Characterization and risk factors of hyperglycaemia during treatment of childhood hematologic malignancies.

BACKGROUND: Secondary forms of diabetes are often understudied and underdiagnosed in children and adolescents with cancer. The objectives of our cohort study were to study the incidence and risk factors for hyperglycaemia in leukaemia and lymphoma patients. METHODS: We retrospectively collected 15 years of data from paediatric patients treated for acute lymphoblastic leukaemia (ALL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL) immediately at cancer diagnosis. We studied risk factors for hyperglycaemia in univariate and multivariate analyses. RESULTS: Our study cohort included 267 patients corresponding to 179 patients with ALL, 48 with NHL and 40 with HL. Eighteen per cent of ALL patients (32/179) and 17% of NHL patients (8/48) developed hyperglycaemia, with more than 61% developing hyperglycaemia within the first month of treatment. No hyperglycaemia was observed in HL patients. Multivariate analysis showed the following hyperglycaemia risk factors for ALL patients: overweight or obesity (OR 3.793) and pubertal onset (OR 4.269) at cancer diagnosis, steroid-resistant disease (OR 3.445) and hematopoietic stem cell transplant (HSCT) (OR 4.754). CONCLUSION: In our cohort, 18% of patients with ALL or NHL developed early-onset hyperglycaemia after chemotherapy/radiotherapy. Patients with ALL with increased hyperglycaemia risk can be readily identified by measuring BMI and puberty stage at cancer diagnosis. Also, glucose monitoring should be reinforced when patients show steroid-resistant disease and/or require HSCT.

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

New Insights into Diabetes Cell Therapy.

Since insulin discovery, islet transplantation was the first protocol to show the possibility to cure patients with type 1 diabetes using low-risk procedures. The scarcity of pancreas donors triggered a burst of studies focused on the production of new ß cells in vitro. These were rapidly dominated by pluripotent stem cells (PSCs) demonstrating diabetes-reversal potential in diabetic mice. Subsequent enthusiasm fostered a clinical trial with immunoisolated embryonic-derived pancreatic progenitors. Yet safety is the Achilles' heel of PSCs, and a whole branch of ß cell engineering medicine focuses on transdifferentiation of adult pancreatic cells. New data showed the possibility to chemically stimulate acinar or α cells to undergo ß cell neogenesis and provide opportunities to intervene in situ without the need for a transplant, at least after weighing benefits against systemic adverse effects. The current studies suggested the pancreas as a reservoir of facultative progenitors (e.g., in the duct lining) could be exploited ex vivo for expansion and ß cell differentiation in timely fashion and without the hurdles of PSC use. Diabetes cell therapy is thus a growing field not only with great potential but also with many pitfalls to overcome for becoming fully envisioned as a competitor to the current treatment standards.

Plasma proteomics in children with new-onset type 1 diabetes identifies new potential biomarkers of partial remission.

Partial remission (PR) occurs in only half of people with new-onset type 1 diabetes (T1D) and corresponds to a transient period characterized by low daily insulin needs, low glycemic fluctuations and increased endogenous insulin secretion. While identification of people with newly-onset T1D and significant residual beta-cell function may foster patient-specific interventions, reliable predictive biomarkers of PR occurrence currently lack. We analyzed the plasma of children with new-onset T1D to identify biomarkers present at diagnosis that predicted PR at 3 months post-diagnosis. We first performed an extensive shotgun proteomic analysis using Liquid Chromatography-Tandem-Mass-Spectrometry (LCMS/MS) on the plasma of 16 children with new-onset T1D and quantified 98 proteins significantly correlating with Insulin-Dose Adjusted glycated hemoglobin A1c score (IDAA1C). We next applied a series of both qualitative and statistical filters and selected protein candidates that were associated to pathophysiological mechanisms related to T1D. Finally, we translationally verified several of the candidates using single-shot targeted proteomic (PRM method) on raw plasma. Taken together, we identified plasma biomarkers present at diagnosis that may predict the occurrence of PR in a single mass-spectrometry run. We believe that the identification of new predictive biomarkers of PR and ß-cell function is key to stratify people with new-onset T1D for ß-cell preservation therapies.

