Prolonged Remission Induced by FENofibrate in children with newly diagnosed type 1 diabetes (PRIFEN): protocol of a randomised controlled trial.

INTRODUCTION: Sphingolipids regulate proinsulin folding, insulin secretion and control beta cells apoptosis. Recent evidence has demonstrated that, among other factors, reduced amounts of sulfatide may be relevant in the development of type 1 diabetes (T1D). Thus, fenofibrate, which activates sulfatide biosynthesis, may prolong remission in subjects with T1D. The aim of the study is to evaluate clinical efficacy of fenofibrate on the maintenance of residual beta-cell function in children with newly diagnosed T1D. METHODS AND ANALYSIS: A total of 102 children aged 10-17 years with newly diagnosed T1D will be enrolled in a double-blind, two-centre randomised, non-commercial, placebo-controlled trial. Subjects who will meet all inclusion criteria will be randomly assigned to receive fenofibrate at a dose of 160 mg or an identically appearing placebo, orally, once daily, for 12 months. The primary endpoint will be the area under the curve of the C-peptide level during 2-hour responses to a mixed-meal tolerance test (MMTT). Secondary endpoints include fasting and maximum C-peptide concentration in the MMTT, parameters of diabetes control and glucose fluctuations, daily insulin requirement, inflammation markers, genetic analysis, safety and tolerance of the fenofibrate ETHICS AND DISSEMINATION: The study protocol was approved by the Bioethics Committee. The results of this study will be submitted to a peer-reviewed diabetic journal. Abstracts will be submitted to international and national conferences. TRIAL REGISTRATION NUMBER: EnduraCT 2020-003916-28.

Elevations in blood glucose before and after the appearance of islet autoantibodies in children.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic ß cells and promote ß cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic ß cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.

Lack of effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomised controlled trial.

INTRODUCTION: The gut microbiota may be relevant in the development of type 1 diabetes (T1D). We examined the effects of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed T1D. RESEARCH DESIGN AND METHODS: Children aged 8-17 years with newly (within 60 days) diagnosed T1D were enrolled in a double-blind, randomised controlled trial in which they received L. rhamnosus GG and B. lactis Bb12 at a dose of 109 colony-forming units or placebo, orally, once daily, for 6 months. The follow-up was for 12 months. The primary outcome measure was the area under the curve (AUC) of the C-peptide level during 2-hour responses to a mixed meal. RESULTS: Ninety-six children were randomised (probiotics, n=48; placebo n=48; median age 12.3 years). Eighty-eight (92%) completed the 6-month intervention, and 87 (91%) completed the follow-up at 12 months. There was no significant difference between the study groups for the AUC of the C-peptide level. For the secondary outcomes at 6 months, there were no differences between the study groups. At 12 months, with one exception, there also were no significant differences between the groups. Compared with the placebo group, there was a significantly increased number of subjects with thyroid autoimmunity in the probiotic group. However, at baseline, there was also a higher frequency of thyroid autoimmunity in the probiotic group. There were no cases of severe hypoglycemia or ketoacidosis in any of the groups. No adverse events related to the study products were reported. CONCLUSIONS: L. rhamnosus GG and B. lactis Bb12, as administered in this study, had no significant effect in maintaining the residual pancreatic beta-cell function in children with newly diagnosed T1D. It remains unclear which probiotics, if any, alone or in combination, are potentially the most useful for management of T1D. TRIAL REGISTRATION NUMBER: NCT03032354.

Factors associated with preservation of C-peptide levels at the diagnosis of type 1 diabetes.

AIMS: The level of C-peptide can identify individuals most likely to respond to immune interventions carried out to prevent pancreatic ß-cell damage. The aim of the study was to evaluate factors associated with C-peptide levels at type 1 diabetes (T1D) diagnosis. METHODS: This study included 1098 children aged 2-17 with newly recognized T1D. Data were collected from seven Polish hospitals. The following variables were analyzed: date of birth, fasting C-peptide, HbA1c, sex, weight, height, pH at diabetes onset. RESULTS: A correlation was observed between fasting C-peptide level and BMI-SDS (p = 0.0001), age (p = 0.0001), and HbA1c (p = 0.0001). The logistic regression model revealed that fasting C-peptide ≥0.7 ng/ml at diabetes diagnosis was dependent on weight, HbA1c, pH and sex (p < 0.0001). Overweight and obese children (n = 124) had higher fasting C-peptide (p = 0.0001) and lower HbA1c (p = 0.0008) levels than other subjects. Girls had higher fasting C-peptide (p = 0.036) and higher HbA1c (p = 0.026) levels than boys. CONCLUSION: Obese and overweight children are diagnosed with diabetes at an early stage with largely preserved C-peptide levels. Increased awareness of T1D symptoms as well as improved screening and diagnostic tools are important to preserve C-peptide levels. There are noticeable gender differences in the course of diabetes already at T1D diagnosis.

