Outcomes of hybrid closed-loop insulin delivery activated 24/7 versus evening and night in free-living prepubertal children with type 1 diabetes: A multicentre, randomized clinical trial.

AIM: To assess the safety and efficacy of hybrid closed-loop (HCL) insulin delivery 24/7 versus only evening and night (E/N), and on extended 24/7 use, in free-living children with type 1 diabetes. MATERIALS AND METHODS: Prepubertal children (n = 122; 49 females/73 males; age, 8.6 ± 1.6 years; diabetes duration, 5.2 ± 2.3 years; insulin pump use, 4.6 ± 2.5 years; HbA1c 7.7% ± 0.7%/61 ± 5 mmol/mol) from four centres were randomized for 24/7 versus E/N activation of the Tandem Control-IQ system for 18 weeks. Afterwards, all children used the activated system 24/7 for 18 more weeks. The primary outcome was the percentage of time spent in the 70-180 mg/dL glucose range (TIR). RESULTS: HCL was active 94.1% and 51.1% of the time in the 24/7 and E/N modes, respectively. TIR from baseline increased more in the 24/7 versus the E/N mode (52.9% ± 9.5% to 67.3% ± 5.6% [+14.4%, 95% CI 12.4%-16.7%] vs. 55.1% ± 10.8% to 64.7% ± 7.0% [+9.6%, 95% CI 7.4%-11.6%]; P = .001). Mean percentage time below range was similarly reduced, from 4.2% and 4.6% to 2.7%, and the mean percentage time above range decreased more in the 24/7 mode (41.9% to 30.0% [-11.9%, 95% CI 9.7%-14.6%] vs. 39.8% to 32.6% [-7.2%, 95% CI 5.0%-9.9%]; P = .007). TIR increased through the whole range of baseline levels and always more with 24/7 use. The results were maintained during the extension phase in those initially on 24/7 use and improved in those with initial E/N use up to those with 24/7 use. Neither ketoacidosis nor severe hypoglycaemia occurred. CONCLUSIONS: The current study shows the safety and efficacy of the Tandem Control-IQ system in free-living children with type 1 diabetes for both E/N and 24/7 use; 24/7 use shows better outcomes, sustained for up to 36 weeks with no safety issues.

Time trend in excess mortality in children with type 1 diabetes from 1987 to 2016 in mainland France.

BACKGROUND: Mortality risk for children with type 1 diabetes (T1D) is unknown in France and their causes of death are not well documented. AIM: To determine the standardized mortality ratios (SMRs) and causes of death in children aged 1-14 years with T1D from 1987 to 2016. METHODS: The French Center for Epidemiology on Medical Causes of Death collected all death certificates in mainland France. SMRs, corrected SMRs (accounting for missing cases of deaths unrelated to diabetes), and 95% confidence intervals were calculated. RESULTS: Of 146 deaths with the contribution of diabetes, 97 were due to T1D. Mean age at death of the subjects with T1D was 8.8 ± 4.1 years (54% males). The cause of death was diabetic ketoacidosis (DKA) in 58% of the cases (70% in subjects 1-4 years), hypoglycemia or dead-in-bed syndrome in 4%, related to diabetes but not described in 24%, and unrelated to diabetes in 14%. The SMRs showed a significant decrease across the years, except for the 1-4 age group. In the last decade (2007-2016), the crude and corrected SMRs were significantly different from 1 in the 1-4 age group (5.4 [2.3; 10.7] and 6.1 [2.8; 11.5]), no longer significant in the 5-9 age group (1.7 [0.6; 4.0] and 2.1 [0.8; 4.5]) and borderline significant in the 10-14 age group (1.7 [0.8; 3.2] and 2.3 [1.2; 4.0]). CONCLUSIONS: Children with T1D aged 1-4 years still had a high mortality rate. Their needs for early recognition and safe management of diabetes are not being met.

GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.

STUDY QUESTION: Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life? SUMMARY ANSWER: Both parameters lack the specificity to discriminate CDGP from CHH. WHAT IS KNOWN ALREADY: GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms. STUDY DESIGN, SIZE, DURATION: The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test. MAIN RESULTS AND THE ROLE OF CHANCE: Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold. LIMITATIONS, REASONS FOR CAUTION: As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. WIDER IMPLICATIONS OF THE FINDINGS: Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Effects of advanced carbohydrate counting on glucose control and quality of life in children with type 1 diabetes.