A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms.

BACKGRUOUND: Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. METHODS: We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. RESULTS: The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. CONCLUSION: We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

Near adult height and BMI changes in growth hormone treated short children with Noonan syndrome: the Belgian experience.

Introduction A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no mutation group). Results After a median (P10; P90) duration of 5.4 (2.2-10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.4; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (beta=0.90, p<0.001), mid-parental height SDS (beta =0.27; p=0.005), birth weight SDS (beta=0.15; p=0.051), age at start (beta=0.07; p=0032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p<0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. Conclusion Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.

Making ß cells from adult cells within the pancreas.

Cell therapy is currently considered as a potential therapeutic alternative to traditional treatments of diabetes. Islet and whole pancreas transplantations provided the proof-of-concept of glucose homeostasis restoration after replenishment of the deficiency of ß cells responsible for the disease. Current limitations of these procedures have led to the search for strategies targeting replication of pre-existing ß cells or transdifferentiation of progenitors and adult cells. These investigations revealed an unexpected plasticity towards ß cells of adult cells residing in pancreatic epithelium (eg, acinar, duct, and α cells). Here we discuss recent developments in ß-cell replication and ß-cell transdifferentiation of adult epithelial pancreatic cells, with an emphasis on techniques with a potential for clinical translation.

Deep Analysis of Clinical Parameters and Temporal Evolution of Glycemic Parameters Based on CGM Data for the Characterization of Severe Hypoglycemia in a Cohort of Children and Adolescents with Type 1 Diabetes.

This study aims to evaluate the determinants and clinical markers of patients at risk for severe hypoglycemia (SH) in children and adolescents with type 1 diabetes. In the EPI-GLUREDIA study, clinical parameters and continuous glucose monitoring metrics from children and adolescents with type 1 diabetes were retrospectively analyzed between July 2017 and June 2022. Their clinical parameters were collected during traditional and quarterly medical consultations according to whether they experienced severe hypoglycemia or not. Then, continuous glucose monitoring metrics were analyzed on days surrounding SH during specific periods. According to the glycemic parameters, glycemic hemoglobin and glycemic mean were significantly lower in the three months preceding a SH compared with during three normal months (p < 0.05). Moreover, the time spent in hypoglycemia(time below the range, TBR<3.3) and its strong correlation (R = 0.9, p < 0.001) with the frequency of SH represent a sensitive and specific clinical parameter to predict SH (cut-off: 9%, sensitivity: 71%, specificity: 63%). The second finding of the GLUREDIA study is that SH is not an isolated event in the glycemic follow-up of our T1DM patients. Indeed, most of the glycemic parameters (i.e., glycemic mean, glycemic variability, frequency of hypoglycemia, and glycemic targets) vary considerably in the month preceding an SH (all p < 0.05), whereas most of these studied glycemic parameters remain stable in the absence of a severe acute complication (all p > 0.05). Furthermore, the use of ROC curves allowed us to determine for each glycemic parameter a sensitive or specific threshold capable of more accurately predicting SH. For example, a 10% increase in the frequency of hypoglycemia predicts a risk of near SH with good combination of sensitivity and specificity (sensitivity: 80%, specificity: 60%). The GLUREDIA study aimed to target clinical and glycemic parameters to predict patients at risk for SH. First, we identified TBR<3.3 < 9% as a sensitive and specific tool to reduce the frequency of SH. In addition, SH was not an isolated event but rather it was accompanied by glycemic disturbances in the 30 days before SH.

Congenital hyperinsulinemic hypoglycemia (HH) requiring treatment as the presenting feature of Kabuki syndrome.

Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the KDM6A gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non-complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a KDM6A mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the KDM6A gene, also known as X-linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first-line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated.

Post-Hypoglycemic hyperglycemia are highly relevant markers for stratification of glycemic variability and partial remission status of pediatric patients with new-onset type 1 diabetes.