Effects of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: protocol of a randomised controlled trial.

INTRODUCTION: Recent evidence has demonstrated that, among other factors, dysbiosis (imbalances in the composition and function of the gut microbiota) may be relevant in the development of type 1 diabetes (T1D). Thus, gut microbiota may be a target for improving outcomes in subjects with T1D. The aim of the study is to examine the effects of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed T1D. METHODS AND ANALYSIS: A total of 96 children aged 8 to 17 years with newly diagnosed T1D, confirmed by clinical history and the presence of at least one positive autoantibody, will be enrolled in a double-blind, randomised, placebo-controlled trial in which they will receive L. rhamnosus GG and B. lactis Bb12 at a dose of 109 colony-forming units or an identically appearing placebo, orally, once daily, for 6 months. The follow-up will be for 12 months. The primary outcome measures will be the area under the curve of the C-peptide level during 2-hour responses to a mixed meal. ETHICS AND DISSEMINATION: The Bioethics Committee approved the study protocol. The findings of this trial will be submitted to a peer-reviewed paediatric journal. Abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: NCT03032354; Pre-results.

Continuous subcutaneous insulin infusion during total parenteral nutrition after gastroscopy complicated by duodenal intramural haematoma in a patient with type 1 diabetes - case repor.

We present the course of the insulin therapy during total parenteral nutrition (TPN) after gastroscopy complicated by duodenal intramural haematoma, in a boy with type 1 diabetes treated with the insulin pump. There is a lack of guidelines regarding the insulin therapy during TPN in children. Additionally, duodenal intramural haematoma is a very rare complication of diagnostic gastroscopy. There are only few cases reported so far.

Does the fat-protein meal increase postprandial glucose level in type 1 diabetes patients on insulin pump: the conclusion of a randomized study.

BACKGROUND: Our study examines the hypothesis that in addition to sugar starch-type diet, a fat-protein meal elevates postprandial glycemia as well, and it should be included in calculated prandial insulin dose accordingly. The goal was to determine the impact of the inclusion of fat-protein nutrients in the general algorithm for the mealtime insulin dose calculator on 6-h postprandial glycemia. SUBJECTS AND METHODS: Of 26 screened type 1 diabetes patients using an insulin pump, 24 were randomly assigned to an experimental Group A and to a control Group B. Group A received dual-wave insulin boluses for their pizza dinner, consisting of 45 g/180 kcal of carbohydrates and 400 kcal from fat-protein where the insulin dose was calculated using the following algorithm: n Carbohydrate Units×ICR+n Fat-Protein Units×ICR/6 h (standard+extended insulin boluses), where ICR represents the insulin-to-carbohydrate ratio. For the control Group B, the algorithm used was n Carbohydrate Units×ICR. The glucose, C-peptide, and glucagon concentrations were evaluated before the meal and at 30, 60, 120, 240, and 360 min postprandial. RESULTS: There were no statistically significant differences involving patients' metabolic control, C-peptide, glucagon secretion, or duration of diabetes between Group A and B. In Group A the significant glucose increment occurred at 120-360 min, with its maximum at 240 min: 60.2 versus -3.0 mg/dL (P=0.04), respectively. There were no significant differences in glucagon and C-peptide concentrations postprandial. CONCLUSIONS: A mixed meal effectively elevates postprandial glycemia after 4-6 h. Dual-wave insulin bolus, in which insulin is calculated for both the carbohydrates and fat proteins, is effective in controlling postprandial glycemia.

Long-acting insulin analogue detemir compared with NPH insulin in type 1 diabetes: a systematic review and meta-analysis.

