Publications by authors named "Jacques Beltrand"

51 Publications

Text message reminders for adolescents with poorly controlled type 1 diabetes: A randomized controlled trial.

PLoS One 2021 15;16(3):e0248549. Epub 2021 Mar 15.

Pediatric Endocrinology, Gynecology, and Diabetology Department, Assistance Publique-Hôpitaux de Paris, Necker University Hospital, Paris, France.

Background: Among adolescents with type 1 diabetes, some experience great difficulties with treatment adherence, putting them at high risk of complications. We assessed the effect of text messaging (Short Messaging Service [SMS]) on glycemic control.

Methods: A two-arm open label randomized controlled trial enrolled adolescents with type 1 diabetes aged 12-21 years with baseline HbA1c ≥ 69 mmol/mol (8.5%). The intervention group received daily SMS reminders at self-selected times about insulin injections while the control group received standard of care. The patients allocated to the control group were not aware of the intervention.

Results: 92 patients were randomized, 45 in the SMS arm and 47 in the control arm. After 6 months, median HbA1c level was significantly lower in the intervention arm: 73 mmol/mol (8.8%) in the SMS arm and 83 mmol/mol (9.7%) in the control arm in the intent-to-treat analysis (P = 0.03) but no longer in the per protocol analysis (P = 0.65). When we consider the proportions of patients whose HbA1c level decreased by at least 1% between baseline and 6 months, we find a significant difference among patients whose baseline HbA1c was ≥ 80 mmol/mol (9.5%) (n = 56): 60% in the SMS arm and 30.6% in the control arm had lowered their HbA1c level (P = 0.03) in the intent-to-treat analysis but not in the per-protocol analysis (P = 0.50). Patients in the SMS arm reported high satisfaction with the intervention.

Conclusions: While there is a trend to lower HbA1c in the intervention group, no firm conclusions can yet be drawn. Further studies are needed to address methodological issues as we believe these interventions can support behavior change among adolescents with poorly controlled type 1 diabetes. ClinicalTrials.gov identifier: NCT02230137.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248549PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959392PMC
March 2021

Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated Permanent Neonatal Diabetes.

Diabetes Care 2021 Jan 12;44(1):35-42. Epub 2020 Nov 12.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.

Objective: mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with PNDM require lower sulfonylurea doses and have milder neurological features than those with PNDM. However, these studies were short-term and included combinations of -PNDM and -TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated -PNDM.

Research Design And Methods: We studied all 24 individuals with PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.

Results: Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1-13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA 7.2% vs. 5.7%, = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA 5.7% vs. 6.5%, = 0.04), = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).

Conclusions: Sulfonylurea treatment of -PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.
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http://dx.doi.org/10.2337/dc20-1520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783935PMC
January 2021

Neonatal Diabetes Mellitus.

Front Pediatr 2020 30;8:540718. Epub 2020 Sep 30.

Paediatric Endocrinology, Gynaecology and Diabetology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute, ENDO-European Reference Network Team, Paris, France.

Neonatal Diabetes (ND) mellitus is a rare genetic disease (1 in 90,000 live births). It is defined by the presence of severe hyperglycaemia associated with insufficient or no circulating insulin, occurring mainly before 6 months of age and rarely between 6 months and 1 year. Such hyperglycaemia requires either transient treatment with insulin in about half of cases, or permanent insulin treatment. The disease is explained by two major groups of mechanism: malformation of the pancreas with altered insulin-secreting cells development/survival or abnormal function of the existing pancreatic β cell. The most frequent genetic causes of neonatal diabetes mellitus with abnormal β cell function are abnormalities of the 6q24 locus and mutations of the or genes coding for the potassium channel in the pancreatic β cell. Other genes are associated with pancreas malformation or insufficient β cells development or destruction of β cells. Clinically, compared to patients with an or mutation, patients with a 6q24 abnormality have lower birth weight and height, are younger at diagnosis and remission, and have a higher malformation frequency. Patients with an or mutation have neurological and neuropsychological disorders in all those tested carefully. Up to 86% of patients who go into remission have recurrent diabetes when they reach puberty, with no difference due to the genetic origin. All these results reinforce the importance of prolonged follow-up by a multidisciplinary pediatric team, and later doctors specializing in adult medicine. 90% of the patients with an or mutation as well as those with 6q24 anomalies are amenable to a successful switch from insulin injection to oral sulfonylureas.
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http://dx.doi.org/10.3389/fped.2020.540718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554616PMC
September 2020

The antidiabetic drug glibenclamide exerts direct retinal neuroprotection.

Transl Res 2021 Mar 17;229:83-99. Epub 2020 Oct 17.

