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Autoimmunity, Type 1 Diabetes Predicted by Plasma Protein Biomarkers

NEW YORK — Researchers have identified plasma protein biomarkers that can predict the development of pancreatic islet autoimmunity (IA) and type 1 diabetes (T1D) in children, which could help with the development of prognostic tests and therapeutics.

In a study published in Cell Reports Medicine on Thursday, researchers from Pacific Northwest National Laboratory and elsewhere used mass spectrometry-based plasma proteomics to identify a set of proteins that indicate the development of IA and T1D prior to the onset of disease.

While it is known that T1D results from autoimmune destruction of insulin-producing beta cells in the pancreas, there are currently no biomarkers available that can predict disease development and progression, the authors noted. A patient is said to have IA when they develop at least two types of islet autoantibodies, however it is largely unknown what triggers the autoimmunity that may lead to diabetes. "There is a desperate need for biomarkers that predict and can be used to monitor the onset of IA," they wrote.

In a blinded, case-control study, the researchers analyzed blood samples from children recruited at six study sites in North America and Europe using mass spectrometry-based proteomics. The children had been participants in a study called The Environmental Determinants of Diabetes in the Young (TEDDY) that focuses on individuals who are more likely than others to develop T1D because of their genetic makeup.

The study was conducted in two phases. In the discovery phase, the team analyzed 2,252 blood samples from 184 children using untargeted proteomics and found 376 proteins that were altered in patients who developed IA or T1D. Twenty-two pathways were overrepresented among the 376 differentially abundant proteins, including thoserelated to the extracellular matrix, antigen presentation, complement and blood clotting, nutrient digestion and absorption, cellular metabolism, and inflammatory signaling processes.

The researchers then conducted a validation study, looking at 6,426 blood samples from 990 children, in which they measured 167 proteins using targeted proteomics. They found 83 biomarkers that were key to many of the same processes unveiled during the discovery phase.

Referring to previous studies, the researchers also saw that many of these processes are also regulated in human pancreatic islets and cultured beta cells stimulated with pro-inflammatory cytokines to mimic the insulitis process. "This suggests that some of these processes also occur in the pancreas during T1D development," they wrote.

Next, using a machine learning algorithm that looked at proteins from nearly 1,000 children, with multiple blood samples from each taken between birth and age 6 years, the researchers identified proteins that can predict both the development of persistent autoantibodies with normoglycemia and T1D up to six months prior to the appearance of the autoimmune response.

Going forward, the researchers plan to continue their study by analyzing additional blood samples that have already been collected from the same children at a later age.

Highlighting one of the limitations of the study, the authors noted that the validation was not performed in an independent cohort of samples. "Validation in independent cohorts of samples can eliminate some confounding factors based on geographical and populational biases," they wrote.