Amnon Zung

Aims/hypothesis: Maternal diabetes confers two opposing risks to fetal growth, resulting in macrosomia in mild cases and intrauterine growth restriction (IUGR) in severe cases. The mechanisms governing these divergent responses are poorly understood, given the intimate regulation of insulin by glucose and insulin’s fetal growth-promoting effects. We hypothesised that the degree of maternal hyperglycaemia dictates a bimodal pattern of fetal insulin secretion that determines fetal growth, and that use of a ketogenic diet (KD) as a nutritional intervention could modify this outcome. Methods: We used the Insulin-rtTA;TET-DTA mouse model to induce preconception diabetes. Dams were stratified based on maternal blood glucose, namely non-diabetes (glucose 16.7 mmol/l), and maintained on either a normal diet or a KD. We assessed fetal growth and plasma C-peptide, performed islet functional assays ex vivo, and characterised changes in plasma metabolites. Fetal pancreases were analysed by immunohistochemistry for beta cell area, proliferation, maturation and mechanistic target of rapamycin complex 1 (mTORC1) activity. Results: Mild maternal diabetes induced fetal macrosomia, driven by beta cell hyperplasia, hyperinsulinaemia and premature beta cell functional maturation, as reflected by glucose-stimulated insulin secretion and upregulated MafA expression. This was associated with strong activation of the mTORC1 pathway. In contrast, severe diabetes caused IUGR associated with reduced beta cell mass and profound functional impairment. The KD had divergent effects: it normalised fetal growth in the mild diabetes group by preventing beta cell proliferation and premature maturation, thereby reducing insulin secretion, but failed to rescue IUGR in the severe diabetes group, despite partially restoring beta cell function. Notably, the KD uncoupled the positive correlation between fetal insulin and body weight, revealing a primary, insulin-independent, growth-restrictive effect. Conclusions/interpretation: Fetal growth in a mouse model of diabetes in pregnancy is governed by a bimodal beta cell response to the maternal glycaemic environment, orchestrated at the molecular level by the mTORC1 pathway. A KD can prevent diabetes-derived macrosomia by reducing beta cell stimulation and through insulin-independent mechanisms, but cannot reverse IUGR, warranting further studies of its role in diabetes during pregnancy.

Context Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, Vital signs, anthropometric measurements and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8^P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients received in the past. Results NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range but elevated liver transaminases were observed. Conclusions In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes.

Objective To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. Research Design and Methods A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. Results During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI,1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI,1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). Conclusions The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Context First-voided urinary LH (FVU-LH) has been suggested as an alternative to gonadotropin-releasing hormone (GnRH) stimulation test for detection of precocious puberty. Objective To evaluate the reproducibility of FVU-LH, its correlation with basal and GnRH-stimulated gonadotropins, and its diagnostic value for differentiating progressive from non-progressive puberty. Design and participants Clinical and endocrine data were obtained from the medical records of 95 girls with suspected progressive puberty who underwent two consecutive FVU-LH tests. In 55 of these participants, GnRH stimulation test was performed close to the FVU-LH test. The reported cutoff levels of 5 IU/L and 1.16 IU/L for GnRH-stimulated LH and FVU-LH, respectively, were used as markers of progressive puberty, clinically defined as bone age advancement of >1 year and/or growth velocity SDS>2, in addition to thelarche. Results The two consecutive measurements of FVU-LH were highly correlated (r= 0.830; p<0.001). The higher of the two results was better correlated with basal gonadotropins and GnRH-stimulated LH. Furthermore, it aligned better with the clinical outcome of girls with early thelarche, which supports the approach of double tests of FVU-LH to distinguish progressive from non-progressive puberty. By comparison to GnRH-stimulated LH, the higher FVU-LH value had better sensitivity (68%), whereas peak LH had better specificity (91%) for the diagnosis of progressive puberty. Both tests had high positive predictive value and poor negative predictive value. Conclusions The higher value of paired FVU-LH tests can be used to screen girls with suspected progressive puberty and can reduce the need for GnRH stimulation test.

