New strategies for type 1 diabetes

By the time of clinical manifestation of type 1 diabetes mellitus, the loss of beta cell mass is already well advanced - early detection of the disease is essential for possibility of effective causal therapy.

Risk markers and approaches of intervention studies

By the time of clinical manifestation of type 1 diabetes mellitus, the loss of beta cell mass is already well advanced - therefore, early detection of the disease before clinical manifestation is essential for the possibility of effective causal therapy. In view of the increasing prevalence of diabetes mellitus type 1, prevention strategies to avoid the disease are the subject of intensive research efforts. Prof. Dr. Peter Achenbach from the Institute of Diabetes Research, Munich (Institut für Diabetesforschung) spoke on this topic under the title "Risk markers and approaches of intervention studies".

The basic problem in type 1 diabetes is the loss of functional beta cell mass, which leads to the appearance of symptoms and hyperglycaemia. The timing varies from individual to individual. There are many different diagnostic markers. Much is now known about genetic predisposition as well as certain environmental factors. The most important immune markers are the autoantibodies against different proteins of the beta cell, which can be used diagnostically. They are very easy to determine in the peripheral blood.

If you combine all the antibodies that have already been found, you will find a prevalence of more than 90% in newly manifested patients up to the age of 20. But not all antibodies are equally significant. The IA-2 antibody plays a major role. Here, the risk of rapid progression is significantly increased. After 5 years, a progression of almost 50% is reached. If another marker is added, the IA-2 beta, a clinical manifestation is already seen after 3 years. Combined with metabolic markers, a risk is seen after 2 years in 50% of those studied. With an oral glucose tolerance test, the effect was even more pronounced. Of those who already had impaired glucose tolerance, 50% were clinically manifested after less than 1 year.

Prospective birth cohorts are helping to better assess the process with increasing accuracy. Several international studies have prospectively included 22,000 children, mostly from families with type 1 diabetes or at genetic risk. An important question is: When does the autoimmune disease start? The first peak in the incidence of autoantibodies is already seen in the first two years of life. In children who start the autoimmune process so early, the autoimmunity is mainly directed against insulin. Other antibodies follow later.

Data from studies in Finland, the USA and Germany with 13,000 children with genetic and familial risk showed, after more than 20 years of follow-up, that all children who have reached a certain intensity of autoimmunity develop symptoms over time. 70% of children who had two or more autoantibodies developed the disease after 10 years, rising to 100% after 15 to 20 years.

These findings have led to a new staging of type 1 diabetes.

Two early stages are defined

After stage 2, it is not far to the clinical manifestation of the disease.

Why so many diabetic ketoacidoses?

Overall, the disease is diagnosed far too late and action is taken accordingly too late. One important reason for this is that most cases come from the population without a relative with the disease. Only about 10% have a close relative who is affected. That is why a pilot study was launched in 2015 to investigate the frequency of the early stage of the disease in the normal population - by means of capillary blood screening for islet autoantibodies at the age of 2 to 5 years. More than 90,000 children took part by 2019. Early stage type 1 diabetes was found with a prevalence of 0.31%. 90% had no first-degree relative with the disease.

Aim of the FR1DA study

Within three years, 25% of the 280 children diagnosed with early stage diabetes developed clinical diabetes. Meanwhile, FR1DA studies continue for ages 2 to 10 years.

Strongest risk factor: IA-2 autoantibodies

What risk factors are associated with progression? Not significant were: age, sex, BMI, first-degree relatives and number of antibodies. The strongest association was the factor IA-2 autoantibodies. Progression in stage 1, which affects 80% of early stage children, is 30% after 3 years. Risk markers besides IA-2 antibodies were obesity and HbA1c levels.

Stopping progression in the early stages

Today, we can speak of treating the disease because the early stages are already defined as a disease. There are many approaches for interventions. The TRIALNet Type 1 Diabetes consortium is investigating different therapies. Most of the studies refer to stage 3, in order to preserve the remaining mass of beta cells. Rituximab, abatacept, teplizumab, ATG/G-CSF were investigated. What they all have in common is that the protective effect is seen after one or two years, but cannot be sustained in the longer term.

Antigen-specific immunotherapy attempts to induce tolerance by administering the target antigen. Patients with relatively short duration of disease had good effects that were sustained over 30 months. However, responder groups need to be further identified.

A current trial of oral insulin intervention in children 2 to 12 years of age in stage 1 treated daily with a higher dosage vs placebo is ongoing. The highest dosage (67.5 mg) achieves an effect in terms of an insulin-specific regulatory immune response.

Outlook: Early diagnosis is part of prevention

One can make a good risk prediction. This is used for the prevention of autoimmune diabetes. For this purpose, diabetes centres of several European countries have joined forces for genetic screening. Children who have a 25-fold increased risk are diagnosed and can then be treated accordingly. So far, 260,000 children have participated. The first results are expected in 2024. Another study, the SINTIA study is currently recruiting participants aged 7 days to 6 weeks with an increased risk of diabetes.

DDG Congress 2021, New strategies for type 1 diabetes