Follow-up and monitoring programme in children identified in early-stage type 1 diabetes during screening in the general population of Italy.

AIM: To provide guidance for follow-up and monitoring of children and adolescents identified as positive to islet autoantibodies (IA) in the general population screening for type 1 diabetes (T1D) in Italy. METHODS: Detection of IA helps to diagnose pre-symptomatic T1D, prevent diabetic ketoacidosis (DKA) and identify persons for new therapies to delay symptomatic diabetes. Italy recently became the first country to approve by law a general autoantibody screening program for T1D and celiac disease in all children and adolescents (age 1-17yr). A pilot study is currently underway in four Italian regions addressing feasibility issues to be used in the scale up to nationwide screening. Meanwhile, a group of experts developed guidance recommendations for follow-up and monitoring of identified IA positive persons. RESULTS: Ten key components have been identified: establishment of a registry for children and adolescents at risk; close collaboration with the national network of family paediatricians; creation of T1D centers with expertise in follow-up and monitoring; educational measures; assurance of solid IA tests; identification of appropriate metabolic tests; feed-back feasibility and acceptability questionnaires; potential access to available therapeutic interventions; valuable outcome measures including DKA incidence; costs monitoring. Distinctive features of this program include single (in addition to multiple) IA antibody-positive persons in follow-up and the use of CGM to assess risk progression, rather than the cumbersome OGTT. CONCLUSION: It is expected that the proposed follow-up and monitoring program will be effective, affordable and acceptable to children and families identified in general T1D screening in Italy.

Recommendations for recognizing, risk stratifying, treating, and managing children and adolescents with hypoglycemia.

There has been continuous progress in diabetes management over the last few decades, not least due to the widespread dissemination of continuous glucose monitoring (CGM) and automated insulin delivery systems. These technological advances have radically changed the daily lives of people living with diabetes, improving the quality of life of both children and their families. Despite this, hypoglycemia remains the primary side-effect of insulin therapy. Based on a systematic review of the available scientific evidence, this paper aims to provide evidence-based recommendations for recognizing, risk stratifying, treating, and managing patients with hypoglycemia. The objective of these recommendations is to unify the behavior of pediatric diabetologists with respect to the timely recognition and prevention of hypoglycemic episodes and the correct treatment of hypoglycemia, especially in patients using CGM or advanced hybrid closed-loop systems. All authors have long experience in the specialty and are members of the Italian Society of Pediatric Endocrinology and Diabetology. The goal of treating hypoglycemia is to raise blood glucose above 70 mg/dL (3.9 mmol/L) and to prevent further decreases. Oral glucose at a dose of 0.3 g/kg (0.1 g/kg for children using "smart pumps" or hybrid closed loop systems in automated mode) is the preferred treatment for the conscious individual with blood glucose <70 mg/dL (3.9 mmol/L), although any form of carbohydrate (e.g., sucrose, which consists of glucose and fructose, or honey, sugary soft drinks, or fruit juice) containing glucose may be used. Using automatic insulin delivery systems, the oral glucose dose can be decreased to 0.1 g/kg. Practical flow charts are included to aid clinical decision-making. Although representing the official position of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED), these guidelines are applicable to the global audience and are especially pertinent in the era of CGM and other advanced technologies.

Incidence of type 1 diabetes in Sardinian children aged 0-14 years has almost doubled in the last twenty years. On top of the world.

AIMS: The primary objectives were to investigate the incidence rate (IR) of type 1 diabetes (T1D) in Sardinian children aged 0-14 years in 2019-2022 and to examine the temporal trend from 1989-1999. METHODS: Data from new-onset T1D patients aged 0-14 years who were residents of Sardinia were collected from all pediatric diabetology clinics. The overall, sex- and age specific (groups 0-4, 5-9, and 10-14 years), and calendar year IRs were calculated. The standardized IR (SIR) was also calculated using the direct method. Poisson regression was used to estimate the temporal trend in the SIRs from 1989-1999 to 2019-2022. RESULTS: In 2019-2022, 512 patients aged 0-14 years were diagnosed with T1D in Sardinia. The overall IR was 73.9 per 100,000 person-years (95 % CI 67.6-80.0). Since 1989, the SIR has increased by 2.3 % per year (CI 1.7-2.8, p < 0.0001). The frequency of ketoacidosis at onset was 26.4 %, with no significant differences among the four years. CONCLUSIONS: The incidence of T1D in Sardinia, unlike in other countries such as Finland, has almost doubled in the last 20 years, and currently, it appears to be the highest in the world.

