Excessive BMI is associated with higher C-peptide level at recognition but also with its greater loss in two years clinical observation in children with new onset type 1 diabetes.

Introduction: The prevalence of obesity in general pediatric population increases without sparing children with T1D. We intended to find factors associated with the possibility of preserving endogenous insulin secretion in individuals with long-standing T1D. At onset, higher BMI is associated with higher C-peptide level, which may indicate to be one of the favorable factors involved in preserving residual ß-cell function. The study determines the influence of BMI on C-peptide secretion in children newly diagnosed with T1D in two years observation. Methods: We assessed the possible relationship between selected pro- and anti-inflammatory cytokines, body mass at recognition and ß-cell function status. 153 pediatric patients with newly diagnosed T1D were divided into quartiles according to BMI-SDS index. We separated a group consisted of patients with BMI-SDS >1. Participants were followed up for two years and examined for changes in body weight, HbA1c, and insulin requirement. C-peptide was assessed at baseline and after two years. We evaluated the patients' levels of selected inflammatory cytokines at baseline. Results: Subjects with higher BMI-SDS presented higher serum C-peptide levels and lower insulin requirements at diagnosis than children with lower body weight. The two-year follow-up showed that C-peptide levels of obese patients dropped more rapidly than in children with BMI-SDS within normal limits. The group with BMI-SDS >1 showed the greatest decrease in C-peptide level. Despite statistically insignificant differences in HbA1c at diagnosis between the study groups, in the fourth quartile and BMI-SDS >1 groups, HbA1c as well as insulin requirements increased after two years. The levels of cytokines varied the most between BMI-SDS <1 and BMI-SDS >1 groups and were significantly higher within BMI-SDS >1 group. Discussion: Higher BMI, associated with enhanced levels of inflammatory cytokines, relates to preservation of C-peptide at T1D recognition in children but is not beneficial in the long term. A decrease in C-peptide levels combined with an increase in insulin requirements and in HbA1c among patients with high BMI occur, which may indicate a negative effect of excessive body weight on the long term preservation of residual ß-cell function. The process seems to be mediated by inflammatory cytokines.

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

Type 1 diabetes (T1D) is autoimmune destruction of the beta cells of pancreatic islets. Due to complexity of that disease, the mechanisms leading to the tolerance breakdown are still not fully understood. Previous hypothesis of imbalance in the Th1 and Th2 cells as the main contributing factor has been recently changed towards role of other lymphocytes - regulatory (Treg) and IL-17A-producing (Th17). Our study aims to assess changes within Treg and Th17 cells in newly diagnosed T1D pediatric patients and their association with disease remission. Flow cytometry implementation allowed for Treg and Th17 analysis in studied groups and further combination with clinical and laboratory data. In addition, expression of diabetes-related genes was tested and evaluated in context of their association with studied lymphocytes. Initial results revealed that Treg and ratio Treg/Th17 are significantly higher in T1D than in healthy controls. Moreover, patients with lower HbA1c and daily insulin requirements demonstrated higher levels of Tregs. Similar tendency for insulin intake was also observed in reference to Th17 cells, together with high levels of these cells in patients demonstrating higher values for c-peptide after 2 years. In low-level Treg patients, that subset correlates with the c-peptide in the admission stage. In addition, higher levels of IL-10 were associated with its correlation with HbA1c and insulin dosage. In the context of gene expression, moderate associations were demonstrated in T1D subjects inter alia between CTLA4 and Treg or ratio Treg/Th17. Cumulatively, our data indicate a possible novel role of Treg and Th17 in mechanism of type 1 diabetes. Moreover, potential prognostic value of these populations has been shown in reference to diabetes remission.

Circulating Hematopoietic (HSC) and Very-Small Embryonic like (VSEL) Stem Cells in Newly Diagnosed Childhood Diabetes type 1 - Novel Parameters of Beta Cell Destruction/Regeneration Balance and Possible Prognostic Factors of Future Disease Course.

AIMS/HYPOTHESIS: We aimed to evaluate hematopoietic stem cells (HSC) and very small embryonic-like stem cells (VSEL) mobilization to establish their role in residual beta cell function maintenance and partial remission occurrence in children newly diagnosed with type 1 diabetes. METHODS: We recruited 59 type 1 diabetic patients (aged 6-18 years) monitored for 2 years, and 31 healthy children as a control group. HSC and VSEL levels were assessed at disease onset in PBMC isolated from whole peripheral blood with the use of flow cytometry. An assessment of beta cell function was based on C-peptide secretion. Studied groups were stratified on the basis of VSEL, HSC and/or C-peptide median levels in regard to beta cell function and partial remission. RESULTS: Patients with higher stimulated C-peptide secretion at disease onset demonstrated lower levels of HSC (p < 0.05), while for VSEL and VSEL/HSC ratio higher values were observed (p < 0.05). Accordingly, after 2 years follow-up, patients with higher C-peptide secretion presented lower initial levels of HSC and higher VSEL/HSC ratio (p < 0.05). Patients with lower values of HSC levels demonstrated a tendency for better partial remission prevalence in the first 3 to 6 months after diagnosis. CONCLUSIONS: These clinical observations indicate a possible significant role of HSC and VSEL in maintaining residual beta cell function in type 1 diabetic patients.

C-peptide and residual ß-cell function in pediatric diabetes - state of the art.

