No other country, next Finland, has as high incidence of Type 1 diabetes (T1D) among children as Sweden. The disease has become more and more common, in recent years with an incidens of ca 45/100 000 children/year. The cause is unknown, although there are several hypothesis. Virus infections, especially enterovirus, are suspected to cause alt least some cases of T1D. Pronounced hygiene may increase the risk for the autoimmune process (“the civil war”) causing destruction of the insulin producing beta cells in pancreas, leading to the insulin deficiency which is characteristic for T1D, 98 % of the diabetes among children in Sweden ( ca 1 % MODY and <%=T2D). However, also factors usually associated with development of T2D such as rapid increase of weight, low physical activity, psychological stress etc might cause beta cell stress and contribute to development of T1D.
T1D cannot be cured. In spite of intensive, very heavy treatment with multiple daily injections of insulin, given by pen or pump, adjusted to regular meals ( carbohydrates, fibers, energy, fat, protein), monitored by daily blood glucose measurements and/or glucose sensors, the children sometimes get serious acute complications (severe hypoglycemia and/or keto-acidosis), and they risk long-term complications in eyes, kidneys, heart, nerves.
T1D patients with near-normal blood glucose that is good metabolic control seems to have a doubled mortality compared with the general population, while those with poor control ( high HbA1c) has 6-8 fold increased mortality.
Johnny Ludvigsson´s diabetes research deals with several areas
Etiology of Type 1 diabetes
To be able to study what happened in early life, many years before the diagnosis of Type 1 diabetes, Johnny Ludvigsson created the ABIS study (All Babies in Southeast Sweden). Ca 17 000 children (78.6%) out of 21700 born in southeast Sweden Oct 1st 1997-1999 were included after that their parents had given their informed consent. At birth and then after 1, 3, 5, 8, 11 years comprehensive questionnaires on environmental factors and life style have been answered by the parents, parallel to collection of biological samples( blood. Urine, stool, hair) from the children, and at birth also samples from the mothers and fathers. Development of T1D has been predicted in a large proportion by determination of diabetes-related auto-antibodies. Up to 2015 116 children had developed T1D, and it has been possible to study how development of auto-antibodies, and manifest Type 1 diabetes, is related to factors like food, stress, infections etc. Such studies continue. For more information see www.abis-studien.se.
Infections have been suspected and studies continue (Malin Ördberg, Jeanette Wahlberg Hughes), and the gut flora (microbiome) may influence the maturation of the immune system and/or directly infect pancreas (Pär Andersson-White; collaboration with prof Eric Triplett, University South Florida, Gainesville, USA). The food has also been suspected, not least cow´s milk proteins, gluten etc, as well as breastfeeding, which in turn might influence gut (Sofia Klingberg, Gothenburg, and Hilde Brekke, Oslo). Based on the Beta Cell Stress Hypothesis (Ludvigsson, 2006) it has been important to study social situation ((Pär Andersson-White, Tomas Faresjö, Åshild Faresjö). And we have also shown that SeriousLife Events early in life are associated with development of autoantibodies (Sepa 2005,2006) and in fact also increase the risk 3-fold for manifest T1D ( Nygren 2015), for the first time ever shown in a prospective unbiased study. We also study antibodies against neo-antigens together with collaborators in London (Rocky STrollo, Ahuva Nasim) and in Rome (Paolo Pozzilli). Obesity is another field of interest which has lead to PhD thesis (Felix Koch, Karina Huus), and studies are ongoing (Karel Duchen, Åshild Farejsö, Tomas Faresjö).
Etiology of T1D is also studied in other collaborative research than ABIS. Thus, in the DIVID trial, initially a project involving GAD-vaccinations, biopsies were taken from newly-diagnosed T1D-patients (Knut Dahl-Jörgensen, Lars Krogvold), and as part of an EU-project (PEVNET) virus infections have been studied, and related to immunological reactions in the islets of Langerhans and also peripheral blood which we have taken care of in Linköping. As part of PEVNET we have also studied virus infections in relation to the GAD-response in patients participating in an immune intervention trial ( DIABGAD).
In addition we have epidemiological studies based on the BDD ( Better Diagnosis of Diabetes) study, a national collection of blood samples at diagnosis of diabetes in all Swedish pediatric clinics. Johnny Ludvigsson has been mem ber of steering group of BDD from its start, and in Linköping we have done studies especially on C-peptide, but also IAPP (Gunilla Westermark). Finally SWEDIABKIDS , then Swedish national register, can be mentioned which has been part of some epidemiological projects (Ulf Samuelsson).
ABIS research beside Type 1 diabetes
ABIS was designed to study not only T1D but also other immune mediated diseases, and therefore we have during the years, and also ongoing, studies on allergy (Karel Duchen), autism (Per Gustafsson), Rheumatoid arthritis (Erik Kindgren), celiac disease (Jonas Ludvigsson).
