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Aim: In the pediatric diabetes clinic, patients with type 1 diabetes mellitus (T1D) account for more than 90% of cases, while monogenic forms represent about 6%. Many monogenic diabetes subtypes may respond to therapies other than insulin and have chronic diabetes complication prognosis that is different from T1D. With the aim of providing a better diagnostic pipeline and a tailored care for patients with monogenic diabetes, we set up a monogenic diabetes clinic (MDC)., Methods: In the first 3 years of activity 97 patients with non-autoimmune forms of hyperglycemia were referred to MDC. Genetic testing was requested for 80 patients and 68 genetic reports were available for review., Results: In 58 subjects hyperglycemia was discovered beyond 1 year of age (Group 1) and in 10 before 1 year of age (Group 2). Genetic variants considered causative of hyperglycemia were identified in 25 and 6 patients of Group 1 and 2, respectively, with a pick up rate of 43.1% (25/58) for Group 1 and 60% (6/10) for Group 2 (global pick-up rate: 45.5%; 31/68). When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes, while pick-up rate was 18.1% (4/22) in patients with mute family history for diabetes. Specific treatments for each condition were administered in most cases., Conclusion: We conclude that MDC may contribute to provide a better diabetes care in the pediatric setting., (© 2022. The Author(s).)

[This corrects the article .]., (Copyright © 2022 Cherubini, Marino, Scaramuzza, Tiberi, Bobbio, Delvecchio, Piccinno, Ortolani, Innaurato, Felappi, Gallo, Ripoli, Ricciardi, Pascarella, Stamati, Citriniti, Arnaldi, Monti, Graziani, De Berardinis, Giannini, Chiarelli, Zampolli, De Marco, Bracciolini, Grosso, De Donno, Piccini, Toni, Coccioli, Cardinale, Bassi, Minuto, D’Annunzio, Maffeis, Marigliano, Zanfardino, Iafusco, Rollato, Piscopo, Curto, Lombardo, Bombaci, Sordelli, Mameli, Macedoni, Rigamonti, Bonfanti, Frontino, Predieri, Bruzzi, Mozzillo, Rosanio, Franzese, Piredda, Cardella, Iovane, Calcaterra, Berioli, Lasagni, Pampanini, Patera, Schiaffini, Rutigliano, Meloni, De Sanctis, Tinti, Trada, Guerraggio, Franceschi, Cauvin, Tornese, Franco, Musolino, Maltoni, Talarico, Iannilli, Lenzi, Matteoli, Pozzi, Moretti, Zucchini, Rabbone and Gesuita.)

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., Competing Interests: No author reported any conflict of interest as regards this study. The following conflicts of interest pointed out are referred to a period from January 2020 to the submission of this manuscript. VCh’s institution has received research grants from AstraZeneca, Novonordisk, Eli Lilly, Movi, Dompè, and Menarini, and VCh received honoraria from Eli Lilly, Tandem, and Insulet for participating on speakers’ bureaus and scientific advisory boards. CR, DT, IRa, BPr, BPi, SZ, ST, and AR has received support Eli Lilly. In addition, SZ’s institution has received support from Pfeizer, ST, BPi, and DT have received support from Abbott and Theras. MM and AR have received support from Menarini. BPr and PB received honoraria for participating on speakers’ bureaus and scientific advisory boards for Sandoz. Lastly, RS has received research grants by Sanofi and received honoraria for participating on speakers’ bureaus and scientific advisory boards for Movi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cherubini, Marino, Scaramuzza, Tiberi, Bobbio, Delvecchio, Piccinno, Ortolani, Innaurato, Felappi, Gallo, Ripoli, Ricciardi, Pascarella, Stamati, Citriniti, Arnaldi, Monti, Graziani, De Berardinis, Giannini, Chiarelli, Zampolli, De Marco, Bracciolini, Grosso, De Donno, Piccini, Toni, Coccioli, Cardinale, Bassi, Minuto, D’Annunzio, Maffeis, Marigliano, Zanfardino, Iafusco, Rollato, Piscopo, Curto, Lombardo, Bombaci, Sordelli, Mameli, Macedoni, Rigamonti, Bonfanti, Frontino, Predieri, Bruzzi, Mozzillo, Rosanio, Franzese, Piredda, Cardella, Iovane, Calcaterra, Berioli, Lasagni, Pampanini, Patera, Schiaffini, Rutigliano, Meloni, De Sanctis, Tinti, Trada, Guerraggio, Franceschi, Cauvin, Tornese, Franco, Musolino, Maltoni, Talarico, Iannilli, Lenzi, Matteoli, Pozzi, Moretti, Zucchini, Rabbone and Gesuita.)

