what we received as a gift. And this recognition of SAZU also falls into this category.
DEMOKRACIJA: How do you combine work at the Paediatric Clinic and the Faculty of Medicine?
Battelino: Routine clinical work, research work and teaching are intertwined in every university hospital. It is this intertwining that is a condition for good clinical work, which cannot be achieved without the simultaneous research and teaching of younger colleagues. It is a bit special that we also have basic research activity – we do not only conduct clinical research, but we also deal with molecular genomics and try to understand the causes of otherwise unexplained diseases. The close link between clinical and research work is two-way: basic research focuses on what is useful and effective for severely or chronically ill people, and the results are then very quickly transferred back into clinical practice. An example is screening for high cholesterol in Slovenia before entering school at the age of five, when cholesterol is determined from a sample taken from each child.
DEMOKRACIJA: Since when has screening for high cholesterol been going on?
Battelino: It has been going on for more than 15 years, it was introduced gradually, and it took quite some time for it to come to life. The research development of molecular genetic diagnostics through next-generation sequencing conducted under the ARRS project culminated in an extensive article published in 2015 in the prestigious Journal of the American College of Cardiology (JACC), they also had a high-profile video of editor-in-chief. Our young researcher received his PhD in this topic, and immediately after that screening began to become routine with the help of a tertiary project at the University Medical Centre Ljubljana, and we finally obtained the consent of the Health Council for its introduction into a compulsory programme paid by ZZZS – this is an example of the development of research work from basic laboratory research to its introduction into routine clinical practice. The programme is now led by Assist. Prof. Urh Grošelj.
DEMOKRACIJA: You are the author of international guidelines formally adopted by all international professional associations for diabetes. What exactly is it about?
Battelino: We are the most internationally recognised in the field of diabetes. It is decades of our team working together in this area. We were among the first to start clinically researching and introducing systems for continuous subcutaneous tissue glucose measurement. Interestingly, even in the developed world, there was initially considerable mistrust in these systems. They were more demanding to work with, and in many places, they did not catch on, but because we saw that they help a lot in regulating sugar levels, we set up the first research for improvements and published them one after another in reputable journals such as Diabetes Care and Diabetologia.
Because we wanted to use these systems in routine practice, we needed to agree on the goals that a person with diabetes should pursue when using these systems. In 2019, these guidelines were published in the central journal of the American Diabetes Association (ADA) Diabetes Care. The guidelines recommend that the glucose concentration be at least 70% of the time in the target range between 3.9 and 10 mm/L, and only 4% of the time below this target range. The new guidelines began to solidify very quickly, and the article already has over 1000 citations. Subcutaneous tissue glucose measurement systems have proven to be extremely useful even during the current pandemic, as users can be advised through remote data transfer.
DEMOKRACIJA: The management of diabetes and other metabolic diseases has improved considerably over the last two decades, and you have also contributed to this. What should be emphasised in this area?
Battelino: Young people get type 1 diabetes and that is just under 10 percent of all people with diabetes. It is an autoimmune disease and not an improper lifestyle. In doing so, the self-defence system attacks and destroys insulin-secreting beta cells in the pancreas for some unknown reason. These people are therefore dependent on insulin replacement. There are a lot of changes in this area: first, insulin pumps have returned, which deliver insulin to the subcutaneous tissue and are technically getting better. After 2000, the systems for the continuous measurement of subcutaneous tissue glucose began to be used, and finally the two systems were merged into a closed loop with the help of artificial intelligence – the system for continuous measurement of glucose in the subcutaneous tissue first measures the sugar, communicates it to the artificial intelligence and the latter, based on algorithms, decides on the current dose of insulin, which is then automatically injected into the subcutaneous tissue by the pump – it is a closed feedback system. These systems have gone through many stages of development – the last one we have is called the advanced hybrid closed loop, advanced because it does almost everything itself, and the hybrid because it still needs to give a manual dose of insulin through the system 15 minutes before a meal. And this system achieves much better results in managing diabetes with less effort from people with diabetes. The ZZZS also quickly established the right to use this system in Slovenia – entirely at the expense of the ZZZS. Initial analyses show that users not only reach the aforementioned 70 percent of the time in the target area, but in most cases exceed it. Artificial intelligence is therefore effective and safe, while reducing the burden of diabetes management on users of all ages as well as their family members. This successful programme is led by Prof. Nataša Bratina.