Université de Paris, Faculté de Santé, Paris, France; Inserm UMRS 1138, Team 17: Physiopathology of Ocular Diseases-Therapeutic Innovations, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Université, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; AP-HP, OphtalmoPôle, Hôpital Cochin, Paris, France. Electronic address:

Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.
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http://dx.doi.org/10.1016/j.trsl.2020.10.003DOI Listing
March 2021

PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review.

Eur J Med Genet 2020 Nov 8;63(11):104033. Epub 2020 Aug 8.

Centre de Référence des Surdités Génétiques, Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP.Centre, Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, AP-HP.Centre, Paris, France; Laboratoire d'Embryologie et de Génétique des Malformations Congénitales, INSERM UMR 1163, Institut Imagine, Université Paris Descartes, Paris, France. Electronic address:

We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this rare condition, both in females and in males. Moreover, our observation of a new family in which hemizygous males display hearing loss without any neurological or ophthalmological symptoms prompts us to suggest analysing PRPS1 in cases of isolated hearing loss. Eventually, PRPS1 variants should be considered as a differential diagnosis of mitochondrial disorders.
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http://dx.doi.org/10.1016/j.ejmg.2020.104033DOI Listing
November 2020

Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study.

Diabetologia 2020 09 1;63(9):1808-1821. Epub 2020 Jul 1.

Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France.

Aims/hypothesis: Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes.

Methods: Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4 T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders.

Results: There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m day doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4 cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders.

Conclusions/interpretation: The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention.

Trial Registration: ClinicalTrials.gov NCT01862120.

Funding: Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).
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http://dx.doi.org/10.1007/s00125-020-05200-wDOI Listing
September 2020

Neonatal diabetes due to potassium channel mutation: Response to sulfonylurea according to the genotype.

Pediatr Diabetes 2020 09 20;21(6):932-941. Epub 2020 Jul 20.

Pediatric Gynecology Diabetes and Endocrinology, APHP Centre - Hôpital Universitaire Necker Enfants Malades, Paris, France.

Objective: A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein, we searched SU efficiency according to the genotype-phenotype correlation, dosage used, and side effects.

Research Design And Methods: Systematic review conducted according the PRISMA control criteria identifying relevant studies evaluating the in vivo and in vitro sensitivity of ATP-dependent potassium channels according to the characteristics of genetic mutation.

Results: Hundred and three selected articles with complete data in 502 cases in whom 413 (82.3%) had mutations in KCNJ11 (#64) and 89 in ABCC8 (# 56). Successful transfer from insulin to SU was achieved in 91% and 86.5% patients, respectively, at a mean age of 36.5 months (0-63 years). Among patients with KCNJ11 and ABCC8 mutations 64 and 46 were associated with constant success, 5 and 5 to constant failure, and 10 and 4 to variable degrees of reported success rate, respectively. The glibenclamide dosage required for each genotype ranged from 0.017 to 2.8 mg/kg/day. Comparing both the in vivo and in vitro susceptibility results, some mutations appear more sensitive than others to sulfonylurea treatment. Side effects were reported in 17/103 of the included articles: mild gastrointestinal symptoms and hypoglycaemia were the most common. One premature patient had an ulcerative necrotizing enterocolitis which association with SU is difficult to ascertain.

Conclusions: Sulfonylureas are an effective treatment for monogenic diabetes due to KCNJ11 and ABCC8 genes mutations. The success of the treatment is conditioned by differences in pharmacogenetics, younger age, pharmacokinetics, compliance, and maximal dose used.
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http://dx.doi.org/10.1111/pedi.13041DOI Listing
September 2020

Long-term Metabolic and Socioeducational Outcomes of Transient Neonatal Diabetes: A Longitudinal and Cross-sectional Study.

Diabetes Care 2020 06 9;43(6):1191-1199. Epub 2020 Apr 9.

Department of Pediatric Endocrinology, Gynecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute Affiliate, Paris, France.

Objective: Transient neonatal diabetes mellitus (TNDM) occurs during the 1st year of life and remits during childhood. We investigated glucose metabolism and socioeducational outcomes in adults.

Research Design And Methods: We included 27 participants with a history of TNDM currently with ( = 24) or without ( = 3) relapse of diabetes and 16 non-TNDM relatives known to be carriers of causal genetic defects and currently with ( = 9) or without ( = 7) diabetes. Insulin sensitivity and secretion were assessed by hyperinsulinemic-euglycemic clamp and arginine-stimulation testing in a subset of 8 TNDM participants and 7 relatives carrying genetic abnormalities, with and without diabetes, compared with 17 unrelated control subjects without diabetes.

