Type 1 diabetes (T1D) is the most common metabolic disorder in children. It progresses through three distinct stages, which are now utilized for preclinical diagnosis. Advances in genetics and screening techniques are enhancing the prediction, prevention, and treatment of the disease. The identification of different T1D subtypes has deepened our understanding of the disease's underlying mechanisms, reflecting genetic, clinical, and immunological diversity. Key genetic variations, including high-risk HLA haplotypes such as DR3 and DR4-DQ8, alongside non-HLA variants. Many of these genetic risk regions are also linked to other autoimmune diseases. Early diagnosis enables secondary prevention strategies, notably with teplizumab, the first approved drug for delaying T1D onset, already in use for stage 2 patients in the USA.

Type 1 diabetes (T1D) affects approximately 1.2 million children and adolescents worldwide. Despite advances in therapy, insulin remains the primary treatment, requiring tight glycemic control to prevent long-term complications. Automated insulin delivery (AID) systems, combining continuous glucose monitoring and insulin pumps with algorithms, have opened a new paradigm in T1D management. This review aims to synthesize data on psychosocial outcomes and quality of life (QoL) from randomized controlled trials (RCTs) comparing AID systems to standard diabetes care in children and adolescents. A systematic search following PRISMA guidelines was conducted across Medline, Embase, PubMed, and Cochrane databases. RCTs evaluating QoL of children with T1D using AID systems were included. Data extracted included participant demographics, AID system types, main outcomes, QoL scales, and results. Studies had to involve children and/or adolescents with T1D using AID systems and/or their caregivers and assess QoL or psychosocial outcomes using validated scales. The search identified 3373 studies, with 14 meeting inclusion criteria, encompassing 1251 participants, mostly children, adolescents and young adults. Studies used various AID systems, including Control-IQ, CamAPS FX, Diabeloop DBL4K, Medtronic MiniMed ® 670G and Advanced Hybrid Closed-Loop, and compared them to standard care. They showed variable improvements in treatment satisfaction and expectations, sleep quality, and QoL, along with a reduction in fear of hypoglycemia when using AID systems. However, the effect on emotional burden and diabetes distress was inconsistent. RCTs indicate that AID systems enhance treatment satisfaction, sleep quality, and hypoglycemia confidence in children with T1D, contributing to better diabetes-specific QoL. Although their impact on emotional burden and diabetes distress outcomes is inconsistent, AID systems generally offer significant benefits over traditional insulin delivery methods, underscoring their importance in pediatric T1D management.

Type 1 diabetes (T1D) is the most common metabolic disorder in children. It progresses through three distinct stages, which are now utilized for preclinical diagnosis. Advances in genetics and screening techniques are enhancing the prediction, prevention, and treatment of the disease. The identification of different T1D subtypes has deepened our understanding of the disease's underlying mechanisms, reflecting genetic, clinical, and immunological diversity. Key genetic variations, including high-risk HLA haplotypes such as DR3 and DR4-DQ8, alongside non-HLA variants. Many of these genetic risk regions are also linked to other autoimmune diseases. Early diagnosis enables secondary prevention strategies, notably with teplizumab, the first approved drug for delaying T1D onset, already in use for stage 2 patients in the USA.

Extremely preterm infants are prone to hyperglycemia which is associated with increased mortality and morbidity. Insulin sensitivity is variable in extreme prematurity, and its monitoring, prevention, and treatment are a significant challenge in the NICU. Frequent changes in fluid composition and volumes, as well as large growth and adaptational nutrient requirements are limited by difficult vascular access and blood sampling and risk of drug incompatibilities. Insulin treatment requires specific access and significantly increases fluid intake and sampling. Clinicians, therefore, often compromise by reducing glucose intake and accepting higher glycemia. We report a case series of 11 extremely low birth weight (ELBW) preterms, born between 23 5/7 and 27 6/7 weeks of gestation, treated for transient hyperglycemia during the first 2 weeks of life by continuous subcutaneous insulin infusion (CSII). Insulin concentration was 10 IU/ml, administered via 13 mm Accu-Chek® Tenderlink catheters and a commercial insulin pump (Accu-Chek® Combo, Roche Diabetes Care). Insulin treatment was initiated when glycemia was > 252 mg/dL (14 mmol/l) in two consecutive blood glucose determinations, except for one case when glycemia was 234 mg/dL (13 mmol/l), despite a previous decrease in glucose infusion rate. The starting dose for the CSII was between 0.01 and 0.08 IU/kg/h. The average duration of the CSII was 5 days (1–16 days). CSII in extreme preterm neonates with hyperglycemia was clinically feasible and practical by sparing IV lines and volume and appeared as more rapidly effective than continuous IV administration. No adverse events like hypoglycemia or skin infection were recorded.