DEMOKRACIJA: Is type 1 diabetes a hereditary disease?
Battelino: We can talk about a hereditary predisposition to type 1 diabetes, perhaps a little more after the father than after the mother, but we do not know much more than that yet. Its cause is shrouded in darkness and is being researched daily by thousands of researchers. Through the European INNODIA programme, we collect data on people with newly diagnosed diabetes and their relatives and conduct clinical research that tests new drugs that could delay or perhaps even prevent new cases of diabetes.
DEMOKRACIJA: How common is juvenile diabetes in our country? What about thyroid disease and other metabolic diseases in children in our country?
Battelino: There are about 2,000 metabolic diseases – thus we cannot mention all of them. In Slovenia, in the age group from 0 to 18 years, we are currently dealing with about 75 new cases of type 1 diabetes per year. The incidence of this disease is increasing by about 3.5 percent per year. We do not know why it is growing, just as we do not know the cause. However, we can improve and facilitate the management of this disease with the help of the already mentioned technology and artificial intelligence. For type 1 diabetes, the frequency in our age range is now around 15 per 100,000 population – and for other metabolic diseases, the incidence is very low. Thus, about 5 new-borns a year has a congenital deficiency of thyroid hormones – congenital hypothyroidism. Metabolic and endocrine diseases include, for example, cortisol deficiency – we discover about 3 cases a year. Then there are metabolic diseases in the narrow sense, such as diseases of amino acids, fatty acids, and sugars, for which we have many years of screening testing and a total of 5 to 10 cases per year, which are then treated in our institution under the guidance of Assist. Prof. Mojca Žerjav Tanšek.
DEMOKRACIJA: You led the expansion of national neonatal screening from two to 19 congenital diseases and the introduction of confirmatory testing using the next-generation sequencing method. What diseases are involved and what is the importance of such early detection?
Battelino: It is true, and we hope to extend this to almost 50 diseases with the new year. Their early detection means more successful treatment and management of these diseases. We have one of the most advanced neonatal screening systems, which will include diseases such as spinal muscular atrophy, which our neurologists now know how to treat with gene therapy, and congenital immune system deficiencies that can cause children to die suddenly, which our immunologists will then be able to prevent. Experts from all fields are involved in screening new-borns to the most important rare diseases, and the laboratory part, led by Assist. Prof. Barbka Repič Lampret, is key.
DEMOKRACIJA: What are you researching now?
Battelino: The Clinical Institute for Special Laboratory Diagnostics at the Paediatric Clinic is currently working on SARS-CoV-2 virus sequencing, involving more than 100 sequences per week. This part is led by Dr Jernej Kovač, we are cooperating with the National Laboratory for Health, Environment and Food and the National Institute of Biology. The epidemic significantly changed our plans; we are paying close attention to new versions of the virus that could be potentially dangerous. I am talking about omicron, which we do not have now and which we hope will not be much more dangerous. However, all areas of diabetes and interventional clinical research within the European INNODIA programme remain the subject of research. In the laboratory work, we continue to investigate vesicles, smaller than cells of large particles, wrapped in cell membranes, which are interesting due to the transmission of messages in plasma. We are also dealing with changes in the genome in connection with diabetes, which is a large programme and in which Assis. Prof. Klemen Dovč is collaborating. In all fields, in addition to laboratory diagnostics, research projects are also underway, among the largest are the field of obesity by Assist. Prof. Primož Kotnik and the field of pubertal development by Assist. Prof. Magdalena Avbelj Stefanija.
DEMOKRACIJA: We really cannot get past covid-19 this time. How does the epidemic affect the work of the Paediatric Clinic?
Battelino: Thanks to our professional director Assist. Prof. Marko Pokorn, the Paediatric Clinic in Ljubljana has taken very good care of its chronic patients during all periods of the covid-19 epidemic. We did not close, we always gave chronically ill children all the help they needed, so we had our own red and grey wards at the clinic.
DEMOKRACIJA: How dangerous is covid-19 for children with diabetes?
Battelino: Covid-19 can cause extremely violent inflammation in the lungs, heart, and even small blood vessels with all the associated complications. If there is high sugar, which further increases inflammation, the outputs are often worse. It can be said that elevated sugar, regardless of age, poses a marked risk of a more severe course of covid-19 disease. We also treated a patient with newly diagnosed diabetes with co-infection with covid-19. However, because we have been very careful that diabetes or any other underlying disease has been maximally regulated, we do not have any deaths among children at the moment.