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features., Design: Retrospective analysis of the Italian data set of patients with TNDM., Methods: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared., Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy., Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Context: An etiologic diagnosis of diabetes can affect the therapeutic strategy and prognosis of chronic complications., Objective: The aim of the present study was to establish the relative percentage of different diabetes subtypes in patients attending Italian pediatric diabetes centers and the influence of an etiologic diagnosis on therapy., Design, Setting, and Patients: This was a retrospective study. The clinical records of 3781 consecutive patients (age, 0 to 18 years) referred to 15 pediatric diabetes clinics with a diagnosis of diabetes or impaired fasting glucose from January 1, 2007 to December 31, 2012 were examined. The clinical characteristics of the patients at their first referral to the centers, type 1 diabetes-related autoantibodies, molecular genetics records, and C-peptide measurements, if requested for the etiologic diagnosis, were acquired., Main Outcome Measures: The primary outcome was to assess the percentage of each diabetes subtype in our sample., Results: Type 1 diabetes represented the main cause (92.4%) of diabetes in this group of patients, followed by monogenic diabetes, which accounted for 6.3% of cases [maturity onset diabetes of the young (MODY), 5.5%; neonatal diabetes mellitus, 0.6%, genetic syndromes, 0.2%]. A genetic diagnosis prompted the transfer from insulin to sulphonylureas in 12 patients bearing mutations in the HNF1A or KCNJ11 genes. Type 2 diabetes was diagnosed in 1% of the patients., Conclusions: Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling., (Copyright © 2017 Endocrine Society)

Objective: Childhood obesity has become epidemic and has been accompanied by an increase in prevalence of type 2 diabetes (T2DM) in youth. Addressing obesity and insulin resistance by drug treatment represents a rational strategy for the prevention of T2DM. A systematic review was performed to evaluate the effectiveness of metformin in reducing weight and ameliorating insulin resistance in obese nondiabetic children., Methods: A PubMed database search was conducted, using 'metformin', 'obesity', 'insulin resistance', 'children', 'adolescents' as search terms., Results: Eleven trials were included in the present review. Metformin was administered for 6-12 months at a dosage of 1,000-2,000 mg/daily, decreasing BMI by 1.1-2.7 compared with placebo or lifestyle intervention alone. Concomitantly, fasting insulin resistance improved after metformin therapy. Posttreatment follow-up was performed in one study, showing that after 1 year of discontinuation of therapy the decrease in BMI disappears., Conclusions: Short-term metformin treatment appears to moderately affect weight reduction in severely obese children and adolescents, with a concomitant improvement in fasting insulin sensitivity. Further studies with longer treatment period are needed to establish how much metformin can reduce weight and its real utility in preventing T2DM development in pediatric patients., (Copyright © 2013 S. Karger AG, Basel.)

Background: Benefit of fitness on children with type 1 diabetes mellitus (T1DM) is still debated., Aim: To evaluate the influence of physical activity on metabolic balance and exercise tolerance in prepubertal children affected by T1DM., Methods: We analyzed 35 pre-/peripubertal T1DM children and 31 matched controls using an activity monitor (SenseWear Armbad) and physical activity questionnaire (PAQ) to assess energy expenditure (EE), total and active, sedentary and physical activities (h/day and Mets = metabolic equivalents). The maximal cardiopulmonary exercise test (CPET) was also performed., Results: Total physical activities and total and active EE (>3 Mets) resulted higher in controls than in T1DM patients and self-reported perception of physical and sedentary activities was altered in T1DM children as well in controls and were different from the measured data. No differences were found in CPET parameters with the exception of a higher maximal blood pressure in T1DM children. In multivariate analysis HbA1c negatively correlated with VO(2)., Conclusion: Prepubertal T1DM children seem to have a lower level of physical activity and EE and a probable altered feeling of physical and sedentary activities. On the other hand, T1DM children do not show any alteration of cardiovascular performance, although glycemic control (HbA1c) may play a role in cardiovascular performance., (Copyright © 2012 S. Karger AG, Basel.)