L’insuline en tant que traitement du diabète de type 1 est toujours utilisée comme seul traitement médicamenteux, 100 ans après son introduction. Les dernières avancées ont contribué à optimiser considérablement le contrôle du métabolisme.

Insulin als Therapie für Typ-1-Diabetes wird 100 Jahre nach Ersteinführung immer noch als einzige medikamentöse Behandlung eingesetzt. Die jüngsten Fortschritte haben zu einer erheblichen Optimierung der Stoffwechselkontrolle beigetragen.

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.

Background Transcriptional regulation of the SHOX gene is highly complex. Much of our understanding has come from the study of copy number changes of conserved non-coding sequences both upstream and downstream of the gene. Downstream deletions have been frequently reported in patients with Leri–Weill dyschondrosteosis or idiopathic short stature. In contrast, there are only four cases in the literature of upstream deletions that remove regulatory elements. Although duplications flanking the SHOX gene have also been reported, their pathogenicity is more difficult to establish. To further evaluate the role of flanking copy number variants in SHOX -related disorders, we describe nine additional patients from a large SHOX diagnostic cohort. Results The nine cases presented here include five with duplications (two upstream of SHOX and three downstream), one with a downstream triplication and three with upstream deletions. Two of the deletions remove a single conserved non-coding element (CNE-3) while the third does not remove any known regulatory element but is just 4 kb upstream of SHOX , and the deleted region may be important in limb bud development. We also describe six families with novel sequence gains flanking SHOX . Three families had increased dosage of a proposed regulatory element approximately 380 kb downstream of SHOX (X:970,000), including one family with the first ever reported triplication of this region. One family had two in cis downstream duplications co-segregating with LWD, and the two others had a duplication of just the upstream SHOX regulatory element CNE-5. Conclusions This study further extends our knowledge of the range of variants that may potentially cause SHOX -related phenotypes and may aid in determining the clinical significance of similar variants.

Identifying gene variants causing monogenic diabetes (MD) increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of MD in youth with diabetes in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young-adult patients with diabetes in Lithuania (n = 1,209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients (n = 153) using targeted high-throughput sequencing of >300 potential candidate genes. In this group, 40.7% had MD, with the highest percentage (100%) in infants (diagnosis at ages 0–12 months), followed by those diagnosed at ages >1–18 years (40.3%) and >18–25 years (22.2%). The overall prevalence of MD in youth with diabetes in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with MD. Prospective treatment change was successful in >50% of eligible candidates, with C-peptide >252 pmol/L emerging as the best prognostic factor.

Abstract Background Mutations in the melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity. Treatment options are limited but glucagon-like peptide-1 receptor agonists (GLP-1 RA) may be of use to induce weight loss. Methods Exome of the patient was captured using the Agilent SureSelect QXT Human All Exon V5 kit and sequenced on Illumina. Clinical findings and results We report obesity-associated diabetes and cirrhosis in a 13-year girl born from consanguineous parents of Afghan origin. Past medical history revealed mild mental retardation and excessive weight gain since infancy. Linear growth was normal. Her father was obese and no diabetes was found in the family. The girl was initially investigated for hoarseness and found to have pulmonary hypertension, later accepted to be secondary to cirrhosis and portal hypertension. Physical examination revealed obesity (BMI 34.9kg/m2) and acanthosis nigricans. Blood exams showed leucopenia and thrombocytopenia without anemia, compatible with portal hypertension. Chest CT revealed important dilatation of the pulmonary arteries, a nodular liver and splenomegaly. Liver biopsy confirmed cirrhosis. An extensive workup including whole exome sequencing identified a homozygous MC4R variant [NM_005912.2 (MC4R): c.63_64del, p.(Tyr21*)], classified as pathogenic according to the ACMG guidelines. Both parents were heterozygous for this variant. An endocrinological workup showed insulin resistance with a HOMA-IR index of 7.27 and diabetes with peak blood glucose of 11.5mmol/l. HbA1c was 5.1% (32mmol/mol). Thyroid tests, leptin, proinsulin levels (3.5pmol/l, n <11.0pmol/l) were normal. The mutation being homozygous with a predicted complete loss of function (https://www.mc4r.org.uk/), no treatment with a MC4R agonist was tried. At the age of 15 years (BMI 36.0kg/m2), the patient underwent liver transplantation because of progressive portal hypertension and to halt the progression of pulmonary hypertension. At the age of 16 years (BMI 33.2kg/m2, HbA1c 4.9% (30.0 mmol/mol), HOMA-IR 5.3) a treatment with GLP-1 RA (liraglutide) was started at a dosage of 0.6mg and progressively increased to 3mg, in an attempt to induce weight loss, avoid the accumulation of liver fat and to protect the graft. GLP-1 RA is supposed to exerts its effects on appetite independently of the MC4R pathway. 2 months after liraglutide introduction, no side effects, a weight loss of 4kg and a decrease of appetite were observed (BMI 31.6kg/m2, HbA1c 4.5% (26mmol/mol), HOMA-IR 3.14). Conclusion Obesity-associated MCR4 mutations, in homozygous state, may lead to diabetes, liver cirrhosis and porto-pulmonary hypertension. Treatment options are scarce, but GLP-1 RA seem to have a rapid, positive effect on weight and metabolic control. Would earlier treatment have prevented progression to end-stage-liver disease and need for liver transplantation?