OBJECTIVE: The effect of advanced carbohydrate counting (ACC) on metabolic and quality of life (QOL) outcomes is uncertain in children with type 1 diabetes. Our aim was to determine whether ACC would improve HbA1c and QOL scores as compared with standard nutrition in this population. METHODS: We randomized 87 patients using pump and rapid-acting analogs in a 1 year randomized multicenter study (age 9.6 ± 3.5 years, diabetes duration 4.6 ± 2.7 years, HbA1c 7.8 ± 0.5% [62 ± 5 mmol/mol]). The ACC group received CC education and the control group received traditional dietary education. HbA1c was measured every 3 months. At 0 and 1 year, general, diabetes-specific, and diet-related QOL were respectively assessed by the KIDSCREEN and WHO-5 questionnaires, the diabetes-specific module of the DISABKIDS, and the diet restriction items of the DSQOLS. RESULTS: Mean HbA1c was lower in the ACC than the control group at 3 months (P < .05) and tended to be lower at 6 months (P = .10), 9 months (P = .10), but not at 12 months. The mean of individual average HbA1c during the one-year study period (from M3 to M12) was 7.63 ± 0.43 in the ACC vs 7.85 ± 0.47% in the control group (60 ± 5 vs 62 ± 5 mmol/mol)(P < .05). ACC was associated with significantly higher scores at 1 year on the KIDSCREEN children's psychological scale and the KIDSCREEN parents' physical scale, the DISABKIDS children's treatment scale, and the children's and parents' dietary restriction scales of the DSQOLS (indicating better QOL or lower perceived diet restriction). CONCLUSIONS: ACC may be associated with small improvements in metabolic control and QOL scores in children.

Closed-loop driven by control-to-range algorithm outperforms threshold-low-glucose-suspend insulin delivery on glucose control albeit not on nocturnal hypoglycaemia in prepubertal patients with type 1 diabetes in a supervised hotel setting.

This randomized control trial investigated glucose control with closed-loop (CL) versus threshold-low-glucose-suspend (TLGS) insulin pump delivery in pre-pubertal children with type 1 diabetes in supervised hotel conditions. The patients [n = 24, age range: 7-12, HbA1c: 7.5 ± 0.5% (58 ± 5 mmol/mol)] and their parents were admitted twice at a 3-week interval. CL control to range or TLGS set at 3.9 mmoL/L were assessed for 48 hour in randomized order. Admissions included three meals and one snack, and physical exercise. Meal boluses followed individual insulin/carb ratios. While overnight (22:00-08:00) per cent continuous glucose monitoring (CGM) time below 3.9 mmol/L (primary outcome) was similar, time in ranges 3.9 to 10.0 and 3.9 to 7.8 mmoL/L and mean CGM were all significantly improved with CL (P < 0.001). These results were confirmed over the whole 48 hour. Disconnections between devices and limited accuracy of glucose sensors in the hypoglycaemic range appeared as limiting factors for optimal control. CL mode was well accepted while fear of hypoglycaemia was unchanged. CL did not minimize nocturnal hypoglycaemia exposure but improved time in target range compared to TLGS. Although safe and well-accepted, CL systems would benefit from more integrated devices.

Insufficient Bone Mineralization to Sustain Mechanical Load of Weight in Obese Boys: A Cross-Sectional Study.

CONTEXT: The increase in bone mineral content (BMC) and density (BMD) measured by dual-energy x-ray absorptiometry (DXA) in obese children may not sustain the mechanical load associated with weight, and the factors influencing bone mineralization are not well known. OBJECTIVE: We described bone mineralization in boys with overweight/obesity and leanness in relation to body composition. METHODS: Cross-sectional study in the Pediatric Endocrinology Unit of Angers University Hospital with 249 overweight/obese boys aged 8-18 who underwent DXA and insulin, testosterone, and IGF-1 measurements. Bone mineralization was compared with data from 301 lean boys of similar age and height from NHANES 2011-2015, using the same DXA model. Path analyses were performed to evaluate factors associated with total body less head (TBLH) BMC. RESULTS: The mean age- and height-adjusted difference in TBLH BMC between obese and lean boys was 241 ± 20 g/cm2. Each 1 kg/m2 increase in BMI was associated with +39 ± 6 g of TBLH BMC in lean subjects vs + 25 ± 3 g in obese subjects (P < .05). Each 1 kg/m2 increase in lean BMI (LBMI) was associated with +78 ± 5 g of TBLH BMC in lean and obese boys, and each 1 kg/m2 increase in fat mass index (FMI) was associated with a decrease of 9 ± 3 g of TBLH BMC. The TBLH BMC was directly positively influenced by LBMI and indirectly and positively influenced by IGF-1, testosterone, and insulin (mediated through height and LBMI). FMI indirectly influenced TBLH BMC, both positively through LBMI and negatively through its negative impact on IGF-1 and testosterone. CONCLUSION: The increase in bone mineralization in obese children does not adapt to the increase in body mass.

Sustained 3-Year Improvement of Glucose Control With Hybrid Closed Loop in Children With Type 1 Diabetes While Going Through Puberty.

