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Objectif: Dans notre hôpital plus de 60 % de nos enfants/adolescents diabétiques de type 1 bénéficient d’un traitement avec une pompe à insuline. Dès le diagnostic ils reçoivent un enseignement pour pratiquer l’insulinothérapie fonctionnelle. Les nouvelles applications des pompes à insuline permettent aux patients d’utiliser la fonction de calcul du bolus d’insuline appelé Assistant Bolus. Objectifs : Développer un programme d’éducation pour l’enseignement de l’utilisation de l’assistant bolus. S’assurer que les porteurs des pompes à insuline et leurs parents puissent acquérir les compétences nécessaires qui leur permettront d’utiliser l’assistant bolus correctement. S’assurer qu’ils le programment et l’utilisent en accord avec l’ajustement du traitement Patients et méthodes: Une revue et une analyse de la littérature sur l’utilisation de l’assistant bolus a été faite. Cette revue nous a donné les bases du programme. Les patients et leurs parents ont été convoqués à une réunion d’information. Critères d’inclusion : diagnostic du diabète depuis plus de 6 mois. Liberté de choisir de participer ou non au programme Résultats: Le programme a une durée totale de 6 heures. Il est composé de 4 séances principales : Évaluation et adaptation de connaissances théoriques et pratiques de l’insulino thérapie fonctionnelle. Introduction de l’utilisation de l’assistant bolus. Exercices pratiques. Évaluation des compétences acquises. À la fin du programme les patients et leurs parents devraient être capables de : Manipuler la programmation de l’assistant bolus. Comprendre et contrôler la proposition de bolus faite par la pompe. Ajuster la proposition selon l’activité physique et la maladie. Refuser un bolus proposé s’ils ont un doute Conclusion: Le programme d’enseignement pour l’utilisation de l’assistant bolus a été développé et mis en application pour 20 patients et leurs parents. La prochaine étape du programme sera d’évaluer l’impact de son utilisation sur le contrôle métabolique ainsi que le degré de satisfaction des utilisateurs de l’asistant bolus [Copyright &y& Elsevier]

Background: Complications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence., Methods: Data from boys with hypospadias born between 2000 and 2020 were obtained from the International Disorders of Sex Development (I-DSD) Registry. Logistic regressions, fisher's exact tests and spearman's correlation tests were performed on the data to assess associations between clinical factors and complication rates., Results: Of the 551 eligible boys, data were available on 160 (29%). Within the cohort, the median (range) External Masculinization Score (EMS) was 6 (2, 9). All presented with one or more additional genital malformation and 61 (38%) presented with additional extragenital malformations. Disorders of androgen action, androgen synthesis and gonadal development were diagnosed in 28 (18%), 22 (14%) and 9 (6%) boys, respectively. The remaining 101 (62%) patients were diagnosed as having non-specific 46,XY Disorders of Sex Development. Eighty (50%) boys had evidence of abnormal biochemistry, and gene variants were identified in 42 (26%). Median age at first hypospadias surgery was 2 years (0, 9), and median length of follow-up was 5 years (0, 17). Postsurgical complications were noted in 102 (64%) boys. There were no significant associations with postsurgical complications., Conclusions: Boys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diabetes mellitus in children is subdivided into several categories depending on the underlying pathological mechanism. Type 1 diabetes is due to the autoimmune destruction of pancreatic beta-cells, type 2 diabetes to progressive impairment in insulin secretion or insulin sensitivity, and monogenic diabetes due to genetic abnormalities, impairing insulin secretion. In monogenic diabetes, genetic defects result in pancreatic or beta-cell defects (abnormal function or destruction), resulting in neonatal or MODY (Maturity-Onset Diabetes of the Young) diabetes, depending on the age of onset. The identification of monogenic diabetes is crucial as it allows the initiation of targeted and personalized treatment., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

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., (© 2022. The Author(s).)

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., (© 2020 by the American Diabetes Association.)

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., (Copyright© of YS Medical Media ltd.)

