Study sheds light for the first time on the dynamics of blood glucose levels and autoimmunity in early childhood: When and why does type 1 diabetes manifest in children? For the first time, researchers have examined blood glucose levels and parallel islet autoantibodies in children at increased genetic risk for type 1 diabetes in the first years of life in a long-term study. Results of the study have now been published in the Journal of Clinical Investigation. The study provides a better understanding of the dynamics of blood glucose regulation in early childhood and new insights into the development of autoimmunity in type 1 diabetes.
As part of the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD), the Primary Oral Insulin Trial (POInt) clinical trial is being conducted multicenter across five countries and seven sites. POInt aims to prevent the development of islet autoantibodies and thus prevent the development of type 1 diabetes. Type 1 diabetes is an autoimmune disease in which the insulin-producing beta cells of the pancreas are destroyed by a faulty reaction of the immune system. Until now, it was assumed that this process initially runs unrecognized in the background and that elevated blood glucose levels are a result of autoimmunity against the beta cells. However, it has never been studied when beta cells are first affected. The POInt study therefore examined over a longer period more than 1000 children from their fourth month of life with a ten percent increased risk of type 1 diabetes. This allowed the researchers to analyze the relationship between blood glucose levels and initial development of islet autoantibodies.
“Our research results change the understanding of the development of type 1 diabetes. We show that metabolic changes occur earlier in the disease process than previously thought,” explains Anette-Gabriele Ziegler, director of the Helmholtz Munich Institute for Diabetes Research (IDF). Together with an international team, she examined the children’s pre- and postprandial blood glucose levels – that is, before and after eating – as well as their islet autoantibodies in the POInT study.
Results provide new impetus for research
The researchers’ evaluation showed that, contrary to previous assumptions, blood glucose concentrations do not reach a steady state shortly after birth. Instead, they fall off in the first year of life and rise again at about 1.5 years of age. “The dynamic changes in blood glucose levels during the first years of life are startling. Presumably, early changes in the pancreatic islets are reflected here. This is a clear signal that we need to study the relationship between sugar metabolism and the pancreas more intensively during the first phase of life,” explains Katharina Warncke, senior physician in pediatric endocrinology/diabetology at the Center for Pediatric and Adolescent Medicine and a scientist at IDF. Another exciting observation: compared to children without an autoimmune reaction, children who developed autoimmunity already had elevated blood glucose levels two months before the autoantibodies formed. This difference remained in the further course. In addition, pre-meal blood glucose levels were also elevated after the first appearance of autoantibodies.
Mystery surrounding the event that promotes the autoimmune response
The researchers found that blood glucose metabolism is dynamic very early in life, mirroring the peak frequency of islet autoantibody development – suggesting a period of islet cell activity and vulnerability. “The marked change in postprandial blood glucose levels just before the first detection of autoantibodies suggests an event that affects beta cell function. This event precedes the autoimmune response and contributes to its development. Since beta cell function continues to deteriorate after the initial antibody formation, it appears to be a permanent damage to the islet cells that destabilizes blood glucose regulation,” Warncke explains.
“The observed relationship between blood glucose levels and first-time autoimmune response is fascinating. Now we know that the disease mechanism is probably triggered directly at the pancreatic islets. This allows us to more specifically investigate the cause of the chronic disease,” says Ezio Bonifacio, professor at the Center for Regenerative Therapies at the Technical University of Dresden (D).
The scientists thus found that metabolic changes become apparent much earlier in the course of the disease than previously assumed: They can precede autoimmunity or take place in parallel. The researchers hypothesize that the sudden increase in blood glucose levels after eating and just before antibodies develop is related to altered islet cell function.
The goal: fewer new cases
“Changes in blood glucose could thus serve in the future as an indicator of islet cell dysfunction and the possible onset of autoimmunity against beta cells,” Ziegler concludes. However, this will require further intensive research into glucose metabolism and other biomarkers in early childhood. The aim of all the scientists’ efforts is to reduce the number of new cases of type 1 diabetes. Currently, four out of 1000 children in the western industrialized nations are affected by the chronic disease.
Source: Warncke, et al: Elevations in blood glucose before and after the appearance of islet autoantibodies in children. 2022 JCI. 10.1172/JCI162123
