Efficacy and safety of advanced hybrid closed loop systems in children with type 1 diabetes younger than 6 years.

Background: Tight glycemic control is essential for the normal growth and development of preschool children. The aim of our study was to evaluate the impact of advanced hybrid closed loop (AHCL) systems in a real-life setting in children younger than 6 years. Methods: We conducted a two-center prospective study. We enrolled 19 patients with a median age at disease onset of 2.6 years [interquartile range (IQR) 1.6; 4.4] and a median disease duration of 1.4 years (IQR 0.9; 2.8) who were switched to AHCL from multiple daily injections or open-loop insulin therapy and with a 6-month follow-up. Clinical data, sensor glycemic metrics, and pump settings were collected and analyzed. Results: After 6 months of follow-up, there was a significant reduction in median HbA1c (p = 0.0007) and glucose management indicator (p = 0.03). A reduction in both mild (>180 mg/dL) (p = 0.04) and severe (>250 mg/dL) (p = 0.01) hyperglycemia was observed after 1 month of auto mode, and in mild hyperglycemia, it persisted up to 6 months (p = 0.02). A small increase in time below range (<70 mg/dL) was observed (p = 0.04) without a significant difference in time <54 mg/dL (p = 0.73). Time in range increased significantly, reaching a 10% increment (p = 0.03) compared with baseline. A significant reduction in the average sensor glucose was observed (p = 0.01) while coefficient of glucose variability (CV%) remained stable (p = 0.12). No episodes of ketoacidosis or severe hypoglycemia have been recorded. Conclusion: AHCL systems are effective and safe for children younger than 6 years and should be considered as a valid therapeutic option from diabetes onset.

Time In Tight Range in children and adolescents with type 1 diabetes: A cross-sectional observational single centre study evaluating efficacy of new advanced technologies.

INTRODUCTION: Early and tight glycaemic control is crucial to prevent long-term complications of Type 1 Diabetes (T1D). The aim of our study was to compare glucose metrics, including Time In Tight Range (TITR), in a real-world setting. METHODS: We performed a single-centre cross-sectional study in 534 children and adolescents with T1D. Participants were divided into four groups (multiple daily injections + real-time Continuous glucose monitoring (CGM), multiple daily injections + intermittently scanned CGM, sensor augmented pump (SAP), and Advanced Hybrid Closed-Loop (AHCL). Demographical and clinical data were collected and analysed. RESULTS: The group with AHCL showed significantly higher Time In Range (TIR) (71.31% ± 10.88) than SAP (57.82% ± 14.98; p < 0.001), MDI + rtCGM (54.56% ± 17.04; p < 0.001) and MDI + isCGM (52.17% ± 19.36; p < 0.001) groups with a lower Time Above Range (p < 0.001). The group with AHCL also showed lower Time Below Range than MDI + isCGM and SAP groups (p < 0.01). The overall TITR was 37% ± 14 with 19% of participants who reached a TITR ≥50% with a mean TIR of 81%. AHCL had significantly higher TITR (45.46% ± 11.77) than SAP (36.25% ± 13.53; p < 0.001), MDI + rtCGM (34.03% ± 13.89; p < 0.001) and MDI + isCGM (33.37% ± 15.84; p < 0.001) groups with a lower Coefficient of Variation (p < 0.001). CONCLUSIONS: Our study indicates that AHCL ensures a better glycaemic control with an improvement in both TIR and TITR, along with a reduction in CV. Implementation of automated insulin delivery systems should be considered in the treatment of children and adolescents with T1D.

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.

A new variant in the GATA6 gene associated with tracheoesophageal fistula, pulmonary vein stenosis and neonatal diabetes.

INTRODUCTION: GATA6 is a gene that encodes a transcription factor with a key role in the development of several organ systems, including the development of the pancreas. It is associated with neonatal diabetes but also with other extra-pancreatic anomalies. CASE PRESENTATION: This report describes the association of tracheoesophageal fistula (TEF), pulmonary vein stenosis (PVS), and neonatal diabetes caused by a novel mutation of the GATA6 gene in a small-for-gestational-age male neonate born at 32 weeks of gestation. Next-Generation Sequencing revealed the novel heterozygous variant c.1502C>G in the GATA6 gene, which determines the introduction of the premature stop codon p.Ser501Ter at the protein level. This de novo nonsense variant was not detected in the analyzed parental DNA samples and has not been previously described in the literature. At about two months of life, a PVS was suspected. The PVS progressively increased with the development of an intramural component, resulting in severe postcapillary pulmonary hypertension. The child died at about 4 months of life. CONCLUSION: TEF can be associated with GATA6 variants. In the case of neonatal diabetes and TEF, neonatologists should be aware of this association and should also investigate the child for complex congenital heart disorders, such as in our case, with a cardiac computed tomography.

The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022.

CONTEXT: In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM). OBJECTIVE: To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS). METHODS: We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset. RESULTS: Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, P = .034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin. CONCLUSION: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy.

The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

Antiplatelet Effect of Melatonin through Breastfeeding: A Pediatric Case Report.

