Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

Abstract

The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and β-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naïve T lymphocytes, regulatory T cells (TREG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-β1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of TREG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.

Combined unsupervised and semi-automated supervised analysis of flow cytometry data reveals cellular fingerprint associated with newly diagnosed pediatric type 1 diabetes

“…Indeed, it is well-established that the major genetic determinants of type 1 diabetes risk are polymorphisms of class II HLA genes encoding DQ and DR ( 30 ), thus indicating a leading contribution of the interactions between CD4 T cells and antigen presenting cells; our results suggest that the phenotypic and functional characterization of N CD4 T cells would allow the identification of candidate subsets with potential pathogenicity in the context of human type 1 diabetes. This hypothesis was further corroborated by the evidence that the frequency of N CD4 T cells at disease onset was associated with partial remission, independently of age, confirming, in a broader cohort, the observations of a recent report ( 31 ), and others associating the frequency of CD4 memory T cells with a longer partial remission ( 32 ). However, N CD4 T cell frequency was found unaltered in pre-symptomatic stages of type 1 diabetes, suggesting that the role of these cells may be crucial in a later phase of the autoimmune response.…”

Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children

“…Furthermore, Gomez-Munos et al. demonstrated increased levels of IL-10 and IL-17 in type I diabetic patients at the time of diagnosis, however, they did not find a significant impact of these on the incidence of the partial remission ( 56 ). Initial levels of the immune cells and corresponding cytokines were not neutral to the remission rates of our diabetic patients.…”

“…An interesting phenomenon documented in the literature, is a partial transient remission characterized by a reduced demand for exogenous insulin and a significant reduction in glycated hemoglobin level ( 56 ). In our study, we were observing that clinical situation between 3 rd and 6 th month of therapy.…”

Global research trends of diabetes remission: a bibliometric study

“…Given this resolution of terminological and criteria disputes concerning T2DM remission, it is anticipatory that ensuing research in diabetes remission will exhibit enhanced cohesion, fostering more streamlined alliances amongst research collectives and nations. Numerous modalities exist for diabetes remission, inclusive of bariatric surgery ( 14 , 15 ), lifestyle interventions ( 16 ), short-term intensive insulin therapy ( 14 ), non-insulin hypoglycemic agents ( 66 ), immune modulation ( 67 , 68 ), and transplantation ( 13 , 69 ). Distinct research paradigms adhered to by various teams might circumscribe collaborative endeavors.…”