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Background Glucose management indicator (GMI) is a useful metric for the clinical management of diabetic patients using continuous glucose monitoring (CGM). In adults, a marked discordance between HbA1c and GMI has been reported. To date, no studies have evaluated this discordance in children/adolescents with type 1 diabetes (T1D). Methods HbA1c and real-life CGM data of the 12 weeks preceding HbA1c measurement were collected from 805 children/adolescents. The absolute difference between HbA1c and GMI was calculated for both the 12-week and 4-week periods preceding HbA1c measurement and the proportion of discordant patients was defined according to specific thresholds in the entire study population and in subjects stratified by type of CGM, insulin therapy, gender, age and puberty. Regression analyses were performed with HbA1c-GMI discordance as dependent variable and patients' characteristics as independent ones. A new GMI equation for children and adolescent was derived from the linear regression analysis between mean glucose and HbA1c. Results HbA1c-GMI discordance calculated on the 12-week period was = 0.5 and >= 1.0 in 24.8, 33.9 and 9.2% of the subjects, respectively. No significant differences in the proportion of discordant patients were found comparing patients stratified by type of CGM, insulin therapy, gender, age and puberty. GMI-HbA1c discordance was not significantly explained by age, gender, BMI, type of CGM, insulin therapy, hemoglobin, anemia and autoimmune diseases (R-2 = 0.012, p = 0.409). HbA1c-GMI discordance calculated on the 4-week period was comparable. GMI (%) equation derived for this cohort was: 3.74 + 0.022x (mean glucose in mg/dl). Conclusions GMI could be meaningfully discordant respect to HbA1c in more than a third of children/adolescents with T1D. This discrepancy should be taken into careful consideration when the two indices are directly compared in daily clinical practice.

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.

Long-term complications of type 1 diabetes (T1D) include microvascular complications and macrovascular disease. Despite the important advances in the treatment of T1D of the last decades, these complications still represent the leading cause of morbidity and mortality in patients with T1D. Extensive evidence indicates that structural and functional alterations of the kidney, retina, nerves and large arteries occur already in the first years after the onset of diabetes. We performed a comprehensive review of the available evidence on screening, diagnosis, prevention and treatment of vascular complications of T1D. In particular, we focused on three major challenges related to long-term complications of T1D: 1) finding of new biomarkers and diagnostic methods able to identify early signs of complications; 2) identifying specific risk factors for the development of these complications; 3) identifying and implementing new therapeutic strategies able to prevent the development and progression of vascular complications.

Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

Objective Vitamin D may potentially play a central role in glucose homeostasis and β-cell function (BCF), although studies are not consistent. Aim of our study was to test the hypotheses of a direct relationship between vitamin D, insulin sensitivity (IS) and BCF in overweight and obese non-diabetic children. Design and methods Cross-sectional study carried out at the Childhood Obesity Outpatient Clinic, University Hospital of Verona. One hundred twenty-two Caucasian overweight and obese children (age: 12.8 ± 0.2 years) were enrolled. Exclusion criteria: genetic or endocrine causes of obesity, chronic diseases or therapies. Patients underwent oral glucose tolerance test. HOMA-IR, Matsuda index and insulinogenic index were calculated. BCF was reconstructed by mathematical modeling and described by Derivative and Proportional Control. Total 25-hydroxyvitamin D and vitamin D-binding protein (VDBP) were measured. Two SNPs (rs4588 and rs7041) in the VDBP gene were studied, and bioavailable vitamin D (BVD) was calculated. Results Hypovitaminosis D was documented in 90% of patients. Forty-seven subjects were homozygous for both SNPs. Total vitamin D was positively correlated with Matsuda index (P = 0.002), VDBP (P = 0.045), and negatively with BMI SDS (P = 0.043), HOMA-IR (P = 0.008), HOMA-B (P = 0.001), IGI (P = 0.007), derivative control (P = 0.036) and proportional control (P = 0.018). Total vitamin D, adjusted for age, gender, BMI SDS, puberty and seasonality of vitamin D measurement, was a predictor of Matsuda index, HOMA-IR, HOMA-B, IGI, proportional control (all P P P = 0.041). Conclusions Hypovitaminosis D negatively influences BCF and IS, suggesting that vitamin D levels might be implicated in glucose metabolism impairment in overweight and obese individuals.

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.

Cystic fibrosis related diabetes (CFRD) is a comorbidity of cystic fibrosis (CF) that negatively impacts on its clinical course. Prediabetes is an important predictor of either CFRD development and unfavorable prognosis of CF in both pediatric and adult patients. International guidelines recommend insulin only in case of CFRD diagnosis. Whether early detection and treatment of prediabetes may contribute to improve the clinical course of CF is still debated. A subgroup of pediatric diabetologists of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) performed a systematic review of the literature based on predefined outcomes: impact of pre-diabetes on clinical outcomes and on the risk of developing CFRD; diagnosis of diabetes and pre-diabetes under 10 years of age; effectiveness of therapy on glycemic control, impact of therapy on pulmonary function and nutritional status. Thirty-one papers were selected for the analysis data presented in these papers were reported in tables sorted by outcomes, including comprehensive evidence grading according to the GRADE approach. Following the grading of the quality of the evidence, the entire ISPED diabetes study group achieved consensus for the Italian recommendations based on both evidence and clinical experience. We concluded that in patients with CF, prediabetes should be carefully considered as it can evolve into CFRD. In patients with CF and prediabetic conditions, after complete evaluation of the OGTT trend, glucometrics, glycemic values measured during pulmonary exacerbations and/or steroid therapy, early initiation of insulin therapy could have beneficial effects on clinical outcomes of patients with CF and prediabetes.