HLA Genotyping in Children With Celiac Disease Allows to Establish the Risk of Developing Type 1 Diabetes.

INTRODUCTION: Celiac disease (CD) and type 1 diabetes (T1D) often co-occur and share genetic components in the human leukocyte antigen (HLA) class II region. We aimed to study the usefulness of HLA genotyping in predicting the risk of developing T1D in patients with CD and the temporal relationship between these diseases. METHODS: A cohort of 1,886 Sardinian patients, including 822 with CD, 1,064 with T1D, and 627 controls, underwent HLA class II typing. Seventy-six of 822 patients with CD were also affected by T1D (CD-T1D), and their HLA genotypes were analyzed for specific HLA associations with CD, T1D, and controls. RESULTS: High-risk HLA-DQ genotypes, including HLA-DQ2.5/DQ8, -DQ2.5/DQ2.5, and -DQ2.5/DQ2.3, were strongly associated with CD-T1D with frequencies of 34.5%, 15.9%, and 18.8%, respectively. Conversely, certain HLA genotypes associated with CD seemed to confer protection against T1D development. Therefore, HLA genotyping allows for the identification of those patients with CD who might develop T1D. The frequency of patients with CD preceding T1D is higher in younger children than older ones, with implications for the early childhood approach to diabetes prevention. DISCUSSION: CD is a condition for future T1D development, and specific HLA genotypes can predict this risk. Early screening for celiac autoimmunity and subsequent HLA typing in CD children could help identify those at high risk of T1D, allowing for proactive interventions and immunotherapies to preserve ß-cell function. These findings may support the re-evaluation of HLA typing in children with CD.

Sustained Effectiveness of an Advanced Hybrid Closed-Loop System in a Cohort of Children and Adolescents With Type 1 Diabetes: A 1-Year Real-World Study.

OBJECTIVE: To investigate glucose metrics and identify potential predictors of the achievement of glycemic outcomes in children and adolescents during their first 12 months of MiniMed 780G use. RESEARCH DESIGN AND METHODS: This multicenter, longitudinal, real-world study recruited 368 children and adolescents with type 1 diabetes (T1D) starting SmartGuard technology between June 2020 and June 2022. Ambulatory glucose profile data were collected during a 15-day run-in period (baseline), 2 weeks after automatic mode activation, and every 3 months. The influence of covariates on glycemic outcomes after 1 year of MiniMed 780G use was assessed. RESULTS: After 15 days of automatic mode use, all glucose metrics improved compared with baseline (P < 0.001), except for time below range (P = 0.113) and coefficient of variation (P = 0.330). After 1 year, time in range (TIR) remained significantly higher than at baseline (75.3% vs. 62.8%, P < 0.001). The mean glycated hemoglobin (HbA1c) over the study duration was lower than the previous year (6.9 ± 0.6% vs. 7.4 ± 0.9%, P < 0.001). Time spent in tight range (70-140 mg/dL) was 51.1%, and the glycemia risk index was 27.6. Higher TIR levels were associated with a reduced number of automatic correction boluses (P < 0.001), fewer SmartGuard exits (P = 0.021), and longer time in automatic mode (P = 0.030). Individuals with baseline HbA1c >8% showed more relevant improvement in TIR levels (from 54.3% to 72.3%). CONCLUSIONS: Our study highlights the sustained effectiveness of MiniMed 780G among youth with T1D. Findings suggest that even children and adolescents with low therapeutic engagement may benefit from SmartGuard technology.