AIMS: To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not. METHODS: In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual ß-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models. RESULTS: PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHHAUC moderately correlated with parameters of glucose homeostasis including TIR (R2 = 0.35, p-value < 0.05), coefficient of variation (R2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA1C) (R2 = 0.32, p-value < 0.05) and with residual ß-cell secretion (R2 = 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA1C and estimated C-peptide (CPEPEST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. CONCLUSION: PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.

Influence of the occurrence and duration of partial remission on short-term metabolic control in type 1 diabetes: the DIABHONEY pediatric study.

Objective: To evaluate the residual effect of partial remission (PR) on immediate post-PR glycemic control according to its occurrence and duration in a cohort of children with type 1 diabetes mellitus (T1DM). Patients and Methods: Values of glycemic control parameters [i.e. HbA1C, insulin dose-adjusted hemoglobin A1C (IDAA1C), glycemic target-adjusted HbA1C (GTAA1C)] and data from glucose monitoring devices from 189 pediatric patients with new-onset type 1 diabetes were collected retrospectively from 24 months. Patients were characterized according to their remission status (PR+ and PR-). PR+ patients were subdivided into three subgroups regarding PR duration [i.e. short (⩾3-⩽6 months), intermediate (>6-⩽12 months), and long PR (>12-⩽14 months)]. We compared glycemic control data from each PR+ subgroup at +6 and +12 months post-PR with PR- patients at the same postdiagnosis time. Second, PR+ subgroups were compared with each other. Results: PR+ patients showed improved glycemic control (i.e. HbA1C, IDAA1C, and GTAA1C) at + 6 months post-PR when compared with nonremitters (PR-), independently of the PR duration subgroups (p < 0.05). Interestingly, patients in long PR+ subgroup exhibited higher positive residual effect than short PR+ subgroup with lower GTAA1C scores (p = 0.02), better time in range (TIR) (p = 0.003), less time in hypoglycemia (10.45 versus 16.13%, p = 0.03) and less glycemic variability (83.1 mg/dl versus 98.84 mg/dl, p = 0.03). No significant differences were found for glucose control between PR+ and PR- patients at +12 months post-PR. Conclusion: This study supports the positive impact of PR occurrence and duration on short-term metabolic control (better HbA1C levels, IDAA1C and GTAA1C scores, TIR, and less glycemic variability) with the residual effect increasing according to PR duration.

Determinants and Characteristics of Insulin Dose Requirements in Children and Adolescents with New-Onset Type 1 Diabetes: Insights from the INSENODIAB Study.

Aims: New-onset type 1 diabetes mellitus (T1D) in pediatric patients represents a clinical challenge for initial total daily insulin dosing (TIDD) due to substantial heterogeneity in practice and lack of consensus on the optimal starting dose. Our INSENODIAB (INsulin SEnsitivity in New Onset type 1 DIABetes) study is aimed at (1) exploring the influence of patient-specific characteristics on insulin requirements in pediatric patients with new-onset T1D; (2) constructing a predictive model for the recommended TIDD tailored to individual patient profiles; and (3) assessing potential associations between TIDD and patient outcomes at follow-up intervals of 3 and 12 months. Methods: We conducted a comprehensive analysis of medical records for children aged 6 months to 18 years, hospitalized for new-onset T1D from 2013 to 2022. The study initially involved multivariable regression analysis on a retrospective cohort (rINSENODIAB), incorporating baseline variables. Subsequently, we validated the model robustness on a prospective cohort (pINSENODIAB) with a significance threshold of 5%. The model accuracy was assessed by Pearson's correlation. Results: Our study encompassed 103 patients in the retrospective cohort and 80 in the prospective cohort, with median TIDD at diagnosis of 1.1 IU/kg BW/day (IQR 0.5). The predictive model for optimal TIDD was established using baseline characteristics, resulting in the following formula: TIDD (IU/d) = ([0.09 × Age2] + [0.68 × %Weight Loss] + [28.60 × Veinous pH] - [1.03 × Veinous bicarbonates] + [0.81 × Weight] - 194.63). Validation of the model using the pINSENODIAB cohort demonstrated a significant Pearson correlation coefficient of 0.74. Notably, no significant correlation was observed between TIDD at diagnosis and partial remission markers (IDAA1C, C-peptide) at 3- and 12-months postdiagnosis time points. Conclusions: In the context of new-onset T1D in pediatric patients, we identified key influencing factors for determining optimal TIDD, including age, percentage of weight loss, weight, veinous pH, and bicarbonates. These findings have paved the way for the development of a dosing algorithm to potentially expedite glycemic control stabilization and facilitate a more individualized approach to treatment regimens.