Results: In TNDM participants, age at relapse correlated positively with age at puberty ( = 0.019). The mean insulin secretion rate and acute insulin response to arginine were significantly lower in TNDM participants and relatives of participants with diabetes than in control subjects (median 4.7 [interquartile range 3.7-5.7] vs. 13.4 [11.8-16.1] pmol/kg/min, < 0.0001; and 84.4 [33.0-178.8] vs. 399.6 [222.9-514.9] µIU/mL, = 0.0011), but were not different between participants without diabetes (12.7 [10.4-14.3] pmol/kg/min and 396.3 [303.3-559.3] µIU/mL, respectively) and control subjects. Socioeducational attainment was lower in TNDM participants than in the general population, regardless of diabetes duration.

Conclusions: Relapse of diabetes occurred earlier in TNDM participants compared with relatives and was associated with puberty. Both groups had decreased educational attainment, and those with diabetes had lower insulin secretion capacity; however, there was no difference in insulin resistance in adulthood. These forms of diabetes should be included in maturity-onset diabetes of the young testing panels, and relatives of TNDM patients should be screened for underlying defects, as they may be treated with drugs other than insulin.
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http://dx.doi.org/10.2337/dc19-0324DOI Listing
June 2020

Proportion of Basal to Total Insulin Dose Is Associated with Metabolic Control, Body Mass Index, and Treatment Modality in Children with Type 1 Diabetes-A Cross-Sectional Study with Data from the International SWEET Registry.

J Pediatr 2019 12 22;215:216-222.e1. Epub 2019 Jul 22.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Objectives: To investigate in a large population the proportion of daily basal insulin dose (BD) to daily total insulin dose (TD) (BD/TD) and its association with glycated hemoglobin A1c (HbA1c), body mass index (BMI)- SDS, and treatment modality in children with type 1 diabetes.

Study Design: Cross-sectional study in subjects with type 1 diabetes, age ≤18 years, and ≥2 years of diabetes duration, registered in the international multicenter Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference registry in March 2018. Variables included region, sex, age, diabetes duration, treatment modality (multiple daily injections [MDI] or continuous subcutaneous insulin infusion [CSII]), self-monitoring blood glucose, HbA1c, BD/TD, and BMI-SDS. BMI was converted to BMI-SDS using World Health Organization charts as reference. Hierarchic linear regression models were applied with adjustment for age, sex, and diabetes duration.

Results: A total of 19 687 children with type 1 diabetes (49% female, 49% CSII users) with median age 14.8 (11.5; 17.2) years and diabetes duration 6.0 (3.9; 9.0) years were included. HbA1c was 63 (55; 74) mmol/mol (7.9 [7.2; 8.9]%), and BMI-SDS 0.55 (-0.13; 1.21). Unadjusted, a lower BD/TD was associated with lower HbA1c, male sex, younger age, shorter diabetes duration, lower BMI-SDS, higher numbers of self-monitoring blood glucose and CSII (all P < .01). After adjustment for confounders, lower BD/TD was associated with lower HbA1c (P < .01) and lower BMI-SDS (P < .01) in children on CSII, but not on MDI.

Conclusions: Lower BD/TD is positively associated with lower HbA1c and lower BMI-SDS in children with type 1 diabetes on CSII. It remains to be investigated in a prospective study whether reducing BD/TD insulin will improve metabolic control and normalize body weight in children with type 1 diabetes.
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http://dx.doi.org/10.1016/j.jpeds.2019.06.002DOI Listing
December 2019

Glibenclamide oral suspension: Suitable and effective in patients with neonatal diabetes.

Pediatr Diabetes 2019 05 21;20(3):246-254. Epub 2019 Feb 21.

Pediatric diabetes and endocrinology, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Results of genetic have led to off-label glibenclamide treatment in patients with neonatal diabetes (NDM) because of potassium channel mutations. No pediatric form of glibenclamide was available. Glibenclamide was designated an orphan drug designation for NDM and a suspension was developed. As a part of the pediatric plan investigation, we assessed its acceptability, efficiency, and safety.

Methods: In this Phase II, prospective, non-randomized, single-center study, patient received glibenclamide tablets for 1 month then the suspension for 3 months. We assessed acceptability using hedonic scales and patient questionnaires, effectiveness using glycated hemoglobin (HbA1C) assays and safety based on hypo and hyperglycemia, and other adverse events.

Results: We included 10 patients (0.1-16.2 years, 6 < 5 years) were included. Younger patients preferred the suspension and older the tablets. All parents were satisfied with the ease of suspension administration. The parents of 5 of 6 younger children preferred the suspension over the tablets and kept it. Switching from tablets to suspension did not affect the excellent metabolic control (median HbA1c change, -0.40%, [-1.3% to 0.5%] P = 0.08). Median frequencies of hypoglycemia and hyperglycemia were less than 5% of routine blood glucose assays and were similar with both dosage forms. Two patients each experienced one episode of hypoglycemia below 35 mg/dL highlighting the need for dosage titration when switching from tablets to suspension. Transient and non-severe abdominal pain or diarrhea occurred in three patients. None of the patients discontinued the treatment.