Quantifying the effect of glucose 6-phosphate dehydrogenase deficiency on glycated hemoglobin values in children and adolescents with type 1 diabetes.

The primary objectives of the study were (a) to confirm that glucose 6-phosphate dehydrogenase (G6PD) deficiency affects HbA1c values in a sample of children and adolescents with type 1 diabetes (T1D) and (b) to quantify this effect so that a correction can be applied to the HbA1c values found in current clinical practice. The following data were collected: age, sex, G6PD, number of daily capillary blood glucose measurements, 90-day average blood glucose levels prior to the study, HbA1c, and glycated hemoglobin estimated (eA1c) obtained from blood glucose levels. Patients were divided into three groups based on G6PD values: deficient, intermediate, and nondeficient. In each group, a comparison between the average eA1C and HbA1c values was performed. Then, the difference between the eA1c and HbA1c values of each patient and the mean of the differences (MD) of all patients was calculated within the three groups. Finally, a comparison of the MD values between groups was performed. Seventy-four subjects with T1D were studied. Based on the G6PD value, 33 subjects were deficient, 8 were intermediate, and 33 subjects were nondeficient. In deficient patients, the eA1c values were significantly higher than the HbA1c values. In the other two groups, however, there were no differences. The MD values between the three groups were significantly different. In deficient patients, MD values were higher than those in intermediate and in nondeficient patients. No difference was found between intermediate and nondeficient subjects. Our study confirms that G6PD deficiency affects HbA1c values in children and adolescents with T1D, both in deficient subjects and, to a much lesser extent, in intermediate subjects. In deficient subjects, there is an average reduction in HbA1c attributable to enzyme deficiency of 1.3% (14 mmol/mol) and in intermediate subjects of 0.3% (3 mmol/mol).

Peripheral blood mononuclear cells reactivity in recent-onset type I diabetes patients is directed against the leader peptide of preproinsulin, GAD65271-285 and GAD65431-450.

Introduction: T cell reactivity against pancreatic autoantigens is considered one of the main contributors to the destruction of insulin-producing cells in type 1 diabetes (T1D). Over the years, peptide epitopes derived from these autoantigens have been described in NOD mice and in both HLA class II transgenic mice and humans. However, which ones are involved in the early onset or in the progressive phases of the disease is still unclear. Methods: In this work we have investigated, in early-onset T1D pediatric patients and HLA-matched controls from Sardinia, the potential of preproinsulin (PPI) and glutamate decarboxylase 65 (GAD65)-derived peptides to induce spontaneous T cell proliferation responses of peripheral blood mononuclear cells (PBMCs). Results: Significant T cell responses against PPI1-18, PPI7-19 and PPI31-49, the first two belonging to the leader sequence of PPI, and GAD65271-285 and GAD65431-450, were found in HLA-DR4, -DQ8 and -DR3, -DQ2 T1D children. Conclusions: These data show that cryptic epitopes from the leader sequence of the PPI and GAD65271-285 and GAD65431-450 peptides might be among the critical antigenic epitopes eliciting the primary autoreactive responses in the early phases of the disease. These results may have implications in the design of immunogenic PPI and GAD65 peptides for peptide-based immunotherapy.

Emotional eating and disordered eating behaviors in children and adolescents with type 1 diabetes.