Background and Aim: Metabolic characteristics and rate of progression to overt Type 2 diabetes (T2D) in low-risk European obese children are not well documented. Aim of the study was to investigate differences in insulin sensitivity and secretion in Italian obese children and youngsters with pre-diabetes., Methods: Ninety-six obese children and youngsters with pre-diabetes, pair-matched with individuals with normal glucose tolerance (NGT) were included in the present study. Participants were screened by oral glucose tolerance. Pre-diabetes was classified as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined IFG-IGT. Homeostasis model assessment of insulin resistance (HOMA-IR), 2-h insulin, insulin sensitivity index (ISI) and disposition index (DI) were calculated to estimate fasting, peripheral and whole body insulin sensitivity and capacity of pancreatic islets to compensate for lower insulin sensitivity, respectively. One-way analysis of variance was used to compare groups., Results: Eleven subjects had IFG (11.5%), 79 IGT (82.3%), 6 combined IFG-IGT (6.3%). Individuals with IFG showed the highest HOMA-IR (p=0.0007), those with IGT the highest 2-h insulin (p<0.0001), those with IFG-IGT the lowest ISI (p<0.0001), with severely reduced DI (p=0.0003). Compared with NGT, DI was 60% lower in those with IFG-IGT., Conclusion: IFG is linked primarily to fasting insulin resistance, IGT to peripheral insulin resistance. IFG-IGT is hallmarked by reduced whole body insulin sensitivity and an additional severe defect in DI. Further longitudinal studies are needed to understand whether the different categories of pre-diabetes in European obese adolescents represent real pre-diabetic alterations.

Objective: Epidemiological studies have shown an association between birth weight and future risk of type 2 diabetes, with individuals born either small or large for gestational age at increased risk. We sought to investigate the influence of birth weight on the relation between insulin sensitivity and beta-cell function in obese children., Subjects and Methods: A total of 257 obese/overweight children (mean body mass index-sd score, 2.2 +/- 0.3), aged 11.6 +/- 2.3 yr were divided into three groups according to birth weight percentile: 44 were small for gestational age (SGA), 161 were appropriate for gestational age (AGA), and 52 were large for gestational age (LGA). Participants underwent a 3-h oral glucose tolerance test with glucose, insulin, and C-peptide measurements. Homeostasis model of assessment for insulin resistance, insulinogenic index, and disposition index were calculated to evaluate insulin sensitivity and beta-cell function. Glucose and insulin area under the curve (AUC) were also considered. One-way ANOVA was used to compare the three groups., Results: SGA and LGA subjects had higher homeostasis model of assessment for insulin resistance than AGA subjects, but they diverged when oral glucose tolerance test response was considered. Indeed, SGA subjects showed higher glucose AUC and lower insulinogenic and disposition indexes. Insulin AUC was not different between groups, but when singular time points were considered, SGA subjects had lower insulin levels at 30 min and higher insulin levels at 180 min., Conclusions: SGA obese children fail to adequately compensate for their reduced insulin sensitivity, manifesting deficit in early insulin response and reduced disposition index that results in higher glucose AUC. Thus, SGA obese children show adverse metabolic outcomes compared to AGAs and LGAs.

No long-term data are available on the efficacy of glargine insulin in comparison with continuous sc insulin infusion (CSII) in children and adolescents affected by Type 1 diabetes (T1D). Our aim was to compare the 2-yr efficacy of the 2 insulin approaches, in order to know how to best supply basal insulin in these patients. Thirty-six 9 to 18-yr-old consecutive children with at least 3 yr previous T1D diagnosis were enrolled. As part of routine clinical care, the patients consecutively changed their previous insulin scheme (isophane insulin at bedtime and human regular insulin at meals) and were randomly selected in order to receive either multiple daily injections (MDI) treatment with once-daily glargine and human regular insulin at meals, or CSII with aspart or lispro insulin. Both groups showed a significant decrease in glycosylated hemoglobin (HbA1c) values during the 1st year of therapy, though only in the CSII treated children was the decrease also observed during the 2nd year. The overall insulin requirement significantly decreased only in the CSII group and exclusively during the 1st year, while no significant differences were observed concerning body mass index SD score, severe hypoglycemic episodes and basal insulin supplementation. The work illustrates the first long-term study comparing the efficacy of CSII to MDI using glargine as basal insulin in children. Only with CSII were better HbA1c values obtained for prolonged periods of time, so that CSII might be considered the gold standard of intensive insulin therapy also for long-term follow-ups.