Conclusion: The glibenclamide oral suspension Amglidia, the first anti-diabetic drug specifically developed for pediatric patients, is acceptable, effective, and safe in patients with NDM (NCT02375828).

Clinical Trial Registration: Glibentek in Patients with Neonatal Diabetes Secondary to Mutations in K + -ATP Channels, clinicaltrials.gov, NCT02375828, https://clinicaltrials.gov/ct2/show/NCT02375828.
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http://dx.doi.org/10.1111/pedi.12823DOI Listing
May 2019

Improved General and Height-Specific Quality of Life in Children With Short Stature After 1 Year on Growth Hormone.

J Clin Endocrinol Metab 2019 06;104(6):2103-2111

Pediatric Endocrinology, Diabetology and Gynecology Department, Hôpital Universitaire Necker-Enfants Malades [Assistance Publique Hôpitaux de Paris (AP-HP)], Paris, France.

Objective: Short stature in children and adolescents may lead to social and emotional stress, with negative effects on quality of life (QoL). GH treatment may improve QoL through height normalization. Our objective here was to evaluate general and height-specific QoL after 1 year of GH treatment.

Design: Prospective, single-center, observational cohort study.

Methods: Children ≥ 4 years of age starting GH at our center from 2012 to 2015 to treat short stature were studied. Patients with serious diseases, syndromic short stature, or developmental delay were excluded. At treatment initiation and 1 year later, patients and their parents completed the general PedsQL 4.0 and height-specific Quality of Life in Short Stature Youth (QoLiSSY) questionnaires. Correlations between self-report and parent-report scores and between height gain and QoL improvements were assessed based on Pearson correlation coefficients.

Results: Seventy-four children (42 boys, 32 girls), median age (± SD), 10.2 ± 3.0 years (range, 4.1 to 16.6 years), were included. The self-report PedsQL indicated significant improvements in emotional (P = 0.02) and social (P = 0.03) QoL. As assessed by the QoLiSSY, children reported improvement of social QoL (+0.2 SD; P = 0.04), and parents reported improvement of children's physical (+0.1 SD; P < 0.0001), emotional (+0.3 SD; P < 0.0001), and social (+0.3 SD; P < 0.0001) QoL. Height SD score (SDS) gains showed moderate positive correlations with QoLISSY self-report score gains (R = 0.53, R2 = 0.28; P < 0.001) and QoLISSY parent-report gains (R = 0.60, R2 = 0.41; P < 0.00001).

Conclusions: After 1 year of GH treatment, children had significant gains in emotional and social QoL, as assessed by a general self-report questionnaire and height-specific parent-report questionnaire.
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http://dx.doi.org/10.1210/jc.2018-02523DOI Listing
June 2019

Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases.

Curr Med Res Opin 2019 03 9;35(3):543-552. Epub 2018 Nov 9.

d Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert Debré , Service d'endocrinologie diabétologie pédiatrique, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Paris , France.

Background: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes.

Review: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males.

Conclusions: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications.
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http://dx.doi.org/10.1080/03007995.2018.1533459DOI Listing
March 2019

The influence of treatment, age at onset, and metabolic control on height in children and adolescents with type 1 diabetes-A SWEET collaborative study.

Pediatr Diabetes 2018 12 10;19(8):1441-1450. Epub 2018 Oct 10.

DECCP, Pediatric Clinic/CHL, Luxembourg, Luxembourg Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.

Objective: To describe the association between height, demographics, and treatment in youths with type 1 diabetes participating in an international network for pediatric diabetes centers (SWEET).

Methods: Data were collected from 55 centers with documented patients' height. All subjects below 20 years of age, diabetes duration >1 year, and without celiac disease were included. World Health Organization growth charts were used to calculate height and body mass index z-scores. Multiple hierarchic regression models adjusting for known confounders were applied.

Results: Data on 22 941 subjects (51.8% male) were analyzed with a median and interquartile range for age 14.8 years (11.2, 17.6), diabetes duration 5.6 years (3.1, 8.9), and height z-score 0.34 (-0.37, 1.03). Children were taller in the youngest age groups: adjusted height z-scores of 0.31 (±0.06) and 0.39 (±0.06), respectively; with shorter diabetes duration (<2 years: 0.36 [±0.06]; 2-<5 years: 0.34 [±0.06]; ≥5 years: 0.21 [±0.06]) and if they were pump users: 0.35 ± 0.05 vs 0.25 ± 0.05 (>three injections/day and 0.19 ± 0.06 [0-3 injections daily]), respectively. High hemoglobin A1c (HbA1c) and low to normal weight were associated with a lower height z-score. Trends were identical in all models except for gender. No gender differences were found except in the final height model where females exhibited higher z-score than males.