Disordered eating behaviors (DEB) are more common in adolescents with type 1 diabetes (T1D) than in peers without diabetes. Emotional eating is a risk factor for binge eating in children and adolescents in the general population and is associated with increased intake of high energy-dense foods rich in sugars and fats. The primary objective is to evaluate whether emotional eating is associated with the metabolic control (glycated hemoglobin, plasma lipids and uric acid) in children and adolescents with type 1 diabetes and whether subjects with DEB (DEPS-R ≥ 20) have higher emotional eating than those without DEB. The secondary objective is to evaluate whether emotional eating is associated with the different symptoms of DEB. Emotional eating is positively correlated with HbA1c, total and LDL cholesterol values in children and adolescents with T1D. Subjects with DEB have a higher emotional eating score than subjects without DEB. Disinhibition is the most common disordered eating behavior in children and adolescents with T1D and is associated with a higher emotional eating score. Early identification and treatment of emotional eating could be tools for preventing DEB in people with type 1 diabetes. A total of 212 adolescents with T1D completed two self-administered questionnaires: the Diabetes Eating Problem Survey-Revised (DEPS-R) and the Emotional Eating Scale for Children and Adolescents (EES-C). Demographic (age, sex, duration of the disease), anthropometric (weight, height, BMI, BMI-SDS), therapeutic (type of insulin therapy, daily insulin dose) and metabolic (HbA1c, total cholesterol, HDL, LDL, triglycerides, uric acid) data were taken from the patients' medical records. The presence of other autoimmune diseases was also recorded.

Corrigendum: The silent epidemic of diabetic ketoacidosis at diagnosis of type 1 diabetes in children and adolescents in italy during the covid-19 pandemic in 2020.

[This corrects the article .].

Uric acid and cardiometabolic risk by gender in youth with type 1 diabetes.

The aim of this study was to investigate the association between uric acid (UA) and cardiometabolic risk factors (CMRFs) by sex in youth with type 1 diabetes (T1D). Retrospective data collected from 1323 children and adolescents (5-18 years; 716 boys) with T1D recruited in 9 Italian Pediatric Diabetes Centers were analyzed. CMRFs included UA, HbA1c, blood pressure (BP), cholesterol (TC), HDL, triglycerides (TG), neutrophils (N) and lymphocytes (L) count, glomerular filtration rate (eGFR) (calculated using Schwartz-Lyon equation). In boys, we found a higher age, daily insulin dose, TG, TG/HDL ratio, TC/HDL ratio, systolic BP, N/L ratio and lower HDL, and eGFR across UA tertiles (p = 0.01-0.0001). Similar results were found in girls but not for TG and systolic BP. In boys, the odds ratio (OR) of high levels of TG/HDL ratio, TC/HDL ratio, BP and mildly reduced eGFR (MRGFR) increased for 0.5 mg/dL of UA. Instead, in girls an increased levels of 0.5 mg/dL of UA were associated with high OR of TC/HDL ratio, N/L ratio and MRGFR. Uric acid may represent a useful marker for identifying youth with T1D at high cardiometabolic risk, and this association appears to vary by sex.

The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020.

Aim/Hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019. Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019. Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively). Conclusions/Interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks.

Significant and persistent improvements in time in range and positive emotions in children and adolescents with type 1 diabetes using a closed-loop control system after attending a virtual educational camp.

OBJECTIVE: To evaluate the six-month impact of the advanced automated functions of a closed-loop control (CLC) system (Control-IQ) and a virtual educational camp (vEC) on emotions and time in range (TIR) of children and adolescents with type 1 diabetes. METHODS: Children and their parents participated in a three-day vEC. Clinical, glucose, and emotion data were evaluated before, just after, and six months after the vEC. Emotions were evaluated using adapted Plutchik's and Geneva Emotion Wheels. RESULTS: Forty-three children and adolescents (7-16 years) showed significant improvements in positive emotions immediately and six months after the vEC (67% and 65% vs 38%, p < 0.05, respectively), while mixed emotions were reduced (32% and 15% vs 61%, p < 0.05 and p < 0.001, respectively). The median percentage TIR increased from 64% (IQR 54-72) to 75% (IQR 70-82) with Control-IQ (p < 0.001) six months after the vEC. CONCLUSIONS: Positive emotions (joy, serenity, and satisfaction) significantly improved while mixed emotions were significantly worse six months after the initiation of a CLC system (Control-IQ) and a vEC.

Effectiveness of a closed-loop control system and a virtual educational camp for children and adolescents with type 1 diabetes: A prospective, multicentre, real-life study.