Case Report: Aggressive neural crest tumors in a child with familial von Hippel Lindau syndrome associated with a germline VHL mutation (c.414A>G) and a novel KIF1B gene mutation.

Introduction: Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10. Case presentation: We diagnosed a 9-year-old girl of normal appearance and severe refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation of VHL gene (c.414A>G), also present in three members of her family. At age 13, a pelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life. Discussion: This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine.

Growth response of syndromic versus non-syndromic children born small for gestational age (SGA) to growth hormone therapy: a Belgian study.

Introduction: A substantial proportion of SGA patients present with a syndrome underlying their growth restriction. Most SGA cohorts comprise both syndromic and non-syndromic patients impeding delineation of the recombinant human growth hormone (rhGH) response. We present a detailed characterization of a SGA cohort and analyze rhGH response based on adult height (AH). Methods: Clinical and auxological data of SGA patients treated with rhGH, who had reached AH, were retrieved from BELGROW, a national database of all rhGH treated patients held by BESPEED (BElgian Society for PEdiatric Endocrinology and Diabetology). SGA patients were categorized in syndromic or non-syndromic patients. Results: 272 patients were included, 42 classified as syndromic (most frequent diagnosis (n=6): fetal alcohol syndrome and Silver-Russell syndrome). Compared with non-syndromic patients, syndromic were younger [years (median (P10/P90)] 7.43 (4.3/12.37) vs 10.21 (5.43/14.03), p=0.0005), shorter (height SDS -3.39 (-5.6/-2.62) vs -3.07 (-3.74/-2.62), p=0.0253) and thinner (BMI -1.70 (-3.67/0.04) vs -1.14 (-2.47/0.27) SDS, p=0.0054) at start of rhGH treatment. First year rhGH response was comparable (delta height SDS +0.54 (0.24/0.94) vs +0.56 (0.26/0.92), p=0.94). Growth pattern differed with syndromic patients having a higher prepubertal (SDS +1.26 vs +0.83, p=0.0048), but a lower pubertal height gain compared to the non-syndromic group (SDS -0.28 vs 0.44, p=0.0001). Mean rhGH dose was higher in syndromic SGA patients (mg/kg body weight/day 0.047 (0.039/0.064) vs 0.043 (0.035/0.056), p=0.0042). AH SDS was lower in syndromic SGA patients (-2.59 (-4.99/-1.57) vs -2.32 (-3.3/-1.2), p=0.0107). The majority in both groups remained short (<-2 SDS: syndromic 71%, non-syndromic 63%). Total height gain was comparable in both groups (delta height SDS +0.76 (-0.70/1.48) vs +0.86 (-0.12/1.86), p=0.41). Conclusions: Compared to non-syndromic SGA patients, syndromic SGA patients were shorter when starting rhGH therapy, started rhGH therapy earlier, and received a higher dose of rhGH. At AH, syndromic SGA patients were shorter than non-syndromic ones, but their height gain under rhGH therapy was comparable.

Characterization, evolution and risk factors of diabetes and prediabetes in a pediatric cohort of renal and liver transplant recipients.