Conclusion: For youths treated at centers offering modern diabetes management, major growth disturbances are virtually eliminated. For children with a young age at onset, high HbA1c, injections, and/or non-intensive diabetes, treatment still requires attention in order to attain normal growth.
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http://dx.doi.org/10.1111/pedi.12751DOI Listing
December 2018

Author Correction: Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes.

Nat Immunol 2018 Sep;19(9):1035

INSERM U1016, Institut Cochin, Paris, France, and Université Paris Descartes, Paris, France.

In the version of this Article originally published, the asterisks indicating statistical significance were missing from Supplementary Figure 6; the file with the correct figure is now available.
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http://dx.doi.org/10.1038/s41590-017-0023-9DOI Listing
September 2018

Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.

Lancet Diabetes Endocrinol 2018 08 4;6(8):637-646. Epub 2018 Jun 4.

KG Jebsen Centre for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Paediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway.

Background: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.

Methods: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.

Findings: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3-10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA and sulfonylurea at all time points (ie, pre-transfer [for HbA], year 1, and most recent follow-up; n=64)-median HbA was 8·1% (IQR 7·2-9·2; 65·0 mmol/mol [55·2-77·1]) before transfer to sulfonylureas, 5·9% (5·4-6·5; 41·0 mmol/mol [35·5-47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9-7·3; 46·4 mmol/mol [41·0-56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2-10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14-0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12-0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5-24·0] vs 4·1 years [1·3-10·2]; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.

Interpretation: High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.

Funding: Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.
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http://dx.doi.org/10.1016/S2213-8587(18)30106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058077PMC
August 2018

Early postnatal growth and neurodevelopment in children born moderately preterm or small for gestational age at term: A systematic review.

Paediatr Perinat Epidemiol 2018 05 25;32(3):268-280. Epub 2018 Apr 25.

Early Determinants of Children's Health and Development Team (ORCHAD), Inserm UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Villejuif, France.

Background: Clinicians' interest in the long-term effects of early postnatal growth (EPG) is growing. There is compelling evidence linking rapid EPG with later cardiovascular risk, but its neurodevelopmental benefits still remain hypothetical in individuals born moderately preterm (MP) or small for gestational at term (SGAT).

Methods: The objective was to perform a systematic review of the relationship between EPG before age 3 years and neurodevelopmental outcome for individuals born MP (32-36 weeks' gestational age) or SGAT. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, 3 independent investigators searched for articles published on this topic in the Web of Science, EMBASE and PubMed from database inception to July 1, 2017. A detailed quality scale was used to evaluate articles.

Results: We selected 19 articles relying on 12 distinct study populations; 7 articles from 3 study populations were considered at moderate or high quality. The lack of standardisation of growth analysis methods prevented performing a meta-analysis. Overall, EPG was positively associated with neurodevelopmental outcome, especially Intelligence Quotient (IQ) when available. In this relationship, the first 6 months of life might be a critical period. Analysis of the few articles investigating the shape of the relationships revealed a non-linear association, with a plateau for IQ with higher weight gain, which suggests a possible ceiling effect.

Conclusions: A positive association was generally found between EPG and neurodevelopmental outcome for individuals born MP or SGAT. Strategies for future epidemiological studies are suggested to improve the characterisation of this relationship.
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http://dx.doi.org/10.1111/ppe.12468DOI Listing
May 2018

Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities.

Pediatr Diabetes 2018 06 4;19(4):663-669. Epub 2018 Mar 4.

Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.

Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.
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http://dx.doi.org/10.1111/pedi.12635DOI Listing
June 2018

Type I interferon-mediated autoinflammation due to DNase II deficiency.

Nat Commun 2017 12 19;8(1):2176. Epub 2017 Dec 19.

INSERM UMR1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, 75015, France.

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.
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http://dx.doi.org/10.1038/s41467-017-01932-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736616PMC
December 2017

Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes.

Nat Immunol 2017 Dec 9;18(12):1321-1331. Epub 2017 Oct 9.

INSERM U1016, Institut Cochin, Paris, France, and Université Paris Descartes, Paris, France.

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic β-cells by the immune system that involves innate and adaptive immune cells. Mucosal-associated invariant T cells (MAIT cells) are innate-like T-cells that recognize derivatives of precursors of bacterial riboflavin presented by the major histocompatibility complex (MHC) class I-related molecule MR1. Since T1D is associated with modification of the gut microbiota, we investigated MAIT cells in this pathology. In patients with T1D and mice of the non-obese diabetic (NOD) strain, we detected alterations in MAIT cells, including increased production of granzyme B, which occurred before the onset of diabetes. Analysis of NOD mice that were deficient in MR1, and therefore lacked MAIT cells, revealed a loss of gut integrity and increased anti-islet responses associated with exacerbated diabetes. Together our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. Monitoring of MAIT cells might represent a new biomarker of T1D, while manipulation of these cells might open new therapeutic strategies.
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http://dx.doi.org/10.1038/ni.3854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025738PMC
December 2017

Efficacy and Safety of Continuous Subcutaneous Infusion of Recombinant Human Gonadotropins for Congenital Micropenis during Early Infancy
.