OBJECTIVE: To evaluate the impact of prolonged hybrid closed loop (HCL) use in children with type 1 diabetes (T1D) on glucose control and BMI throughout pubertal progression. RESEARCH DESIGN AND METHODS: We used a prospective multicenter extension study following the Free-Life Kid AP (FLKAP) HCL trial. The 9-month previously reported FLKAP trial included 119 prepubertal children (aged 6-12 years). During the extension study, participants could continue to use HCL for 30 months (M9 to M39). HbA1c values were collected every 3 months up to M39, while continuous glucose monitoring metrics, BMI Z scores, and Tanner stages were collected up to M24. Noninferiority tests were performed to assess parameter sustainability over time. RESULTS: One hundred seventeen children completed the extension study, with mean age 10.1 years (min-max 6.8-14.0) at the beginning. Improvement of HbA1c obtained in the FLKAP trial was significantly sustained during extension (median [interquartile range], M9: 7.0% [6.8-7.4], and M39: 7.0% [6.6-7.4], P < 0.0001 for noninferiority test) and did not differ between children who entered puberty at M24 (Tanner ≥ stage 2; 54% of the patients) and patients who remained prepubertal. BMI Z score also remained stable (M9: 0.41 [-0.29 to 1.13] and M24: 0.48 [-0.11 to 1.13], P < 0.0001, for noninferiority test). No severe hypoglycemia and one ketoacidosis episode not related to the HCL system occurred. CONCLUSIONS: Prolonged use of HCL can safely and effectively mitigate impairment of glucose control usually associated with pubertal progression without impact on BMI in children with T1D.

Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.

Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.

Hybrid Closed Loop Overcomes the Impact of Missed or Suboptimal Meal Boluses on Glucose Control in Children with Type 1 Diabetes Compared to Sensor-Augmented Pump Therapy.

Background: It is unclear whether hybrid closed-loop (HCL) therapy attenuates the metabolic impact of missed or suboptimal meal insulin bolus compared with sensor-augmented pump (SAP) therapy in children with type 1 diabetes in free-living conditions. Methods: This is an ancillary study from a multicenter randomized controlled trial that compared 24/7 HCL with evening and night (E/N) HCL for 36 weeks in children between 6 and 12 years old. In the present study, the 60 children from the E/N arm underwent a SAP phase, an E/N HCL for 18 weeks, then a 24/7 phase for 18 weeks, extended for 36 more weeks. The last 28-30 days of each of the four phases were analyzed according to meal bolus management (cumulated 6817 days). The primary endpoint was the percentage of time that the sensor glucose was in the target range (TIR, 70-180 mg/dL) according to the number of missed boluses per day. Findings: TIR was 54% ± 10% with SAP, 63% ± 7% with E/N HCL, and steadily 67% ± 7% with 24/7 HCL. From the SAP phase to 72 weeks of HCL, the percentage of days with at least one missed meal bolus increased from 12% to 22%. Estimated marginal (EM) mean TIR when no bolus was missed was 54% (95% confidence intervals [CI] 53-56) in SAP and it was 13% higher (95% CI 11-15) in the 24/7 HCL phase. EM mean TIR with 1 and ≥2 missed boluses/day was 49.5% (95% CI 46-52) and 45% (95% CI 39-51) in SAP, and it was 15% (95% CI 14-16) and 17% higher (95% CI 6-28), respectively, in the 24/7 HCL phase (P < 0.05 for all comparisons vs. SAP). Interpretation: HCL persistently improves glycemic control compared with SAP, even in case of meal bolus omission. ClinicalTrials.gov (NCT03739099).

The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Lower Circulating Sertoli and Leydig Cell Hormone Levels During Puberty in Obese Boys: A Cross-sectional Study.

CONTEXT: Alterations in semen characteristics and circulating Sertoli and Leydig cell hormones have been described in obese male adults. Whether hormonal alterations occur before adulthood has not been fully evaluated. OBJECTIVE: We describe circulating Sertoli and Leydig cell hormone levels in overweight-obese (ow/ob) boys through childhood and adolescence in a cross-sectional study. METHODS: Monocentric study in the Pediatric Endocrinology Unit of Angers University Hospital. Three hundred and fifty-one obese and overweight boys aged 5-19 years underwent physical examination, dual-energy X-ray absorptiometry for body composition, oral glucose tolerance test on insulin and glucose, and measurements of follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone (AMH), inhibin B, testosterone, and estradiol. Hormonal levels were compared with normative data obtained from 652 healthy nonoverweight nonobese boys of similar age or Tanner stage. RESULTS: Median inhibin B and testosterone levels during puberty were significantly lower in ow/ob than in healthy boys (1) from age >12 years and thereafter for inhibin B, and (2) from age >14 years and thereafter for testosterone. At Tanner stages 4 and 5, 26%, 31%, and 18% of inhibin B, testosterone, and AMH values were below the 5th percentile in ow/ob subjects (P < .01). In multiple regression analyses, estradiol and total bone mineral density Z-score were negative predictors of inhibin B, fat mass percentage was a negative predictor of testosterone, and insulin was a negative predictor of AMH. CONCLUSION: Lower Sertoli and Leydig cell hormone levels during puberty were observed in the ow/ob boys.