Background: Prevention of type 1 diabetes mellitus (T1DM)-related complications is dependent on metabolic control. The recommended glycated hemoglobin (HbA1c) values <7.5% (58.5 mmol/mol) are met only by a minority of diabetic children and especially adolescents. The aim of this study was to evaluate the impact of an intervention comprising the use of Webdia, a patient-designed app for smartphones, on metabolic control of T1DM in children., Methods: Fifty-five patients with T1DM, 10-18 years of age, were included in this single-center, randomized double-crossover study. We tested an intervention consisting of using Webdia for 3 months with monthly feedback and adaptation of the treatment. Main outcome was modification of HbA1c. Secondary outcomes were the prevalence of hypoglycemia and quality of life (QoL)., Results: Of the 55 included patients, 33 completed the study, 9 dropped out, and 13 were excluded due to insufficient use of the app. The app was well accepted by the users who completed the study (46.4% rated the program as good and 39.3% as excellent). The intervention led to a reduction of HbA1c by 0.33%, compared to the control group in which HbA1c rose by 0.21% (P = 0.048) in patients with HbA1c values >8.0% (63.9 mmol/mol) at inclusion, without increasing the prevalence of hypoglycemia (8.52 ± 9.45 hypoglycemic events during last 2 weeks of intervention vs. 7.62 ± 6.37 observation, P = 0.680). QoL scores were not modified., Conclusions: The intervention resulted in a significant decrease in HbA1c, without increasing the prevalence of hypoglycemia in patients with initial HbA1c >8.0% (63.9 mmol/mol).

Background: The study aimed to assess accuracy, satisfaction and usability of a flash glucose monitoring system (FGM) in children and adolescents with type 1 diabetes mellitus (T1DM) attending a diabetes summer camp., Methods: Sixty-six children and adolescents with T1DM aged 6 to 17 years participating in a 7-day medically supervised summer camp were enrolled. Capillary blood glucose (BG) and flash glucose (FG) values were measured simultaneously at breakfast, lunch, and dinner and for any given FG value <72 mg/dL (<4.0 mmol/L) during daytime, <108 mg/dL (<6.0 mmol/L) at nighttime, >270 mg/dL (>15.0 mmol/L) or when patient symptoms were discordant with sensor readings. Sensor-related issues were documented and patients' and healthcare professionals' (HCPs) satisfaction was evaluated., Results: FGM demonstrated satisfactory clinical accuracy compared to reference capillary BG values with 98.8% of values falling within the clinically acceptable zones (A and B) of the consensus error grid. Overall mean absolute relative difference (MARD) was 16.7% ± 16.1%. Specific calculations of mean absolute difference (MAD), mean relative difference (MRD), and mean difference (MD) demonstrated that FGM overestimated BG values across all glycemic ranges. Overall satisfaction with the FGM was high in 91.7% participants and 95.0% HCPs, although confidence in the system was low in 18.0% participants and 40.0% HCPs., Conclusions: The FGM exhibited satisfactory clinical accuracy. However, based on the present data, we conclude that no decision should be taken on the basis of a single, non-verified, FGM value alone. Our study highlights the need for revised therapeutic education for patients/families and further investigation on the integration of sensor readings in clinical decision-making., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cystic fibrosis-related diabetes (CFRD) is the most frequent extrapulmonary complication of cystic fibrosis (CF)., Methods: We report the first combined pancreatic islet-lung-liver transplantation in a 14-year-old adolescent. CFTR was analyzed by Sanger sequencing. Further genes were analyzed by high-throughput sequencing., Results: The patient was diagnosed with CF at the age of 14 months. Nine years later, after diagnosis of CFRD, the patient's BMI and lung function began to decline. Bilateral lung transplantation with simultaneous liver transplantation was performed at the age of 14.5 years. The first islet transplantation (IT) was carried out 10 days later. Six months later, C-peptide secretion after arginine stimulation showed peak values of 371 pmol/L (vs. 569 pmol/L before IT) and insulin doses had slightly increased (1.40 vs. 1.11 units/kg/day before IT). A second IT was performed at the age of 15 years, a third at 16 years. Two years after the first IT, arginine-stimulated C-peptide secretion increased to 2,956 pmol/L and insulin doses could be reduced to 0.82 units/kg/day. HbA1c decreased from 7.3% (57.4 mmol/mol) to 5.9% (41.0 mmol/mol)., Conclusion: IT following lung and liver transplantation, with injection of islets into a transplanted organ, is feasible. It improves C-peptide secretion, decreases insulin needs, and lowers HbA1c., (© 2018 S. Karger AG, Basel.)