AIM: To evaluate the impact of a virtual educational camp (vEC) on glucose control in children and adolescents with type 1 diabetes using a closed-loop control (CLC) system. MATERIALS AND METHODS: This was a prospective multicentre study of children and adolescents with type 1 diabetes using the Tandem Basal-IQ system. Insulin pumps were upgraded to Control-IQ, and children and their parents participated in a 3-day multidisciplinary vEC. Clinical data, glucose metrics and HbA1c were evaluated over the 12 weeks prior to the Control-IQ update and over the 12 weeks after the vEC. RESULTS: Forty-three children and adolescents (aged 7-16 years) with type 1 diabetes and their families participated in the vEC. The median percentage of time in target range (70-180 mg/dL; TIR) increased from 64% (interquartile range [IQR] 56%-73%) with Basal-IQ to 76% (IQR 71%-81%) with Control-IQ (P < .001). After the vEC, more than 75% of participants achieved a TIR of more than 70%. The percentage of time between 180 and 250 mg/dL and above 250 mg/dL decreased by 5% (P < .01) and 6% (P < .01), respectively, while the time between 70 and 54 mg/dL and below 54 mg/dL remained low and unaltered. HbA1c decreased by 0.5% (P < .01). There were no episodes of diabetic ketoacidosis or severe hypoglycaemia. CONCLUSIONS: In this study of children managing their diabetes in a real-world setting, more than 75% of children who participated in a vEC after starting a CLC system could obtain and maintain a TIR of more than 70%. The vEC was feasible and resulted in a significant and persistent improvement in TIR in children and adolescents with type 1 diabetes.

Albuminuric and non-albuminuric reduced eGFR phenotypes in youth with type 1 diabetes: Factors associated with cardiometabolic risk.

BACKGROUND AND AIM: Albuminuria and reduced eGFR are hallmarks of Diabetic Kidney Disease in adults. Our aim was to analyze factors associated with albuminuric and non-albuminuric mildly reduced eGFR phenotypes in youths with type 1 diabetes. METHODS AND RESULTS: This multicenter cross-sectional study included 1549 youths (age 5-17 years) with type 1 diabetes enrolled at 14 Italian Pediatric Diabetes Centers. Albuminuria, creatinine, glycosylated hemoglobin (HbA1c), lipids, blood pressure (BP), neutrophils (N) and lymphocytes (L) count were analyzed. Uric acid (UA) was available in 848 individuals. Estimated GFR (eGFR) was calculated using bedside Schwartz's equation. The sample was divided in three phenotypes: 1) normoalbuminuria and eGFR ≥90 mL/min/1.73 m2 (reference category, n = 1204), 2) albuminuric and normal GFR phenotype (n = 106), 3) non-albuminuric mildly reduced GFR (MRGFR) phenotype (eGFR 60-89 mL/min/1.73 m2, n = 239). Albuminuric and non-albuminuric reduced eGFR phenotypes were significantly associated with autoimmune thyroiditis (P =0.028 and P=0.044, respectively). Albuminuric phenotype showed high risk of high HbA1c (P=0.029), high BP (P < 0.001), and low HDL-C (P =0.045) vs reference category. Non-albuminuric MRGFR phenotype showed high risk of high BP (P < 0.0001), low HDL-C (P =0.042), high Triglycerides/HDL-C ratio (P =0.019), and high UA (P < 0.0001) vs reference category. CONCLUSION: Non albuminuric MRGFR phenotype is more prevalent than albuminuric phenotype and shows a worst cardiometabolic risk (CMR) profile). Both phenotypes are associated with autoimmune thyroiditis. Our data suggest to evaluate both albuminuria and eGFR earlier in type 1 diabetes to timely identify young people with altered CMR profile.

Socioeconomic Inequalities Increase the Probability of Ketoacidosis at Diagnosis of Type 1 Diabetes: A 2014-2016 Nationwide Study of 2,679 Italian Children.