INTRODUCTION: Although numerous studies showed an improvement in glycemic control in type 1 diabetic patients treated with long-acting insulin analogue detemir compared with Neutral Protamine Hagedorn (NPH) insulin, the beneficial effects of insulin detemir has not been confirmed by all investigators. OBJECTIVES: The aim of the study was to compare the effect of treatment with detemir insulin vs. NPH insulin on metabolic control, hypoglycemic episodes, and body weight gain in patients with type 1 diabetes by means of a systematic review and a meta-analysis. METHODS: The following electronic databases were searched up to November 2010: MEDLINE, EMBASE, and the Cochrane Library. Additional references were obtained from the reviewed articles. Only randomized controlled trials of at least 12-week duration with basal-bolus regimen therapies using detemir insulin vs. NPH insulin were included. RESULTS: The analysis included 10 studies involving 3825 patients with type 1 diabetes. Combined data from all trials showed a statistically significant reduction in hemoglobin A1c (HbA1c) (weighted mean difference: [WMD] -0.073, 95% CI -0.135 to -0.011, P = 0.021) in the detemir group compared with the NPH group. There was also a significant reduction of fasting plasma glucose (FPG) (WMD - 0.977 mmol/l, 95% CI -1.395 to -0.558, P <0.001), all-day hypoglycemic episodes (relative risk [RR] 0.978, 95% CI 0.961-0.996), severe hypoglycemic episodes (RR 0.665, 95% CI 0.547-0.810), nocturnal hypoglycemic episodes (RR 0.877, 95% CI 0.816-0.942), as well as smaller body weight gain (WMD -0.779 kg, 95% CI -0.992 to -0.567) in patients using detemir insulin compared with those using NPH insulin. CONCLUSIONS: Basal-bolus treatment with insulin detemir, as compared with NPH insulin, provided a minor benefit in terms of the HbA1c value and significantly reduced FPG in type 1 diabetic patients. Treatment with detemir insulin was also superior to NPH insulin in reducing the risk of all-day, nocturnal, and severe hypoglycemic episodes, with the added benefit of reduced weight gain.

Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children with type 1 diabetes.

BACKGROUND: An insulin pump is an advanced technology offering new options of bolus - normal (N), dual wave (D-W) or square wave (S-W) bolus to deliver mealtime insulin. OBJECTIVES: To assess the impact of D-W/S-W boluses on metabolic control (glycated haemoglobin A1c, HbA1c) and to estimate the paediatric patients compliance with implementation of this system in daily practice. METHODS: The cross-sectional study included 499 records of patients aged 0-18 yr. Data from the insulin pump memory provided information on the number of D-W/S-W boluses during a 2-wk period, the insulin requirement (U/kg/d) and the percentage of basal insulin. The HbA1c value (%) and the patient's weight were determined during medical examinations. Mealtime dose of insulin in D-W/S-W bolus was calculated based on the amount of carbohydrate and fat/protein products. RESULTS: The number of applied D-W/S-W boluses was 16.6 +/- 0.77/14 d (ranged 0-95), while 18.8% of patients did not program D-W/S-W boluses. The lowest HbA1c value was found in the group using two and/or more D-W/S-W boluses per day (p = 0.001) compared with the group administrating less than one D-W/S-W bolus/d. Patients with HbA1c level <7.5% had a statistically higher relevant number of D-W/S-W boluses, 19.55 (95% CI: 17.44-21.65) vs. 12.42 (95% CI: 10.22-14.61) (p < 0.001), while there was no correlation between the number of boluses and HbA1c in patients in the remission phase (<0.5 IU/kg/d) (r = 0.012, p = 0.930). CONCLUSIONS: Patients using at least one D-W/S-W bolus per day achieved a recommended level of HbA1c. Paediatric patients with type 1 diabetes mellitus were found to be able to apply D-W/S-W boluses in daily self-treatment process based on food counting.

Insulin requirement in preschoolers treated with insulin pumps at the onset of type 1 diabetes mellitus.

THE AIM: The aim of this study is to analyze changes in the basal insulin requirement in preschoolers treated with insulin pump at the onset of T1DM, using system to calculate meal time insulin. METHODS: 58 children (31 girls) under 6 years (mean age 3.3 +/- 1.5 years) initiated on insulin pump therapy within 2 months after recognition of T1DM and treated at least for 1 year were analyzed during a follow-up period of 165 patient-years. Data was collected every 6 months: HbA1c, BMI SDS, diabetic ketoacidosis, severe hypoglycaemia, total daily insulin dose (TDD) and basal insulin. RESULTS: Basal insulin rose from 10% in the third month and did not exceed 30% of TDD after 12 months (p<0.0001). In the third month, 46% of children were without basal insulin; this group included significantly older children (3.7 +/- 1.4 vs. 2.8 +/- 1.4 years; p = 0.01), which had lower TDD (0.33 +/- 0.18 vs. 0.54 +/- 0.23 u/kg/d; p = 0.0007) than children with basal insulin. HbA1c persisted < or =7.3%. CONCLUSION: In preschool children initiated on CSII therapy at the time of T1DM diagnosis the first year of treatment is critical for altering the basal insulin dose. Preschoolers with TDD lower than 0.5 U/kg/d may not require basal insulin. Moreover, basal insulin did not exceed 30% of TDD in the first years after T1DM onset.

Age-dependent basal insulin patterns in children with type 1 diabetes treated with continuous subcutaneous insulin infusion.