Aims: To evaluate the relationships between HbA1c and Continuous Glucose Monitoring (CGM) metrics in children/adolescents with Type 1 Diabetes (T1D). Methods: HbA1c and real-life CGM data of the 12 weeks preceding its measurement were retrospectively collected from 654 children/adolescents with T1D. The relationships between HbA1c and CGM metrics were assessed by Spearman correlation coefficient. Participants were categorized into groups based on HbA1c and CGM metrics values. ANOVA was run across HbA1c and CGM metrics groups in the entire study population and in subjects stratified by CGM type, insulin therapy, age and puberty. Results: HbA1c was positively correlated with mean glucose, SD, %TAR > 180 mg/dL, %TAR > 250 mg/dL, HBGI and negatively with %TIR, %TBR and %time < 54 mg/dL. HbA1c-based groups were significantly associated with these metrics, but for each group their value widely ranged with a substantial overlap between them. HbA1c and HbA1c-based groups were not associated with %CV and LBGI, as well as %CV and LBGI-based groups had not significantly different HbA1c. Comparable results were found analysing subjects according to age, type of CGM, insulin therapy and puberty. Conclusions: The relationships between HbA1c and CGM metrics described in this cohort of paediatric subjects with T1D support the importance of the evaluation of these metrics, in particular %CV and LBGI, independently of HbA1c value.

Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glucose regulation—beta-cell function, insulin clearance, and insulin sensitivity—in patients with cystic fibrosis (CF), categorized according their glucose tolerance status, including early elevation of mid-level oral glucose tolerance test (OGTT) glucose values (>140 and Methods A total of 232 CF patients aged 10 to 25 years underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modeling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between glucometabolic variables and 5 glucose tolerance stages (normal glucose tolerance [NGT], AGT140, indeterminate glucose tolerance [INDET], impaired glucose tolerance [IGT], cystic fibrosis–related diabetes CFRD]) was assessed with a general linear model. Results Beta-cell function and insulin sensitivity progressively worsened across glucose tolerance stages (P Conclusions In CF patients, each of the 5 glucose tolerance stages shows a unique pattern of defects of the direct determinants of glucose regulation, with AGT140 patients significantly differing from NGT and being similar to IGT. These findings suggest that AGT140 should be recognized as a distinct glucose tolerance stage and that reconsideration of the grade of glucometabolic deterioration across glucose tolerance stages in CF is warranted.

Background: No studies have assessed if 2-week of continuous glucose monitoring (CGM) data provide good estimation of long-term glycemic control and glucose variability (GV) in pediatric patients with type 1 diabetes (T1D) as in adults. Methods: Six hundred fifty-four T1D pediatric patients were enrolled and 12-weeks of CGM data, before HbA1c measurement, were collected. Metrics of glycemic control and GV in incremental sampling periods were calculated. The agreement between metrics calculated in the sampling periods and the full 12-week period was assessed with correlation analysis (R2), median relative absolute difference (RAD) or absolute difference in the entire study populations and subjects stratified by age, pubertal status, insulin therapy (MDI,CSII), type of CGM (intermittently scanned [isCGM], real-time [rtCGM]), and HbA1c level. Results: Correlations with metrics of the full 12-week period improved by extending the sampling periods. R2 values close to 0.90 using 4-week period were significantly higher than 2-week period, particularly for coefficient of variation, mean glucose SD, percentage of time below the range

Aims to assess the prevalence of cardiovascular risk factors (CVRFs) and to identify the variables associated with CVRFs in a cohort of children and adolescents with Type 1 Diabetes. Methods 2,021 subjects, 2-18 year-old, were recruited in 17 Italian Pediatric Diabetes Centers. Anthropometric, blood pressure, biochemical (HbA1c, lipid profile, ACR), insulin therapy, physical activity level, smoking and family socio-economic status data were collected. CVRFs prevalence and their distribution were analyzed according to age and binary logistic regression was performed with positivity for at least one major CVRF (BMI-SDS>+2SD, blood pressure>90th percentile, LDL cholesterol>100 mg/dl) as dependent variable and age, duration of illness, gender, HbA1c and physical activity, as independent variables. Results The prevalence of CVFRs not at the recommended target was respectively: 32.5% one CVRF, 6.7% two CVRFs and 0.6% three CVRFs, with no significant differences across the 3 age groups (2-10, 10-15, 15-18 years). In the total sample, HbA1c and inadequate physical activity were associated with a higher probability of having at least one major CVRF. This probability was associated with physical activity in the 2-10-year-old group, with physical activity and HbA1c in the 10-15-year-old group and with HbA1c only in subjects older than 15 years. Conclusions More than 30% of subjects had at least a major CVRF. Early detection of CVRFs may be useful to enforce the therapeutic intervention in this subgroup, in order to reduce the risk to develop cardiovascular complications. This article is protected by copyright. All rights reserved.