Multinational Trial Reveals Genetic Clues for Personalized Type 1 Diabetes Prevention
The POInT trial was launched in 2017 to explore whether oral insulin treatment could delay or prevent the development of islet autoantibodies – which are associated with the development of type 1 diabetes – in children at increased genetic risk of the condition. Conducted across five European countries, this unprecedented collaboration unites more than 30 years of genetic and immunological research and stands as one of the largest early prevention efforts in autoimmunity to date.
The researchers report that daily intake of insulin powder was well tolerated by the study population. However, oral insulin intake did not influence the overall development of islet autoantibodies during the study period. Although this means that the primary trial outcome was negative, the exploratory analyses revealed promising secondary findings: children who received oral insulin showed delayed progression to clinical type 1 diabetes compared to those in the placebo group. Notably, the treatment’s effect varied depending on the child’s specific insulin gene variant – pointing to new possibilities for genetically tailored prevention strategies.
“The POInT study will change how we approach antigen-based therapies in type 1 diabetes. While the oral insulin therapy could not prevent the development of islet autoantibodies as we had hoped, the trial data suggest that this therapy may positively influence the course of the disease,“ says Prof. Anette-Gabriele Ziegler, lead researcher of the study, Chair of Diabetes and Gestational Diabetes at the TUM University Hospital, and the Director of the Helmholtz Munich Institute of Diabetes Research.
“First, we saw a delay in the progression to clinical disease in those who had received oral insulin, which is already a positive message. Second, a striking finding was how the treatment effect varied depending upon the genetics of the child. In particular, among children with type 1 diabetes risk variants of the insulin gene, a delay in the onset of type 1 diabetes appears possible, opening the door to targeted, personalized prevention of type 1 diabetes,” Anette-Gabriele Ziegler explains.
“As POInT brings together decades of pioneering work on understanding and preventing type 1 diabetes, the study represents a major scientific milestone and is also closely connected to my personal mission: a world without type 1 diabetes,” Ziegler adds.
Outcome Dependent on the Personal Insulin Gene Variant
The gene encoding for the insulin protein naturally occurs in different variants. “Over half of the participants had variants that increase the risk for type 1 diabetes,” explains Ezio Bonifacio, member of the GPPAD study group and Professor at the Center for Regenerative Therapies at the TU Dresden. “In these children, oral insulin treatment protected against the development of diabetes. In contrast, among those with the non-risk variants, we observed an increase in the development of islet autoantibodies in the group treated with oral insulin.”
These findings suggest that oral insulin treatment might be beneficial for a genetically defined subgroup of children.
“Although the underlying mechanism remains unclear, the results offer grounds for cautious optimism: with the right selection of those to treat, it may in the future be possible to decisively alter the course of the disease,” Bonifacio adds.
Next Steps: Advancing Personalized Prevention Strategies
Building upon the initial findings, the POInT study will continue with an extended follow-up until participants reach the age of twelve – with continued support from The Leona M. and Harry B. Helmsley Charitable Trust. Roughly ten percent of the participating children developed islet autoantibodies by the age of six, and the majority of these will develop clinical type 1 diabetes. The extended monitoring allows researchers to assess the longer-term effects of early oral insulin treatment and provides continued care for participating children. In addition, biological samples and data collected during the trial will be used in ancillary research projects. These studies aim to uncover how oral insulin may modify the autoimmune reaction and influence the course of the disease. Ultimately, this will help to understand the early biological mechanisms that lead to type 1 diabetes. This way, the researchers hope to identify pharmacogenetic mechanisms that could enable personalized prevention of type 1 diabetes. To this end, the trial POInT cohort is especially relevant, as it is the first primary prevention trial to recruit children at risk from the general population.
Background Information
First Primary Prevention Trial to Recruit Children at Risk from the General Population
To enroll infants with a genetic risk of over ten percent of developing type 1 diabetes in POInT, GPPAD established a multinational screening program (called Freder1k in Germany). Nearly 242,000 infants under four months of age were screened across the participating sites in Belgium, Germany, Poland, Sweden, and the UK. Using a genetic risk score, approximately one percent of infants was identified as high-risk, and 1,050 children were enrolled into POInT. Recruitment for the trial was completed ahead of schedule, highlighting the strong commitment of the participating families and the effectiveness of the multinational approach. The researchers demonstrated that newborn screening in the general population is feasible for recruitment into primary prevention trials. Helmholtz Munich provided the infrastructure that enabled this ambitious multicenter study.
Scientific Rationale for Oral Immune Intervention
Type 1 diabetes is caused by an autoimmune reaction in which the body’s immune system mistakenly attacks insulin-producing cells in the pancreas. This process often begins in early childhood and is marked by autoantibodies – often starting with insulin itself as a target. The researchers hypothesized that oral exposure to high doses of insulin could help build immune tolerance, similar to approaches used in allergy prevention. Starting between age four to seven months of age, POInT participants received either a daily dose of oral insulin (7.5 mg, eventually increasing to 67.5 mg over 4 months) or placebo until the age of three years. The follow-up continued until the age of six and a half years. POInT is the first randomized, double-blind, placebo-controlled clinical trial to examine the effect of oral insulin on the development of islet autoimmunity and type 1 diabetes in at-risk children.
About the Researchers
Prof. Anette-Gabriele Ziegler, Director of the Institute of Diabetes Research at Helmholtz Munich and Chair of Diabetes and Gestational Diabetes at the TUM University Hospital.
Prof. Ezio Bonifacio, member of the GPPAD study group and Professor at the Center for Regenerative Therapies at TU Dresden.
About Helmholtz Munich
Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies, and chronic lung diseases. With the power of artificial intelligence and bioengineering, researchers accelerate the translation to patients. Helmholtz Munich has around 2,500 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 43,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en
About the Global Platform for the Prevention of Autoimmune Diabetes
GPPAD is a European platform that identifies children at increased genetic risk of developing type 1 diabetes and conducts studies on primary prevention. The studies aim to reduce the occurrence of islet autoimmunity and type 1 diabetes in children. Following the POInT study and the SINT1A Study (Supplementation with B. INfantis for Mitigation of Type 1 Diabetes Autoimmunity), GPPAD is currently recruiting for its third clinical trial, AVAnT1A (Antiviral Action against Type 1 Autoimmunity). GPPAD research centres are located in Belgium (Leuven), Germany (Dresden, Hannover, Munich), Sweden (Malmö), the United Kingdom (Newcastle, Cambridge), and Austria (Vienna). The research platform is financed by The Leona M. and Harry B. Helmsley Charitable Trust.
About the Helmsley Charitable Trust
The Leona M. and Harry B. Helmsley Charitable Trust aspires to improve lives by supporting exceptional efforts in the U.S. and around the world in health and select place-based initiatives. Since beginning active grantmaking in 2008, Helmsley has granted more than $4.5 billion for a wide range of charitable purposes. The Helmsley Type 1 Diabetes (T1D) Program is the largest private foundation funder in the world with a focus on T1D, with more than $1 billion to date committed to transform the trajectory of the disease and to accelerate access to 21 century care, everywhere. For more information on Helmsley and its programs, visit helmsleytrust.org.