AIMS: Identifying age-dependent basal rates in type 1 diabetic children treated with continuous subcutaneous insulin infusion (CSII). METHODS: CSII-treated children with type 1 diabetes exhibiting insulin requirement > 0.5 U/kg and glycated haemoglobin (HbA1c) < 8%. The study population was composed of 198 Caucasian children (111 girls) with mean age of 9.8 +/- 3.8 years, mean duration of diabetes of 4.3 +/- 3.1 years and mean HbA1c value of 6.7 +/- 0.7%. Data were evaluated for four age groups (0-6; 6-9; 9-12, 12-18 years). Basal rates records were downloaded from pump memory. HbA1c, weight, height were measured at scheduled visits. RESULTS: Significant differences in the average hourly basal rate between groups were observed: I gr. 0.14 versus II gr. 0.24 versus III gr. 0.39 versus IV gr. 0.72 units/h; p < 0.0001. The average hourly basal rate correlated with age, body weight, BMI, diabetes duration and total insulin daily dose. Insulin peaks were observed for: I gr. - before midnight, II gr. - before midnight and in the early morning, gr. III and IV - in the early morning. CONCLUSION: Basal insulin infusion rate profiles in well-controlled paediatric patients on CSII reflect the age-dependent amount of basal insulin (20-40%) and affect circadian distribution of insulin needs.

[Principle rules in establishing recommendations. Comparison of contemporary diabetes recommendations]. / Zasady tworzenia rekomendacji. Porównanie obecnych standardów postepowania w cukrzycy typu 1.

Creation of systematic guidelines for clinical use in diabetes emerges from the necessity of treatment quality improvement. Recommendations are validated according to current clinical data. Strength of recommendations is established based on systematic review of studies, each of which is of certain category due to its methodology. There exists an organization called Grades of Recommendation, Assessment, Development and Evaluation, the aim of which is to create homogenous quality assessment system and category of recommendations. It will be accomplished through the evaluation of data quality, creation of recommendations and defining its strength. The recommendations of NICE, ADA and PTD (Polish Diabetes Association) are very similar with regard to the significance of education of patients as well as performing frequent screening for late complications of diabetes and autoimmunological diseases. The recommendations are different when it comes to target glycemia (fasting blood glycemia, postprandial glycemia and HbA1c), especially depending on patient's age. The knowledge on the principles of recommendations creation and the symbols of recommendation's strength are essential for medical doctors taking care of diabetic patients while choosing the treatment method as well as the individualized approach towards every patient with diabetes.

[The prevalence of autoimmune thyroid disease and celiac disease in children and adolescents with type 1 diabetes mellitus]. / Czestosc wystepowania autoimmunologicznego zapalenia tarczycy i celiakii u dzieci i mlodziezy z cukrzyca typu 1.

INTRODUCTION: Patients with type 1 diabetes mellitus have an increase the risk of developing other autoimmune diseases, among them, autoimmune thyroid disease, mainly Hashimoto are more frequently observed. The aim of the study was to assess the prevalence of celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus. MATERIAL AND METHODS: The study included 260 children (124 girls, 136 boys) aged 1.3-18 years (mean 11+/-4.01), the diabetes duration 3.99+/-3.7 years. Endomysial antibody (EMA) was measured and all patients with positive EMA had small-bowel biopsy. Antibodies against thyroperoxidase (a-TPO), thyroglobulin (a-Tg), TSH, fT4, HbA1c and ultrasound examination of thyroid glands were assessed. RESULTS: The prevalence of EMA was 10% (27/260) and 9% (25/260) had biopsy-proven celiac disease. The median age of T1DM at onset was significantly lower in patients with EMA than those without EMA 6.2+/-5.6 vs. 7.7+/-4.2 p=0.04. 20% of children diagnosed with type 1 diabetes at age <4 years had celiac disease p=0.001. The prevalence of thyroid antibodies was 29% (75/260). In the group with positive thyroid antibodies, in 28% (21/75) thyroid ultrasonography showed scattered hypoechogenicity and 23% (17/75) required treatment with thyroxine. Children with positive a-TPO had higher TSH level (2.87+/-2.1 vs. 1.95+/-0.9) p<0.01 and HbA1c level (8.32+/-1.64 vs. 7.59+/-1.67) p=0.03 than children without thyroid antibodies. More frequently thyroid antibodies were positive in girls than in boys. CONCLUSIONS: Out of five patients with T1DM, one is diagnosed with Hashimoto or celiac disease. Both diseases occurred independently. Autoimmune thyroid disease and celiac disease occur more frequently in children with T1DM, therefore screening at an onset and repeated measurements are recommended.