Horm Res Paediatr 2017 12;87(2):103-110. Epub 2017 Jan 12.

Background: Early postnatal administration of gonadotropins to infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty, thereby increasing penile growth. We assessed the effects of gonadotropin infusion on stretched penile length (SPL) and hormone levels in infants with congenital micropenis.

Methods: Single-center study including 6 males with micropenis in case of isolated CHH (n = 4), panhypopituitarism (n = 1), and partial androgen insensitivity syndrome (PAIS; n = 1). Patients were evaluated at baseline, monthly and at the end of the study through a clinical examination (SPL, testicular position and size), serum hormone assays (testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Müllerian hormone [AMH]), and ultrasound of penis/testes.

Results: In CHH, significant increases occurred in serum testosterone (from undetectable level to 3.5 ± 4.06 ng/mL [12.15 ± 14.09 nmol/L]), SPL (from 13.8 ± 4.5 to 42.6 ± 5 mm; p < 0.0001), inhibin B (from 94.8 ± 74.9 to 469.4 ± 282.5 pg/mL, p = 0.04), and AMH (from 49.6 ± 30.6 to 142 ± 76.5 ng/mL, p = 0.03). Micropenis was corrected in all patients, except one. On treatment, in the patient with PAIS, SPL was increased from 13 to 38 mm.

Conclusions: Early gonadotropin infusion is a safe, well-tolerated and effective treatment. The effect in PAIS has not been reported previously. Long-term follow-up is needed to assess the impact, if any, on future fertility and reproduction.
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http://dx.doi.org/10.1159/000454861DOI Listing
June 2017

Revisiting autoimmune gastritis in children and adolescents with type 1 diabetes.

Pediatr Diabetes 2017 Dec 22;18(8):772-776. Epub 2016 Dec 22.

Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Objective: Assess the frequency of anti-H /K adenosine triphosphatase (ATPase) autoantibodies (AAB) and symptoms of autoimmune gastritis in children and adolescents with type 1 diabetes (T1D).

Research Design And Methods: Anti-H /K ATPase AAB were measured in 402 children and adolescents (210 boys and 192 girls, 11.1 ± 4.5 years) treated for T1D (screened positive for β-cell AAB), along with search of symptoms of anemia (hemoglobin, serum iron, and ferritin levels) and gastric pain. The AAB specific for thyroperoxydase, thyroglobulin, and transglutaminase were also measured.

Results: Anti-H /K ATPase AAB were present in 6.5% of children. Their frequency increased with age: 4% at 10 years, 10% at 15 years, and 20% at 20 years. Iron deficiency (45% vs 3.8%), iron deficiency anemia (36% vs 3.8%), antithyroid AAB (24% vs 9.7%), and family history of Graves' disease (25% vs 5.6%) were more frequent in patients with anti-H /K ATPase AAB. Two patients, a 13-year-old girl and a 11-year-old boy, experienced symptoms (iron deficiency anemia and epigastric pain) which led to diagnosis of autoimmune gastritis confirmed upon fibroscopy. Both showed high levels of anti-H /K ATPase AAB and atrophic gastritis.

Conclusions: Autoimmune gastritis presents an age-dependent frequency in children and adolescents with T1D but is rarely symptomatic. Screening for anti-H /K ATPase AAB should thus target patients with iron deficiency, anemia, epigastralgia, autoimmune thyroiditis, or age over 15 years.
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http://dx.doi.org/10.1111/pedi.12482DOI Listing
December 2017

CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism.

EBioMedicine 2016 Nov 4;13:225-236. Epub 2016 Oct 4.

INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. Electronic address:

Primary aldosteronism (PA) is the most common form of secondary hypertension. Mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are found in aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH). A recurrent mutation in CACNA1H (coding for Cav3.2) was identified in a familial form of early onset PA. Here we performed whole exome sequencing (WES) in patients with different types of PA to identify new susceptibility genes. Four different heterozygous germline CACNA1H variants were identified. A de novo Cav3.2 p.Met1549Ile variant was found in early onset PA and multiplex developmental disorder. Cav3.2 p.Ser196Leu and p.Pro2083Leu were found in two patients with FH, and p.Val1951Glu was identified in one patient with APA. Electrophysiological analysis of mutant Cav3.2 channels revealed significant changes in the Ca current properties for all mutants, suggesting a gain of function phenotype. Transfections of mutant Cav3.2 in H295R-S2 cells led to increased aldosterone production and/or expression of genes coding for steroidogenic enzymes after K stimulation. Identification of CACNA1H mutations associated with early onset PA, FH, and APA suggests that CACNA1H might be a susceptibility gene predisposing to PA with different phenotypic presentations, opening new perspectives for genetic diagnosis and management of patients with PA.
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http://dx.doi.org/10.1016/j.ebiom.2016.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264314PMC
November 2016

A description of clinician reported diagnosis of type 2 diabetes and other non-type 1 diabetes included in a large international multicentered pediatric diabetes registry (SWEET).