We present a pediatric case of the antiplatelet effect of melatonin taken through breast milk in an 18-month-old child. The child was referred to our hematology outpatient clinic because of bleeding episodes that she presented since birth. Blood tests excluded the presence of blood coagulation diseases. The family history was negative for bleeding disorders. The child did not consume any drugs, food supplements, herbal teas or infusions. We performed an aggregation platelet test, which showed a reduced platelet aggregation. Shortly before, the baby had been breastfed. We speculated that breast milk could interfere with the result of the test; therefore, we decided to repeat the test in a fasting state. This time the test showed a normal platelet aggregation time. We learned that the child's mother was taking a mixture of valerian and melatonin. Thus, we decided to suspend maternal intake of melatonin and perform a new platelet aggregation test after three months. The test results were negative. After the suspension of melatonin, the patient did not present further bleeding events. In this case, melatonin, through the inhibition of platelet aggregation, had an important role on the hemostatic system of the child. Melatonin is considered as a dietary supplement and is mostly available as an alternative medicine without formal prescription and dosage regulation. It is important, especially during breastfeeding, to investigate personal and medication history, including also homeopathic remedies or dietary supplements.

Monogenic diabetes clinic (MDC): 3-year experience.

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.

Pathophysiology of Type 1 Diabetes and Gut Microbiota Role.

Type 1 diabetes (T1D) is a multifactorial autoimmune disease driven by T-cells against the insulin-producing islet ß-cells, resulting in a marked loss of ß-cell mass and function. Although a genetic predisposal increases susceptibility, the role of epigenetic and environmental factors seems to be much more significant. A dysbiotic gut microbial profile has been associated with T1D patients. Moreover, new evidence propose that perturbation in gut microbiota may influence the T1D onset and progression. One of the prominent features in clinically silent phase before the onset of T1D is the presence of a microbiota characterized by low numbers of commensals butyrate producers, thus negatively influencing the gut permeability. The loss of gut permeability leads to the translocation of microbes and microbial metabolites and could lead to the activation of immune cells. Moreover, microbiota-based therapies to slow down disease progression or reverse T1D have shown promising results. Starting from this evidence, the correction of dysbiosis in early life of genetically susceptible individuals could help in promoting immune tolerance and thus in reducing the autoantibodies production. This review summarizes the associations between gut microbiota and T1D for future therapeutic perspectives and other exciting areas of research.

Functional and Taxonomic Traits of the Gut Microbiota in Type 1 Diabetes Children at the Onset: A Metaproteomic Study.

Type 1 diabetes (T1D) is a chronic autoimmune metabolic disorder with onset in pediatric/adolescent age, characterized by insufficient insulin production, due to a progressive destruction of pancreatic ß-cells. Evidence on the correlation between the human gut microbiota (GM) composition and T1D insurgence has been recently reported. In particular, 16S rRNA-based metagenomics has been intensively employed in the last decade in a number of investigations focused on GM representation in relation to a pre-disease state or to a response to clinical treatments. On the other hand, few works have been published using alternative functional omics, which is more suitable to provide a different interpretation of such a relationship. In this work, we pursued a comprehensive metaproteomic investigation on T1D children compared with a group of siblings (SIBL) and a reference control group (CTRL) composed of aged matched healthy subjects, with the aim of finding features in the T1D patients' GM to be related with the onset of the disease. Modulated metaproteins were found either by comparing T1D with CTRL and SIBL or by stratifying T1D by insulin need (IN), as a proxy of ß-cells damage, showing some functional and taxonomic traits of the GM, possibly related to the disease onset at different stages of severity.

Gut Microbiota Functional Traits, Blood pH, and Anti-GAD Antibodies Concur in the Clinical Characterization of T1D at Onset.

Alterations of gut microbiota have been identified before clinical manifestation of type 1 diabetes (T1D). To identify the associations amongst gut microbiome profile, metabolism and disease markers, the 16S rRNA-based microbiota profiling and 1H-NMR metabolomic analysis were performed on stool samples of 52 T1D patients at onset, 17 T1D siblings and 57 healthy subjects (CTRL). Univariate, multivariate analyses and classification models were applied to clinical and -omic integrated datasets. In T1D patients and their siblings, Clostridiales and Dorea were increased and Dialister and Akkermansia were decreased compared to CTRL, while in T1D, Lachnospiraceae were higher and Collinsella was lower, compared to siblings and CTRL. Higher levels of isobutyrate, malonate, Clostridium, Enterobacteriaceae, Clostridiales, Bacteroidales, were associated to T1D compared to CTRL. Patients with higher anti-GAD levels showed low abundances of Roseburia, Faecalibacterium and Alistipes and those with normal blood pH and low serum HbA1c levels showed high levels of purine and pyrimidine intermediates. We detected specific gut microbiota profiles linked to both T1D at the onset and to diabetes familiarity. The presence of specific microbial and metabolic profiles in gut linked to anti-GAD levels and to blood acidosis can be considered as predictive biomarker associated progression and severity of T1D.