Background: Hyperglycemia (HG) and prediabetes are rarely sought in pediatric liver (LT) and renal (RT) transplantation, yet their presence indicates a high risk of diabetes and cardiovascular disease. The objectives of our DIABGRAFT study were to retrospectively (rDIABGRAFT) and longitudinally (pDIABGRAFT) characterize HG and (pre)diabetes in a cohort of children with LT or/and RT. Methods: We retrospectively analyzed risk factors of HG from 195 children with LT from 2012 to 2019 and twenty children with RT from 2005 to 2019 at Cliniques universitaires Saint-Luc. In addition, we prospectively followed four LT and four RT children to evaluate the evolution of their glucose metabolism. Results: Our rDIABGRAFT study showed that 25% and 35% of LT and RT children respectively presented transient HG and 20% of RT developed diabetes. The occurrence of HG was associated with the use of glucocorticoids and with acute events as graft rejection and infection. In our pDIABGRAFT cohort, biological markers of diabetes were in the normal range for HbA1C, fasting glucose and insulin levels. However, oral glucose tolerance test and glucose sensors showed insulin resistance, impaired glucose tolerance and HG in the post-prandial afternoon period. Conclusion: Our study shows that children with LT and RT were more at risk of developing HG when glucocorticoids were required and that HbA1C and fasting glucose lack sensitivity for early detection of glucose intolerance. Also, measurement of glycemia immediately after the transplantation and in postprandial period is key to detect dysglycemia since insulin resistance prevailed in our cohort. ClinicalTrialsgov ID: NCT05464043.

Characterization of Post-Hypoglycemic Hyperglycemia in Children and Adolescents With Type 1 Diabetes: The EPHICA Study.

Background: In patients with diabetes, the dynamics in which hypoglycemia recovers impacts cardiovascular disease risk. Our study investigated the extents of "post-hypoglycemic hyperglycemia (PHH)" (i.e. hypoglycemia that recover to hyperglycemia in any circumstance) and factors likely to influence PHH characteristics in a pediatric cohort of patients with type 1 diabetes (T1D). Methods: We collected retrospective continuous glucose monitoring (CGM) data from 142 pediatric patients with T1D to characterize episodes of PHH during a two-month follow-up period. Factors influencing PHH were determined using univariate and multivariate analyses. Results: In our EPHICA cohort, PHH rate was 0.6 ± 0.3 episode/day and correlated (r=0.33; p<0.0001) with hyperglycemia rate (2.6 ± 0.5 episodes/day). The global proportion of hyperglycemia corresponding to PHH was 0.22 ± 0.1, yet 14.8% of patients had more than 1/3 of hyperglycemia related to PHH. Episodes of PHH lasted 239.6 ± 124.8 minutes with a hyperglycemic peak of 258.8 ± 47.1 mg/dL. Only 12.2% of PHH occurred at night. While a younger age (<12 years) and lower body mass index (BMI) (SDS: -2 to 1.6) were associated with higher daily PHH rates, teenagers (≥12 years) and obese patients experienced longer PHH and higher hyperglycemic peaks. Parameters of glycemic variability (i.e. HbA1C, IDAA1C and GTAA1C) moderately correlated with PHH duration and related hyperglycemic peak. Multivariate analysis confirmed these results, as factors likely to influence PHH rate were phenotype (age and BMI) and glycemic variability parameters (time in range, mean glycemia, HbA1C and GTAA1C). Conclusion: Our EPHICA study highlights the importance of PHH as a prominent component of hyperglycemia in some children and adolescents with T1D. Factors associated with PHH features are age, BMI and parameters of glycemic control. Young and lean children are more prone to experience hypoglycemia that recover with hyperglycemia, but adolescents and obese children tend to experience hyperglycemia of longer duration.

Glycemic Variability Patterns Strongly Correlate With Partial Remission Status in Children With Newly Diagnosed Type 1 Diabetes.