Prevention of Type 1 diabetes
In blood samples from the ABIS children autoantibodies have been determined and high risk children identified. Certain groups have been followed more carefully and their beta cell function studied (Linda Åkerman, Camilla Skoglund) as well as association to microRNA. Prevention protocols have been planned, and one pilot trial using probiotics (PRODIA) was performed (Outi Vaarala). Johnny Ludvigsson has also been national coordinator from early 1990ies in the studies first lead by Hans Åkerblom, later Mikael Knip, Helsinki, on how to reduce T1D by avoiding cow´s milk protein early in life (TRIGR trial) which finally 2017 will give its end results. In the meantime other ancillary studies have been started related to gut flora, and also allergy/asthma development.
Efforts to make Type 1 diabetes milder
Interventions to preserve residual beta cell function
GAD (Glutamic Acid Decarboxylase;GAD65) was first discovered as the antigen 64kD in Linköping children (Nature 1982) when we treated newly-diagnosed Type 1 diabetic children with plasmapheresis (BMJ 1983). It was later shown that the antigen , actually 65kD, was Glutamic Acid Decarboxylase (GAD). We have used this auto-antigen in several studies to preserve residual beta cell function by stopping theautoimmune process. The studies were first very successful (NEJM 2008), but later a European Phase III trial failed to reach the primary endpoint (NEJM 2012). However, the efficacy was good in several pre-specified subgroups, and a later meta-analyses has shown a probability of 98% that GAD-alum 20 mikrog sc x 2 has effect, although we need to improve the efficacy. Thus Johnny Ludvigsson is sponsor and Principal Investigator ( PI) for several intervention trials using GAD-alum but in combination with other therapies.
DIABGAD is a randomized double-blind placebo-controlled Phase II trial including 64 patients 12-18 years old with recent onset Type 1 diabetes, with 4 arms, when GAD-alum 20 mikrog x 2 sc has been given in combination with vitamin D 2000 U/d for 15 months and Ibuprofen 400 mg/d given for 3 months (Johnny Ludvigsson, Rosaura Casas). The results weill be analysed 2017.
EDCR is another open-labelled pilot trial when GAD-alum 20 mikrg sc x 2 is combined with vitamin D per os 2000 U/d and Etanercept (TNFalfa-inhibitor) given sc0.8 mg/kg once a week for 3 months.20 patients 8-18 years old with recent onset Type 1 diabetes are included and will be followed for 30 months. DIAGNODE is a third open-labeled pilot trial when GAD-alum 4 mikrg is given 3 times with one month interval directly into inguinal lymph-nodes by the help of ultrasound needle guide. This is the first trial ever when an auto-antigen is given directly into lymph-nodes to get tolerance in an autoimmune disease. Initially only adult patients with recent onset Type 1 diabetes were allowed to participate, The results from the first 6 patients, aged 21-22 years old are very encouraging with pronounced Th2 deviation of the immune response and remarkably good preservation of beta cell function still after 15 months in the first 4 patients followed so far (Ludvigsson NEJM 2017). The trial is now enlargened to 15 patients and the age decreased to 12 years. Immunological studies are done (Rosaura Casas, Beatriz Tavira Iglezias, Hugo Barcenilla).
In another project (EU-project EE-ASI with Colin Dayan, Cardiff, UK as PI) we collaborate in an international research group which should lead to a Phase I trial treating >16 year old Type 1 diabetic patients intra-cutaneously three times with one month interval with a proinsulin peptide fixed to gold nano-particles. The immune response is studied by lymph-node biopsies before and after treatment ( Rosuara Casas, Ingela Johansson). We are also involved in studies on mesenchymal stem cells given to newly-diagnosed Typ 1 diabetes patients ( Pre-Ola Carslsson, Uppsala, PI) as our group has made the immunologival studies (Rosaura Casas, Louise Magnusson), and Johnny Ludvigsson involved in the design of the main study. In recent years we have also worked with intervention using monoclonal antibodies against the CD3-recpeptor (Teplizumab) which has shown encouraging results, although the treatment hase been very heavy (14 days iv treatment x 2) (Lancet 2011, Diabetes 2013).
Prevention of diabetes complications
All diabetic children in the catchment area of our hospital, diagnosed <15 years of age since 1960 and onwards have been involved in the Linköping Complication trial. We were first in the world to show in a general population of patients that nephropathy can be postponed or prevented , relat4ed to good metabolic control (NEJM 1994) . Later we also showed that retinopathy can be prevented (Hanrs Arnqvist, Maria Nordwall). We continue these studies also based on the VISS-study (Type 1 diabetic patients in the southeast region diagnosed 1983-87 and followed by HbA1c from diagnosis and onwards. We have shown that longterm HbA1c < 60 mmol/mol seems to protecting against severe retinopathy, and HbAc < 68 seems to protect against nephropathy during 25 years follow-up.
To prevent complications good metabolic control is needed. One project started from our group lead to the education portal DiabIT (Sam Nordfeldt, Lena Hanberger) which is now used all over Sweden. We also participate in studies on the use of new insulins and devices.