Pediatr Diabetes 2016 10;17 Suppl 23:24-31

Children's University Hospital Children's Endocrinology Centre, Riga Stradins University, Riga, Latvia.

Background: Although type 1 diabetes (T1D) remains the most frequent form of diabetes in individuals aged less than 20 years at onset, other forms of diabetes are being increasingly recognized.

Objectives: To describe the population of children with other forms of diabetes (non-type 1) included in the multinational SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) database for children with diabetes.

Methods: Cases entered in the SWEET database are identified by their physician as T1D, type 2 diabetes (T2D) and other types of diabetes according to the ISPAD classification. Etiologic subgroups are provided for other types of diabetes. Descriptive analyses were tabulated for age at onset, gender, daily insulin doses, and hemoglobin A1c (A1C) for each type and subtype of diabetes and when possible, values were compared.

Results: Of the 27 104 patients included in this report, 95.5% have T1D, 1.3% T2D, and 3.2% other forms of diabetes. The two most frequent etiologies for other forms of diabetes were maturity onset diabetes of the young (MODY) (n = 351) and cystic fibrosis-related diabetes (CFRD) (n = 193). The cause was unknown or unreported in 10% of other forms of diabetes. Compared with T1D, children with T2D and CFRD were diagnosed at an older age, took less insulin and had lower A1C (all P < .0001).

Conclusion: In centers included in SWEET, forms of diabetes other than type 1 remain rare and at times difficult to characterize. Sharing clinical information and outcome between SWEET centers on those rare forms of diabetes has the potential to improve management and outcome.
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http://dx.doi.org/10.1111/pedi.12426DOI Listing
October 2016

Evaluation of the pharmacokinetics of glibenclamide tablet given, off label, orally to children suffering from neonatal syndromic hyperglycemia.

Eur J Clin Pharmacol 2016 Nov 25;72(11):1373-1379. Epub 2016 Aug 25.

Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.

Purpose: Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy.

Methods: Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients). A total of 229 plasma Gb concentrations and 187 blood glucose measurements were available. A population model was developed with NONMEM.

Results: Body weight was the most significant parameter on clearance and explained a substantial part of the variability. A variant genotype of CYP2C9 (i.e., *1/*2 and *1/*3) explained also a part of the remaining variability on Gb clearance. Patients carrying these allelic variants had a clearance decreased by 45 %. A link between daily area under the curve (AUC) and metabolic control diabetes was found.

Conclusions: This study evaluates for the first time the pharmacokinetics of oral Gb in children and constitutes a first step towards dose individualization of this drug in a particularly vulnerable population.
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http://dx.doi.org/10.1007/s00228-016-2119-9DOI Listing
November 2016

Response to Comment on Beltrand et al. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care 2015;38:2033-2041.

Diabetes Care 2016 09;39(9):e155

Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France; Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France; INSERM U1016, Institut Cochin, Paris, France; and Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France

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http://dx.doi.org/10.2337/dci16-0002DOI Listing
September 2016

A unique CD8(+) T lymphocyte signature in pediatric type 1 diabetes.

J Autoimmun 2016 09 16;73:54-63. Epub 2016 Jun 16.

Institut National de la Sante et de la Recherche Médicale, Unité 1151, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, 75015 Paris, France; Centre National de la Recherche Scientifique, UMR8253, 75015 Paris, France. Electronic address:

Human type 1 diabetes results from a destructive auto-reactive immune response in which CD8(+) T lymphocytes play a critical role. Given the intense ongoing efforts to develop immune intervention to prevent and/or cure the disease, biomarkers suitable for prediction of disease risk and progress, as well as for monitoring of immunotherapy are required. We undertook separate multi-parameter analyses of single naïve and activated/memory CD8(+) T lymphocytes from pediatric and adult patients, with the objective of identifying cellular profiles associated with onset of type 1 diabetes. We observe global perturbations in gene and protein expression and in the abundance of T cell populations characterizing pediatric but not adult patients, relative to age-matched healthy individuals. Pediatric diabetes is associated with a unique population of CD8(+) T lymphocytes co-expressing effector (perforin, granzyme B) and regulatory (transforming growth factor β, interleukin-10 receptor) molecules. This population persists after metabolic normalization and is especially abundant in children with high titers of auto-antibodies to glutamic acid decarboxylase and with elevated HbA1c values. These findings highlight striking differences between pediatric and adult type 1 diabetes, indicate prolonged large-scale perturbations in the CD8(+) T cell compartment in the former, and suggest that CD8(+)CD45RA(-) T cells co-expressing effector and regulatory factors are of interest as biomarkers in pediatric type 1 diabetes.
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http://dx.doi.org/10.1016/j.jaut.2016.06.003DOI Listing
September 2016

Insulin regimens, diabetes knowledge, quality of life, and HbA1c in children and adolescents with type 1 diabetes.