DEMOKRACIJA: What about children and vaccination against covid-19?
Battelino: EMA has now approved the vaccination of children between the ages of 5 and 12 in Europe, and in the United States, high-speed vaccination of children is already taking place in schools. The CDC in the US has reported nearly 1,000 children dying from covid-19 and no deaths from vaccination, so the risk-benefit balance is perfectly clear. The argument on evidence-based medicine is clear. Of course, someone will say – but children do not get so sick of covid-19, with few exceptions. That is true, but it needs to be looked at much more broadly. Firstly, some children become seriously ill and die in some countries. In Slovenia, we have not yet had a death case, most likely due to health care, which has worked very hard. Secondly, children may have an unusual complication called MIS-C, which is a multi-organ autoimmune inflammatory reaction, and we also treated very difficult cases: more than 30 children, including myocarditis and the need for intensive care. This fact must also be put aside by the risk equation. We also treated some peripheral vasculitis – inflammation of small blood vessels and changes in the fingers and skin of children, all because of covid-19 infection. On the other hand, the side effects of vaccination in children are so far milder. The most severe of these is very rare: inflammation of the heart muscle – myocarditis – which is more common in boys (we do not know why), but in all cases has disappeared without consequences.
DEMOKRACIJA: What else would you highlight?
Battelino: Children are known carriers of the disease, and especially in the last wave, many unvaccinated adults who died of covid-19 got the infection from a child. Let us not forget: the fact that children can be a source of infection has an extremely negative effect on their psyche, so they must be given the opportunity to free themselves from the fact that when they get vaccinated, they will no longer be dangerous to their grandparents, who for various reasons are never sufficiently protected. In addition, children like to socialise, so it is imperative to reduce the current pressure on them that has arisen because they are isolated and do not have enough contact with each other. And vaccination is the only way to free children. It is therefore a whole range of health, psychological and sociological aspects that speak in favour of vaccination, including the fact that if a significant part of the population is not vaccinated, the virus is given time and space to mutate again. That the virus will go away can only be achieved by high vaccination coverage of the entire population and all age groups for which the vaccine is good.
DEMOKRACIJA: How would you encourage people to get vaccinated?
Battelino: The incomprehensible fear of vaccination that prevails among a significant part of the population of Slovenia is difficult for many, especially for those of us who deal with evidence-based medicine. It is worrying that so many people here are unable to accept scientific facts and respond reasonably. Parents accept a whole lot of other risks about their children without thinking (just think of the risks in traffic where too many children die every year), and they are afraid of vaccinations. That is why it is a great challenge for us, the doctors, and for society, to present the facts to people so that they can accept them. Allow me, at this point, to ask all experts, psychologists, sociologists, philosophers, and all people of good will to help increase vaccination coverage in Slovenia, as this is the only way out of this difficult and complex pandemic. At this point, as a society, we need to stand together, make an informed decision, and end the epidemic so that we can live normally again. Then all the other quarrels can continue!
Biography
Prof. Tadej Battelino, MD, heads the Clinical Department of Endocrinology, Diabetes and Metabolic Diseases at the Paediatric Clinic of the University Medical Centre Ljubljana and the Department of Paediatrics of the Medical Faculty of the University of Ljubljana. He leads the research programme and projects at ARRS, he is a researcher at the European INNODIA project and at clinical research funded by the National Institute of Health (NIH, Bethesda, USA) and the Helmsley Foundation (USA). He has been awarded several times for his top scientific achievements. He is a member of the editorial boards of the journals Diabetes Care and the Journal of Paediatric Endocrinology and Metabolism and a member of many professional associations, including the International Society for Paediatric and Adolescent Diabetes, where he was president of the 35th Annual Congress in Ljubljana. He was a member of the board of the European Association for the Study of Diabetes (EASD) and co-organiser of the fifteen annual ATTD (Advanced Technologies and Treatment of Diabetes) congresses. He has published 276 scientific papers that have been cited more than 13,000 times in the last 10 years. He is an associate member of the Slovenian Academy of Sciences and Arts (SAZU), a founding member of the Slovenian Medical Academy and a full member of the European Academy of Sciences and Arts.