C-peptide, the molecule produced in an equimolar concentration to insulin, has become an established insulin secretion biomarker in diabetic patients. Measurement of C-peptide level can be helpful in clinical practice for assessing insulin-producing b-cells residual function, especially in the patients who have already started exogenous insulin therapy. Advances in assays have made measurement of C-peptide more reliable and inexpensive. Traditionally, C-peptide is widely used to differentiate between type 1, type 2 and monogenic types in diabetic patients of all ages, both when the diabetes occurs and even months and years after the initial diagnosis. Moreover, in the patients with type 1 diabetes, the C-peptide secretion can become a reliable predictor of the clinical partial remission in the first months after diagnosis, although noteworthy, its' any specified level is not included in the definition of this phase of the disease. Many other clinical factors such as age, use of innovative technologies, the intensity of physical activity or body mass influence the concentration of C-peptide as well as diabetes remission occurrence and duration. They may interfere the interpretation of C-peptide level in the diabetes course. There is a great need to assess the new, adjusted C-peptide levels in these situations. A multitude novel therapies including immunomodulative factors and stem cell transplants can also use C-peptide in the patient selection and post-therapeutic monitoring of the outcome in researches aimed in extension of remission period. Recent research proves C-peptide presence and preserved function and being the possible important player in better metabolic control in long-lasting diabetes type 1. These findings may open the area for trials to regenerate b-cells and save endogenous insulin secretion for many years after diagnosis. Last but not the least, C-peptide presents its own physiological effect on other tissues, among others on the endothelial function, thus participates in inhibiting micro- and macrovascular diabetes complications. The idea of C-peptide as a new, additional to insulin cure remains as much attractive as elusive.

Increasing Co-occurrence of Additional Autoimmune Disorders at Diabetes Type 1 Onset Among Children and Adolescents Diagnosed in Years 2010-2018-Single-Center Study.

Objectives: The prevalence of type 1 diabetes mellitus (T1D) in children is growing, but its relation to other autoimmune disorders that coexist since the onset of diabetes is not recognized. The objective of this study was to assess the incidence of T1D and the prevalence of autoimmune illnesses additionally coexisting since the diabetes mellitus onset in children during a period of 9 years' observation. Methods: In this retrospective study, the incidence rate (IR) of the T1D was calculated as the total number of all cases that were newly diagnosed per 100,000 population people between 0 and 18 years of age. The selected age groups (0-4, 5-9, 10-14, and 15-18 years) were examined, respectively. The studied group included 493 children (264 [53.55%] boys) between 0 and 18 years old newly diagnosed with T1D in one of the Polish centers in the years 2010-2018. Other autoimmune illnesses diagnoses were obtained from medical records taken from the first hospital treatment, when T1D was recognized. Results: The annual standardized IR of T1D increased from 19.2/100,000 in year 2010 to 31.7/100,000 in 2018 (1.7-fold over 9 years' observation), with an increase in the incidence rate ratio (IRR) by 4% per year. The highest growth in IR was recorded in 5- to 9-year-olds (from 19.61 in 2010 to 43.45 in 2018). In 61 (12.4%) of the studied group, at least one additional autoimmune disease was diagnosed. The prevalence doubled from 10.4% in the year 2010 to 20.8% in the year 2018. Autoimmune thyroid illnesses were found in 37 children (7.5%); their incidence increased from 6.3% to almost 2-fold, 12.5%, in 2018. In 26 children (5.3%), celiac disease was recognized; the prevalence increased from 4.2 to 9.8% in the study period. The prevalence of additional autoimmune thyroid disease was higher in glutamic acid decarboxylase-positive antibodies (χ2 = 3.4, p = 0.04) patients, the oldest age group (15-18 years) (χ2 =7.1, p = 0.06), and in girls (χ2 =7.1, p = 0.007). Conclusions:The standardized IR of T1D in children increased 1.7-fold over the 9-year observation period, and IRR increased 4% per year. Additional autoimmunity represents a significant comorbidity in patients with new-onset T1D. The number of children diagnosed with additional autoimmune diseases that accompany T1D is rapidly growing in all age groups throughout recent years.

Regular physical activity as a physiological factor contributing to extend partial remission time in children with new onset diabetes mellitus-Two years observation.

BACKGROUND: Beneficial effects of physical activity (PA) are confirmed in patients with all types of long-lasting diabetes. The possibility of PA to be a factor prolonging remission phase in children with new-onset type 1 diabetes (T1D) has not yet been thoroughly studied. OBJECTIVE: The aim of the study was to elucidate the influence of regular PA on prevalence of partial remission (PR), metabolic control, daily insulin requirement (DIR), and C-peptide secretion in children newly diagnosed with T1D. METHODS: A total of 125 children diagnosed with T1D were studied prospectively for 2 years. Patients were controlled every 3 months and advised with PA according to ISPAD recommendations. Anthropometric parameters, HbA1c, C-peptide level and DIR were analyzed. Patients' PA level was assessed using a self-designed questionnaire. RESULTS: We classified 43% of participants as physically-active. In this group, lower HbA1c after 2 years, lower DIR after 3, 6 months, and after 2 years (all P < .05) were found. At discharge from hospital, the prevalence of DIR < 0.5 U/kg/24 h with near normoglycemia was similar in both groups. Then, we observed higher PR prevalence in active group lasting over time and resulting in 44% vs 13% after 2 years (P < .001). C-peptide after 2 years was comparable in both groups, with higher prevalence of clinically significant levels (>0.2 nmoL/L) in active group: 79.6% vs 61.4% (P = .029). CONCLUSIONS: These data support the view that regular PA may essentially contribute to extending PR time in pediatric diabetes, and may therefore lead to a better long-term metabolic control of the disease.