Pediatr Diabetes 2017 08 10;18(5):340-347. Epub 2016 May 10.

Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Necker, Paris, France.

Objectives: To further describe the changes in insulin therapy regimens and hemoglobin A1c (HbA1c) in children and adolescents with type 1 diabetes, and their associations with diabetes knowledge and quality of life.

Research Design And Methods: The study included 4293 children and adolescents (12.9 ± 2.6 yr, diabetes >1 yr) attending AJD (Aide aux Jeunes Diabétiques) summer camps between 2009 and 2014. The distribution of insulin regimens and associations between HbA1c, therapeutic regimens, diabetes knowledge (AJD questionnaire), and Quality of Life (Ingersoll et Marrero, Hvidoere Study Group short version) were assessed.

Results: The percentage of youth treated with insulin pumps increased up to about 45%, basal bolus stabilized around 40%, and other regimens decreased majorly. HbA1c was higher with premixed insulins only regimens (9.05 ± 2.43%), but there was no difference between pump (8.12 ± 1.09%), basal bolus (8.32 ± 1.33%) and two to three injections (8.18 ± 1.28%). Mean HbA1c decreased by 0.014% per year. The percentage of HbA1c <7.5% increased by 1.5% per year, and the percentages of HbA1c >9% or >10% decreased by 4 and 5.5%, changes being greater with the pump. HbA1c was weakly associated with diabetes knowledge, and strongly with general health perception and perception about diabetes.

Conclusion: The percentage of children and adolescents with the highest risk of complications decreased markedly. The distribution of HbA1c better depicts the glycemic control in a population than the mean or the percentage of patients reaching the target (7.5%). HbA1c was more strongly associated with general health perception than with therapeutic regimens and diabetes knowledge.
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http://dx.doi.org/10.1111/pedi.12397DOI Listing
August 2017

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations.

Diabetes Care 2015 Nov 5;38(11):2033-41. Epub 2015 Oct 5.

Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm U1016, Institut Cochin, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France

Objective: Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin.

Research Design And Methods: We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing.

Results: At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change -1.55% [range -3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin.

Conclusions: SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.
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http://dx.doi.org/10.2337/dc15-0837DOI Listing
November 2015

Inadequate cortisol response to the tetracosactide (Synacthen®) test in non-classic congenital adrenal hyperplasia: an exception to the rule?

Horm Res Paediatr 2015 7;83(4):262-7. Epub 2015 Feb 7.

Service d'Endocrinologie, Gynécologie et Diabétologie Pédiatriques, Hôpital Universitaire Necker-Enfants Malades, Paris, France.

Aims: To describe cortisol response to tetracosactide and to review the literature on adrenal function in non-classic congenital adrenal hyperplasia (NCCAH) patients.

Methods: We compared cortisol responses to tetracosactide (250 μg) between NCCAH patients and a comparison group (CG) of patients with premature pubarche and normal tetracosactide test. An adequate cortisol response was defined as a peak ≥18 μg/dl.

Results: We included 35 NCCAH patients (26 girls, 9 boys), whose mean age at testing was 7.0 years (0.8-15.6), and 47 patients in the CG (39 girls, 8 boys), whose mean age was 7.2 years (0.5-9.9). Baseline cortisol was significantly higher in the NCCAH group than in the CG [12.9 (4.3-22.2) vs. 9.7 (4.2-16.2) μg/dl, respectively; p = 0.0006]. NCCAH patients had lower cortisol peak response compared to the CG [18.2 (6.3-40) vs. 24.9 (12-30.3) μg/dl, respectively; p < 0.0001]. Peak cortisol was <18 μg/dl in 21/35 (60%) NCCAH patients versus 1/47 (2.1%) in the CG. No NCCAH patients had acute adrenal insufficiency, but 2 reported severe fatigue that improved with hydrocortisone.

Conclusions: The cortisol response to tetracosactide was inadequate (<18 μg/dl) in 60% of patients with NCCAH. Hydrocortisone therapy may deserve consideration when major stress (surgery, trauma, childbirth) or objectively documented fatigue occurs in NCCAH patients with inadequate cortisol response.
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http://dx.doi.org/10.1159/000369901DOI Listing
February 2016