OBJECTIVE: To evaluate whether indexes of glycemic variability may overcome residual ß-cell secretion estimates in the longitudinal evaluation of partial remission in a cohort of pediatric patients with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: Values of residual ß-cell secretion estimates, clinical parameters (e.g., HbA1c or insulin daily dose), and continuous glucose monitoring (CGM) from 78 pediatric patients with new-onset type 1 diabetes were longitudinally collected during 1 year and cross-sectionally compared. Circadian patterns of CGM metrics were characterized and correlated to remission status using an adjusted mixed-effects model. Patients were clustered based on 46 CGM metrics and clinical parameters and compared using nonparametric ANOVA. RESULTS: Study participants had a mean (± SD) age of 10.4 (± 3.6) years at diabetes onset, and 65% underwent partial remission at 3 months. ß-Cell residual secretion estimates demonstrated weak-to-moderate correlations with clinical parameters and CGM metrics (r2 = 0.05-0.25; P < 0.05). However, CGM metrics strongly correlated with clinical parameters (r2 >0.52; P < 0.05) and were sufficient to distinguish remitters from nonremitters. Also, CGM metrics from remitters displayed specific early morning circadian patterns characterized by increased glycemic stability across days (within 63-140 mg/dL range) and decreased rate of grade II hypoglycemia (P < 0.0001) compared with nonremitters. Thorough CGM analysis allowed the identification of four novel glucotypes (P < 0.001) that segregate patients into subgroups and mirror the evolution of remission after diabetes onset. CONCLUSIONS: In our pediatric cohort, combination of CGM metrics and clinical parameters unraveled key clinical milestones of glucose homeostasis and remission status during the first year of type 1 diabetes.

Effect of nationwide reimbursement of real-time continuous glucose monitoring on HbA1c, hypoglycemia and quality of life in a pediatric type 1 diabetes population: The RESCUE-pediatrics study.

Objective: Real-time continuous glucose monitoring (RT-CGM) can improve metabolic control and quality of life (QoL), but long-term real-world data in children with type 1 diabetes (T1D) are scarce. Over a period of 24 months, we assessed the impact of RT-CGM reimbursement on glycemic control and QoL in children/adolescents with T1D treated with insulin pumps. Research design and methods: We conducted a multicenter prospective observational study. Primary endpoint was the change in HbA1c. Secondary endpoints included change in time in hypoglycemia, QoL, hospitalizations for hypoglycemia and/or ketoacidosis and absenteeism (school for children, work for parents). Results: Between December 2014 and February 2019, 75 children/adolescents were followed for 12 (n = 62) and 24 months (n = 50). Baseline HbA1c was 7.2 ± 0.7% (55 ± 8mmol/mol) compared to 7.1 ± 0.8% (54 ± 9mmol/mol) at 24 months (p = 1.0). Participants with a baseline HbA1c ≥ 7.5% (n = 27, mean 8.0 ± 0.3%; 64 ± 3mmol/mol) showed an improvement at 4 months (7.6 ± 0.7%; 60 ± 8mmol/mol; p = 0.009) and at 8 months (7.5 ± 0.6%; 58 ± 7mmol/mol; p = 0.006), but not anymore thereafter (endpoint 24 months: 7.7 ± 0.9%; 61 ± 10mmol/mol; p = 0.2). Time in hypoglycemia did not change over time. QoL for parents and children remained stable. Need for assistance by ambulance due to hypoglycemia reduced from 8 to zero times per 100 patient-years (p = 0.02) and work absenteeism for parents decreased from 411 to 214 days per 100 patient-years (p = 0.03), after 24 months. Conclusion: RT-CGM in pump-treated children/adolescents with T1D showed a temporary improvement in HbA1c in participants with a baseline HbA1c ≥ 7.5%, without increasing time in hypoglycemia. QoL was not affected. Importantly, RT-CGM reduced the need for assistance by ambulance due to hypoglycemia and reduced work absenteeism for parents after 24 months. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT02601729].

Intra-amniotic levothyroxine infusions in a case of fetal goiter due to novel Thyroglobulin gene variants.

Indications and administration of intra-amniotic infusions of L-thyroxine in the context of non-immune fetal hypothyroidism with goiter lack of standardization. Systematic follow-up of clinical features related to thyroid hormonal homeostasis may be useful to evaluate their efficiency and develop standardized management guidelines.