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 ( FGFR1 ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

For patients with type I diabetes, transition from pediatric to adult care is a challenge due to complex treatment requirements and the physical, psychological and social changes of adolescence. Members of the care team must recognize that while these emerging adults need to develop self-management skills, this may conflict at times with the developmentally appropriate desire for increasing autonomy. The role of nursing in coordinating a successful transition is critical for maintaining continuity of patient-centered care that responds to the specific needs of these young adults.

Background: SRY, located on the Y chromosome, is one of the key genes involved in human sex determination. SRY mutations are responsible for 10-15% of all cases of 46,XY gonadal dysgenesis (GD) but are rarely implicated in the pathogenesis of mixed GD., Methods: SRY was analyzed by sequence analysis of DNA extracted from blood leukocytes. SRY activity was evaluated by SOX9 immunostaining, one of the targets of SRY., Results: We report a case of mixed GD due to a novel SRY point mutation in a patient with a 46,XY karyotype, without mosaicism or submicroscopic genomic imbalances. Hormonal studies showed low anti-müllerian hormone and histological examination of the gonads showed a streak gonad on the right side and a left dysgenetic testis, thus permitting the diagnosis of mixed GD. Immunostaining for SOX9, a target of SRY, was positive in nuclei of Sertoli and epididymal cells in the left gonad and negative on the right, thus indicating asymmetric activation of SRY., Conclusion: Mixed GD can result from SRY mutations without mosaicism, neither in peripheral blood, nor within the gonads. The asymmetric effect of the point mutation implies the presence of local factors modulating SRY expression or action., (Copyright © 2012 S. Karger AG, Basel.)

Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disorder of mineralocorticoid resistance characterized by salt wasting, hyperkalemia, high aldosterone levels, and failure to thrive. An autosomal recessive form (AR-PHA1) is caused by mutations in the epithelial sodium channel ENaC with usually severe and persisting multiorgan symptoms. The autosomal dominant form of PHA1 (AD-PHA1) is due to mutations in the mineralocorticoid receptor causing milder and transient symptoms restricted to the kidney. We identified a homozygous missense mutation in the SCNN1A gene (c.727T>C/p.Ser(243)Pro), encoding α-subunit of ENaC (α-ENaC) in a prematurely born boy with a severe salt-losing syndrome. The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo. Interestingly, the patient's sibling born at term and harboring the same homozygous Ser(243)Pro mutation showed no symptom of salt-losing nephropathy. In vitro expression of the αSer(243)Pro ENaC mutant revealed a slight but significant decrease in ENaC activity that is exacerbated in the presence of high Na(+) load. Our study provides the first evidence that ENaC activity is critical for the maintenance of salt balance in the immature kidney of preterm babies. Together with previous studies, it shows that, when the kidney is fully mature, the severity of the symptoms of AR-PHA1 is related to the degree of the ENaC loss of function. Finally, this study identifies a novel functional domain in the extracellular loop of ENaC.

Diabetes type I (DTI) is an autoimmune disease characterized by a progressive destruction of the insulin producing beta cells of the pancreas that requires insulin substitution therapy. Recent epidemiological data show an annual increase of the incidence of DTI of 3.9%. Children with new onset diabetes typically present with polyuria, polydipsia and weight loss. As of today no cure for DTI exists. However new therapeutic immunomodulary approaches are under investigation. In the meantime adherence to insulin therapy is mandatory to achieve near physiological glucose levels. Monogenic forms of diabetes remain rare in children, but their diagnosis is important in order to propose a specific treatment. A critical period for the diabetic patient is the transition from pediatric to adult care.

The incidence of diabetes type I has increased considerably in young children with an annual increase in Switzerland of 23,8% over the last ten years. The development of rapid acting and long acting analogues allowed a significant progress in treatment. Multiple daily insulin injections together with carbohydrate counting as well as continuous subcutaneous insulin infusion (CSII) improved the quality of life and led to an increased daily flexibility. The incidence of severe hypoglycaemic events has decreased at the same time metabolic control improved. The development of interstitial glucose measurement (online) coupled to the insulin pump represents a step further towards the artificial pancreas. The new therapeutic strategies of immunomodulation will hopefully lead to secondary and tertiary prevention of diabetes.