This study aims to compare the frequency of Diabetic Ketoacidosis (DKA) at diagnosis in 2014-2016 with the one previously reported in 2004-2013; and to assess the association between family socioeconomic status and DKA at type 1 diabetes (T1D) diagnosis in children <15 years of age from 2014 to 2016. Methods: This nationwide, population-based, observational study included 2,679 children diagnosed with T1D from 54 Italian centers for pediatric diabetes during 2014-2016. The ISPAD criteria for DKA were used as a standard reference. The overall and by age frequency of DKA between the two time periods were compared. The association between family socioeconomic status and DKA was assessed using multiple logistic regression analysis. Results: Nine hundred and eighty nine children had DKA (36.9, 95% CI: 35.1-38.8). The frequency of DKA was significantly lower in 2014-2016 in comparison to 2004-2013 (40.3, 95% CI: 39.3-41.4, p = 0.002). The probability of having DKA at diagnosis was lower in mothers with a high level of education (OR = 0.69, 95% CI: 0.51-0.93) or a high level of occupation (OR = 0.76, 95% CI: 0.58 0.99), and in fathers with a high level of occupation (OR = 0.72, 95% CI: 0.55-0.94). Children living in Southern Italy had a higher probability of diagnosis with severe DKA than children living in Central Italy. Conclusion: There was a decrease in the frequency of DKA in children diagnosed with T1D under 15 years of age during 2014-2016. However, DKA frequency remains unacceptably high. This study demonstrated that socioeconomic inequalities, measured as low education and occupational levels, were associated with an increased probability of DKA at T1D diagnosis.

Second-generation antipsychotic and diabetes mellitus in children and adolescents.

Second generation antipsychotics (SGA) are used in children for the treatment of various psychiatric diseases, including pervasive developmental disorders. These drugs can cause metabolic effects as hyperglycemia and diabetes. A 16-year-old young-boy, diagnosed with autism, developed diabetes mellitus type 1 whilst he was on treatment with olanzapine (started 4 months before), clomipramine, valproic acid and lithium. The hypothesis of druginduced diabetes imposed olanzapine interruption and clozapine initiation. Insulin therapy was practiced, with progressive dosage reduction, until complete cessation of treatment after 13 months. Blood sugar and HbA1c levels remained stable for about a year and then increased again, requiring the introduction of metformin that improved glycemia. In children and adolescents assuming SGA serum glucose and lipid profile should always be assessed before therapy and then frequently monitored. Drug selection must consider family history and the individual risk. Molecule final choice remains equilibrium between efficacy and safety.

Zinc transporter 8 and MAP3865c homologous epitopes are recognized at T1D onset in Sardinian children.

Our group has recently demonstrated that Mycobacterium avium subspecies paratuberculosis (MAP) infection significantly associates with T1D in Sardinian adult patients. Due to the potential role played by MAP in T1D pathogenesis, it is relevant to better characterize the prevalence of anti-MAP antibodies (Abs) in the Sardinian population, studying newly diagnosed T1D children. Therefore, we investigated the seroreactivity against epitopes derived from the ZnT8 autoantigen involved in children at T1D onset and their homologous sequences of the MAP3865c protein. Moreover, sera from all individuals were tested for the presence of Abs against: the corresponding ZnT8 C-terminal region, the MAP specific protein MptD, the T1D autoantigen GAD65 and the T1D unrelated Acetylcholine Receptor. The novel MAP3865c281-287 epitope emerges here as the major C-terminal epitope recognized. Intriguingly ZnT8186-194 immunodominant peptide was cross-reactive with the homologous sequences MAP3865c133-141, strengthening the hypothesis that MAP could be an environmental trigger of T1D through a molecular mimicry mechanism. All eight epitopes were recognized by circulating Abs in T1D children in comparison to healthy controls, suggesting that these Abs could be biomarkers of T1D. It would be relevant to investigate larger cohorts of children, followed over time, to elucidate whether Ab titers against these MAP/Znt8 epitopes wane after diagnosis.