Globally it is estimated that over 1 million children and adolescents have Type 1 diabetes with large variations in incidence between different contexts. Health systems need to provide a variety of elements to ensure appropriate diabetes care, such as service delivery; healthcare workforce; information; medical products and technologies; financing and leadership and governance. Describing these elements between Geneva, Switzerland, a high-income country with high spending on healthcare and a large density of doctors, and low- and middle-income countries this article aims to highlight the global inequality of diabetes care. Type 1 diabetes can serve as a litmus as we move towards the centenary of the discovery of insulin and beyond as there is a need for a global movement to ensure that innovation in the management of diabetes benefits the whole diabetes community and not just a select few.

Objective: Lactate is often used as a surrogate marker of inappropriate oxygen delivery. It has been shown that hyperlactatemia is associated with worse clinical outcome in children after cardiac surgery. The purpose of this study is to evaluate the association of hyperlactatemia, low systemic oxygen delivery, and hyperglycemia, in children admitted to the pediatric critical care unit after cardiopulmonary bypass. Design: Secondary analysis of an observational cohort study. Setting: Tertiary pediatric critical care unit (PICU). Patients: Ninety-three patients, aged 6 months to 16 years, undergoing cardiac surgery with cardiopulmonary bypass. Interventions: None. Measurements and Main Results: Metabolic tests (blood glucose, lactate, lactate/pyruvate ratio, and ketones) and oxygen extraction (SaO2-SvO2) were performed before anesthesia, at the end of cardiopulmonary bypass, at PICU admission, and at 4 and 12 h after PICU admission. Four hours after PICU admission, 62% of the patients had hyperlactatemia (>2 mmol/L), of whom 55% had normal oxygen extraction (SaO2-SvO2 < 30%). There was no correlation between lactate and oxygen extraction (R = -0.09, p = 0.41) but there was a moderate correlation between lactate and blood glucose (R = 0.55, p < 0.001). Using a logistic regression model, hyperlactatemia at 4 h after PICU admission was independently associated with hyperglycemia (p = 0.007) and lactate/pyruvate ratio (p = 0.007) at the same timepoint, as well as with lactate at PICU admission (p = 0.002), but not with weight (p = 0.45), severity of the cardiac lesion (p = 0.85), duration of bypass (p = 0.16), or oxygen extraction, as evaluated by SaO2-SvO2 (p = 0.54). At 12 h after PICU admission, there was a very week correlation between lactate and blood glucose (R = 0.27, p = 0.007), but none between lactate and oxygen extraction (R = 0.13, p = 0.20). Conclusion: In children after cardiopulmonary bypass, lactates are not correlated with higher oxygen extraction, but are correlated with hyperglycemia, at both 4 and 12 h after PICU admission. Future research is warranted to better define this relationship.

a Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland; b Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland; c Cell Isolation and Transplantation Center, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland; d Division of Pediatric Gastroenterology, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland; e Pediatric Pneumology Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland; f Service of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland; g Division of Pediatric Surgery, University Centre of Pediatric Surgery of Western Switzerland, University Hospitals of Geneva, Geneva, Switzerland; h Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, University of Basel Children’s Hospital, Basel, Switzerland; i Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland; j Division of Transplantation, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland Received: November 22, 2017 Accepted: February 28, 2018 Published online: April 18, 2018 HORMONE RESEARCH IN PÆDIATRICS