The diagnosis of GH deficiency is difficult to establish: clinical, radiological and hormonal data are combined to suspect the disease. GH stimulation tests are an essential part of the evaluation, although the cut-off values are determined arbitrarily. There are different stimulation tests. Their use depends on the patient's age. Once the diagnosis is ascertained, the treatment is started and maintened until the end of statural growth. The persistence of GH deficiency needs to be confirmed during the transition phase. If required, GH treatment can be continued until the achievement of peak bone mass. Thereafter the benefit of continuing GH treatment are mainly related to the quality of life. The long term effects on cardiovascular morbidity/mortality are not demonstrated.

Objective: Obese non-diabetic patients are characterized by an extra-hepatic insulin resistance. Whether obese patients also have decreased hepatic insulin sensitivity remains controversial., Research Methods and Procedures: To estimate their hepatic insulin sensitivity, we measured the rate of exogenous insulin infusion required to maintain mildly elevated glycemia in obese patients with type 2 diabetes, obese non-diabetic patients, and lean control subjects during constant infusions of somatostatin and physiological low-glucagon replacement infusions. To account for differences in insulin concentrations among the three groups of subjects, an additional protocol was also performed in healthy lean subjects with higher insulin infusion rates and exogenous dextrose infusion., Results: The insulin infusion rate required to maintain glycemia at 8.5 mM was increased 4-fold in obese patients with type 2 diabetes and 1.5-fold in obese non-diabetic patients. The net endogenous glucose production (measured with 6,6-(2)H(2)-glucose) and total glucose output (measured with 2-(2)H(1)-glucose) were approximately 30% lower in the patients than in the lean subjects. Net endogenous glucose production and total glucose output were both markedly increased in both groups of obese patients compared with lean control subjects during hyperinsulinemia., Discussion: Our data indicate that both obese non-diabetic and obese type 2 diabetic patients have a blunted suppressive action of insulin on glucose production, indicating hepatic and renal insulin resistance.

Objective: To assess the short-term consequences of carbohydrate or fat overfeeding or of food restriction on the metabolic effects of mental stress in healthy lean women., Research Methods and Procedures: The effects of a sympathetic activation elicited by mental stress were evaluated in a group of healthy women after standardized isocaloric feeding (ISO) or after a 3-day overfeeding with 40% excess calories as either carbohydrate overfeeding (CHO OF) or fat overfeeding (FAT OF). Oxygen consumption rate (VO(2)) was measured as an index of energy expenditure, and subcutaneous glycerol concentrations were monitored with microdialysis. The same measurements were performed in another group of healthy women after ISO and after a 3-day period of underfeeding with a protein sparing modified fast (UF)., Results: In all conditions, mental stress significantly increased heart rate, blood pressure, plasma norepinephrine and epinephrine concentrations, and VO(2), and produced a nonsignificant increase in subcutaneous glycerol concentrations. CHO OF and FAT OF did not alter the effects of mental stress on VO(2) and subcutaneous glycerol concentrations. In contrast, UF increased basal VO(2) but significantly reduced its stimulation by mental stress. UF also enhanced the increase in subcutaneous glycerol concentrations during mental stress., Discussion: UF reduces the stimulation of energy expenditure and enhances lipolysis during sympathetic activation. These adaptations may be involved in mobilization of endogenous fat while limiting weight loss. In contrast, short-term overfeeding fails to alter the sympathetic control of energy expenditure and lipolysis.

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 micromol. kg(-1). min(-1) fructose. Glucose rate of disappearance (GR(d)), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-(2)H(2)]- and [2-(2)H(1)]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-(13)C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GR(d) under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 micromol. kg(-1). min(-1) increase in TGO, a 7.8 micromol. kg(-1). min(-1) increase in NEGP, a 2.2 micromol. kg(-1). min(-1) increase in GC, and a 7.2 micromol. kg(-1). min(-1) decrease in GR(d) (P < 0. 05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.