Objectives: Recommendations for vitamin D (VitD) intake and target serum levels of 25(OH)D in preterm infants are diverse. We hypothesized that preterm infants with low birth weight (BW) have low dietary intake of VitD and therefore should be supplemented with higher amounts of VitD. Methods: Infants with BW < 2 kg were supplemented with 600 units of VitD a day during the first 2–6 weeks of life, whereas infants with BW>2 kg continued with the routine supplementation of 400 units of VitD daily. Serum levels of 25(OH)D, calcium, phosphorous, alkaline phosphatase (AP) and parathyroid hormone (PTH) were assessed 24 h after birth and before discharge. The total daily intake of vitD was calculated in each infant. Results: Sixty-two infants were enrolled, 49 with BW < 2 kg. After birth, only 24% had sufficient levels of 25(OH)D, whereas before discharge 45 of 54 infants (83%) available for analysis reached sufficient levels of 25(OH)D. All 54 infants demonstrated significant elevation in serum levels of calcium, phosphorous, AP and significant reduction in PTH levels. The total daily intake of VitD was lower than recommended (800–1000 IU/d) in 16 of 45 infants with BW < 2 kg (36%) and in all nine infants with BW>2 kg. Nevertheless, only 2 of 25 infants with insufficient intake of VitD demonstrated insufficient levels of serum 25(OH)D. No case of vitamin D excess was recorded. Conclusions: Increased supplementation of VitD (600 IU/d) for premature newborns with BW < 2 kg is effective in increasing both total daily intake of VitD and serum levels of 25(OH)D.

Objective To assess the clinical and neurological outcomes in newborns with primary congenital hypothyroidism presented with delayed TSH elevation (dTSH), and to define parameters that may predict the evolution of transient vs. permanent hypothyroidism in these newborns. Design and patients An observational study was performed of a cohort of 113 children with a history of dTSH. Measurements Birth parameters, thyroid screening results, thyroid gland imaging, levothyroxine dose and neurological outcome were compared between newborns with spontaneous recovery and children with a final diagnosis of either transient or permanent hypothyroidism. Results Of the children with a history of dTSH, 93% demonstrated recovery, either spontaneously or following levothyroxine treatment (transient hypothyroidism). Newborns with spontaneous recovery demonstrated milder thyroid dysfunction at the newborn screening compared to those who started levothyroxine treatment. Levothyroxine dose was lower in children with transient vs. permanent hypothyroidism only during the first 6 months of life; otherwise, these groups were similar in birth parameters, thyroid screening results and gland images. Seventeen out of 61 children (28%) that underwent neurological assessment demonstrated a developmental delay. Duration of treatment was highly variable in children with transient hypothyroidism. Conclusions Thyroid dysfunction is transient in most cases of dTSH. No reliable parameters can predict a priori transient vs. permanent hypothyroidism.

Background The global rise in incidence of type 1 diabetes (T1D) is too rapid to be attributed to susceptible genetic background, pinpointing a significant role for environmental factors. Unlike the theory that the need for genetic susceptibility has lessened over time, we hypothesized that the rise in T1D incidence is faster in a genetically susceptible population. Subjects and methods The study population comprised of 5080 patients aged 0 to 17 years who were reported to the National Israel Diabetes Registry between 1997 and 2014. The patients were divided into familial cases (first-degree relative has T1D), and sporadic cases. Demographic and clinical data were retrieved from the registry. The change in annual percent (from the entire cohort) was computed separately for the sporadic and familial cohorts. Results The familial (n = 546; 10.7%) and sporadic (n = 4534; 89.3%) cases were comparable for gender, ethnicity, and age at diagnosis. Consanguinity was more common in the familial vs sporadic group (10% vs 6.1%; P = .001). The average annual percent change increased by 1.9% in the familial cases and decreased by 0.2% in the sporadic cases (P = .04). Conclusions The rapid rise in the proportion of familial cases of T1D suggests that environmental factors impose higher diabetogenic pressure in patients with a susceptible genetic background.

Context: Delayed thyrotropin (TSH) elevation (dTSH) is defined as elevated TSH at the second neonatal screening (after normal TSH levels at the initial screening) in premature, low-birth-weight, and ill newborns, mostly in the neonatal intensive care unit (NICU) setting. The pathogenesis of dTSH is elusive. Objective: To identify the risk factors for dTSH development among newborns in the NICU. Design, Setting, and Patients: A retrospective medical record review of neonates with dTSH was conducted in eight university-affiliated NICUs. Two controls were selected for each patient, matched for sex and birth weight. The risk factors for dTSH were identified by univariate analysis, followed by multivariate analysis. Main Outcome Measures: Maternal variables, types of NICU treatments and procedures, syndromes, and various medical conditions were compared between dTSH patients and their matched controls. Results: We enrolled 100 dTSH patients and 200 matched controls and 46 variables were compared between the two groups. Twelve risk factors for dTSH were identified on univariate analysis: cesarean section, mechanical ventilation, patent ductus arteriosus (PDA), pneumothorax, and administration of cefotaxime, vancomycin, fluconazole, dopamine, ibuprofen, furosemide, insulin, and packed red blood cells. On multivariate analysis, four risk factors were identified: PDA and vancomycin, insulin, and furosemide administration. In 26 twin pairs, in which one twin had dTSH, all variables presented similarly in both twins. Conclusions: Although some variables had direct effects on pituitary–thyroid axis dysfunction, these variables, altogether, reflect the severity of the clinical conditions in the NICU, which is the common basis for dTSH.