How to investigate a child with excessive growth?

The diagnostic approach to tall stature in children is based on collecting birth data (macrosomia), sizes and family puberty, a family history of constitutional or pathological tall stature, search for a delay of development, dysmorphia, disproportion, analysis of the growth velocity (normal or accelerated), general examination and assessment of puberty, and bone age. When there is a history of psychomotor retardation, a family history of pathological tall stature, or a disproportion in the clinical examination, the genetic causes of tall stature will be mentioned. The most frequent causes are Marfan syndrome and similar, Sotos syndrome, Beckwith-Wiedemann syndrome, Klinefelter syndrome, and MEN2B. There are many genetic syndromes with tall stature, justifying consultation with the geneticist. When the speed of growth is accelerated, first of all it evokes puberty and early pseudopuberty, obesity and acromegaly. Finally, when the growth velocity is regular, and the parents are of tall stature, it evokes constitutional tall stature: this is the most frequent diagnosis, to retain after having rejected pathological tall statures.

Bariatric surgery in adolescents with severe obesity: Review and state of the art in France.

Severe obesity (body mass index>120% of BMI IOTF-30 cut off) and morbid obesity (BMI>140% of BMI IOTF-30 cut off) affect 5 to 10% of obese adolescents in France. Organic complications can be found in about 50% of these patients, and depressive symptoms in one-third of them. Finally, over 70% will suffer from adult morbid obesity associated with a marked increase in morbidity and mortality. However, the reversion of obesity strongly decreases, and may even cancels, these risks. In controlled randomized studies, lifestyle interventions have limited effectiveness on BMI in children (and none in adolescents). Bariatric surgery has been shown to have short-term effectiveness in adolescents with severe and morbid obesity: the average BMI loss after gastric banding was 11.6kg/m2 (95% confidence interval from 9.8 to 13.4), 16.6kg/m2 (95% confidence interval from 13.4 to 19.8) after bypass, and 14.1kg/m2 (95% confidence interval 10.8 to 17.5) after sleeve gastrectomy. The resolution of comorbidities was the main aim, as well as the improvement of quality of life. This is not a simple surgical intervention, and minor side effects have been reported in approximately 10-15% of teenagers who underwent surgery (more common with the gastric band), and severe side effects in nearly 1-5% (mainly with bypass). In France, recommendations regarding indications, the care pathway, multidisciplinary meetings, reference management structures and postoperative care have been published by the French National Health Authority (HAS) in 2016 to provide a framework for bariatric surgery in underage patients.

Birth Weight Is Associated With the IGF-1 Response to GH in Children: Programming of the Anabolic Action of GH?

CONTEXT: Intrauterine programming of the somatotropic axis has been hypothesized in cases of intrauterine growth retardation. OBJECTIVE: The objective of the study was to study the effects of birth weight and body composition on GH sensitivity. DESIGN: This was a cross-sectional study with a single GH administration to assess GH sensitivity. SETTING: The study was conducted at the Department of Pediatric Endocrinology of an academic medical center. PATIENTS: One hundred normal short children aged from 4 to 17 years old (44 girls, 56 boys) separated into four groups: early childhood (aged 4-8 y, n = 14), late childhood (aged 9-12 y, pubertal stage 1, n = 30), early puberty (aged 10-15 y, stage 2, n = 32), and midpuberty (aged 12-17 y, stages 3 and 4, n = 24). INTERVENTION AND MAIN OUTCOME MEASURE: Serum IGF-1 at baseline and 24 hours after a single administration of GH (2 mg/m(2)) were measured. RESULTS: δIGF-1 significantly increased across the groups (P < .0001) with no gender difference, whereas the percentage of change in IGF-1 was similar (47% ± 32%). Independent predictors of δIGF-1 were birth weight SD score, fat percentage, fasting insulin (all positive predictors), and free fatty acids (negative predictor), with age, puberty, and baseline IGF-1 as adjusting variables (multiple R = 0.73, P < .0001). Independent predictors of the percentage of change in IGF-1 were birth weight SD score, fat percentage, and baseline IGF-1 (multiple R = 0.43, P < .001). CONCLUSION: This study suggests that in cases of low birth weight, intrauterine programming of GH sensitivity may be an adaptation to an expected poor postnatal nutritional environment, serving to restrict the anabolic action of GH. Conversely, postnatal excess energy stores may promote the anabolic action of GH.