Natural history of type 1 diabetes on an immunodysregulatory background with genetic alteration in B-cell activating factor receptor: A case report.

The immunological events leading to type 1 diabetes (T1D) are complex and heterogeneous, underscoring the necessity to study rare cases to improve our understanding. Here, we report the case of a 16-year-old patient who showed glycosuria during a regular checkup. Upon further evaluation, stage 2 T1D, autoimmune thrombocytopenic purpura (AITP), and common variable immunodeficiency (CVID) were diagnosed. The patient underwent low carb diet, losing > 8 kg, and was placed on Ig replacement therapy. Anti-CD20 monoclonal antibody (Rituximab, RTX) was administered 2 years after diagnosis to treat peripheral polyneuropathy, whereas an atypical mycobacteriosis manifested 4 years after diagnosis and was managed with prolonged antibiotic treatment. In the fifth year of monitoring, the patient progressed to insulin dependency despite ZnT8A autoantibody resolution and IA-2A and GADA autoantibody decline. The patient had low T1D genetic risk score (GRS = 0.22817) and absence of human leukocyte antigen (HLA) DR3/DR4-DQ8. Genetic analysis identified the monoallelic mutation H159Y in TNFRSF13C, a gene encoding B-cell activating factor receptor (BAFFR). Significant reduced blood B-cell numbers and BAFFR levels were observed in line with a dysregulation in BAFF-BAFFR signaling. The elevated frequency of PD-1+ dysfunctional Tfh cells composed predominantly by Th1 phenotype was observed at disease onset and during follow-up. This case report describes a patient progressing to T1D on a BAFFR-mediated immunodysregulatory background, suggesting a role of BAFF-BAFFR signaling in islet-specific tolerance and T1D progression.

The application of precision medicine in monogenic diabetes.

INTRODUCTION: Monogenic diabetes, a form of diabetes mellitus, is caused by a mutation in a single gene and may account for 1-2% of all clinical forms of diabetes. To date, more than 40 loci have been associated with either isolated or syndromic monogenic diabetes. AREAS COVERED: While the request of a genetic test is mandatory for cases with diabetes onset in the first 6 months of life, a decision may be difficult for childhood or adolescent diabetes. In an effort to assist the clinician in this task, we have grouped monogenic diabetes genes according to the age of onset (or incidental discovery) of hyperglycemia and described the additional clinical features found in syndromic diabetes. The therapeutic options available are reviewed. EXPERT OPINION: Technical improvements in DNA sequencing allow for rapid, simultaneous analysis of all genes involved in monogenic diabetes, progressively shrinking the area of unsolved cases. However, the complexity of the analysis of genetic data requires close cooperation between the geneticist and the diabetologist, who should play a proactive role by providing a detailed clinical phenotype that might match a specific disease gene.

Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2.

BACKGROUND/AIMS: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. METHODS: Variant screening was used to identify the cause of neonatal diabetes, and continuous glucose monitoring was used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. RESULTS: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [p.Tyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (intermediate DEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. CONCLUSIONS: In this subject, the KCNJ11 (c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution and highlights the need for molecular analysis of such mutations.

Estimated insulin sensitivity, cardiovascular risk, and hepatic steatosis after 12 years from the onset of T1D.

AIM: To test the hypothesis that intensive insulin treatment and optimal glycaemic control are not fully protective against reduction of insulin sensitivity in children with type 1 diabetes. MATERIAL AND METHODS: Cohort study of 78 normal-weight patients with prepubertal onset (T0 ) and follow-up waves at 1 (T1 ), 5 (T5 ), 10 (T10 ), and 12 (T12 ) years; matched for age and sex to 30 controls at T12 . Estimated insulin sensitivity (eIS) by three formulae; ultrasound evaluation of para and perirenal fat thickness; hepatic steatosis (HS); carotid intima media thickness (cIMT) at T12 . RESULTS: At T12, the 36 patients (46%) who had constantly or prevalently haemoglobin A1c (HbA1c) < 58 mmol/l during follow-up showed better eIS indexes (p = 0.049 to <0.0001); lipid profile (p = 0.042 to <0.0001), reduced fat mass (p = 0.012) and required lower insulin dose (p = 0.032) than the 42 patients (54%) with HbA1c ≥ 58 at T12. Patients (N = 25) with eISEDC  < 8.77 mg kg-1  min-1 showed higher cIMT (p < 0.0001). HS was found in 6 patients (∼8%). In patients and normal-weight controls, fat mass (p = 0.03), age (p = 0.03), cIMT (p = 0.05) predicted HS; eIS indexes (p from 0.04 to <0.0001) predicted cIMT. Body mass index, perirenal fat, fat mass, and triglycerides to high density lipoprotein cholesterol ratio were associated with eIS indexes (p from 0.03 to <0.0001). CONCLUSIONS: Young T1D patients have reduced insulin sensitivity and higher cIMT. Adiposity, glucose, and lipid control over follow-up are likely to influence both. Enhanced adiposity seems of paramount relevance for the onset of HS in T1D patients alike in healthy youths.

Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy.

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.