Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings. To inform this monitoring, JDRF, in conjunction with international experts and societies, developed consensus guidance. Broad advice from this guidance includes the following: 1) partnerships should be fostered between endocrinologists and primary care providers to care for people who are IAb+; 2) when people who are IAb+ are initially identified, there is a need for confirmation using a second sample; 3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; 4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; 5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and 6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care.

Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

Nondisclosure of Type 1 Diabetes in Adolescence: A Single-Center Experience.

Objective: The aim of this study was to assess the extent of nondisclosure of type 1 diabetes in adolescents and investigate its association with several psychosocial parameters and clinical outcomes. Research design and methods: This was a cross-sectional study based on data collected from 69 adolescents with type 1 diabetes who were 12-18 years of age and followed at our diabetes clinic. The degree of disclosure, demographics, diabetes management, and psychosocial issues were assessed via questionnaires. Clinical parameters were derived from medical records. Associations between nondisclosure status and clinical and psychosocial study variables were assessed. Results: Fifty-three participants (77%) reported some extent of nondisclosure. Nondisclosure was associated with low self-esteem, reduced friend support, and increased diabetes-related worries. Nondisclosure was also found to be associated with diminished self-care behaviors related to insulin administration and with elevated A1C. Conclusion: Our results demonstrate that nondisclosure of type 1 diabetes in adolescents may be more common than initially recognized and is likely associated with unfavorable psychological outcomes and reduced self-care and diabetes management. Our results emphasize the importance of social interactions and disclosure in adolescents and may serve as a potential stepping stone to address other social barriers hindering diabetes management.

Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study.

Objectives: To investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings. Methods: This case-control study, conducted at the Schneider Children's Medical Center's Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation. Results: Fecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (p<0.001). ISS children with higher levels of Methanobrevibacter, the dominant species in the archaeal gut community, were significantly shorter in stature than those with lower levels (p=0.022). Mice receiving fecal transplants from ISS children did not experience stunted growth, probably due to the eradication of Methanobrevibacter caused by exposure to oxygen during fecal collection. Discussion: Our findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS.

Disordered Eating Behaviors Among Adolescents and Young Adults with Type 1 Diabetes Treated with Insulin Pumps and Hybrid Closed-Loop Systems.

Background and Aims: Disordered eating behaviors (DEB) are more common among individuals with type 1 diabetes (T1D) compared to those without, and for insulin pump users may be associated with higher hemoglobin A1c (HbA1c). We investigated DEB risk factors among insulin pump-treated individuals with T1D and clinical characteristics of hybrid closed-loop (HCL) systems' users by DEB level. Methods: An observational, cross-sectional study of 167 insulin pump-treated individuals with T1D, 13-21 years of age. Data were obtained from patients' medical charts with additional self-reported questionnaires, including assessment of DEB. Results: DEB were found in 71 (42.5%) individuals, and positively associated with female sex (ß = 2.98 [standard error (SE) = 1.31], P = 0.025), body mass index (BMI)-Z-score (ß = 2.12 [SE = 0.64], P = 0.001), HbA1c (ß = 1.40 [SE = 0.45], P = 0.02), and higher rate of pump discontinuation (ß = 4.48 [SE = 1.99], P = 0.026). The use of HCL systems compared to insulin pumps was associated with higher BMI-Z-score (odds ratio [OR]: 3.46 [95% confidence interval, CI: 1.52-7.87], P = 0.003) and tendency to lower HbA1c level (OR: 0.44 [95% CI: 0.18-1.09], P = 0.078) among individuals without DEB, and with lower HbA1c level (OR: 0.29 [95% CI: 0.10-0.83], P = 0.022) and higher socioeconomic status (OR: 1.73 [95% CI: 1.09-2.74], P = 0.020) among individuals with DEB. Conclusions: DEB are common among individuals with T1D treated with insulin pumps and are associated with higher HbA1c levels. Among T1D individuals with DEB, HCL system use is associated with lower HbA1c compared to insulin pump treatment. Our findings highlight the importance of regular screening for DEB and its risk factors to improve pump treatment and diabetes management. Moreover, individuals with DEB using HCL systems may benefit from reduced HbA1c levels.

Clinical and immunological characteristics of children diagnosed with-Type 1 diabetes during the COVID-19 pandemic.

AIMS: To find clinical and immunological signatures of the SARS-CoV-2 and the COVID-19 pandemic on children newly diagnosed with type 1 diabetes (T1D). METHODS: A single-centre, retrospective, observational study comparing the clinical and immunological characteristics of children diagnosed with T1D the year before and during the first 2 years of the COVID-19 pandemic. Data extracted from the medical records included clinical and demographic parameters, COVID-19 PCR results and the presence of anti-islet, thyroid and celiac-related antibodies. Also obtained from the medical records was a family history of T1D, celiac disease and autoimmune thyroid disease in a first-degree family member. RESULTS: A total of 376 children were diagnosed with T1D during the study period. A total of 132 in the pre-COVID era and 246 in the first 2 years of the pandemic. At diagnosis, the pH in children with DKA was lower, and HbA1c tended to be higher in the COVID-19 group compared to the pre-COVID-19 group (7.30 [7.18, 7.35] vs 7.33 [7.19, 7.36], p = 0.046) and (110.9 [86.9, 129.5] vs 100 [80.3, 129.5], p = 0.067]) respectively. Multiple islet antibodies (IA) were significantly more common among patients in the pre-COVID-19 group compared to the COVID-19 group (72% vs 61%, p = 0.032). Tissue transglutaminase antibodies were more common among children diagnosed in the COVID-19 compared to the pre-COVID group (16.6% vs 7.9%, p = 0.022). CONCLUSIONS: Our findings suggest that SARS-CoV-2 and the environmental alterations caused by the pandemic affected the clinical characteristics and the immunological profile of children diagnosed with T1D. It is, therefore, plausible that the virus plays a role in the autoimmune process causing T1D.

Gonadotropin-releasing hormone analogs treatment in girls with central precocious puberty and early fast puberty.

BACKGROUND: Gonadotropin-releasing hormone analog (GnRHa) is the standard treatment for children with central precocious puberty (CPP). We assessed efficacy and safety of GnRHa treatment in girls with CPP and early fast puberty (EFP). METHODS: This retrospective observational study included anthropometric, clinical and laboratory data retrieved from medical files of girls with CPP or EFP, treated with GnRHa and followed at a tertiary endocrine clinic during 2007-2021. RESULTS: For both CPP (n = 144) and EFP (n = 231) groups, mean height-SDS at GnRHa initiation and termination and at the last follow-up visit was greater than mid-parental height-SDS (P < 0.001). Only among girls with EFP, mean BMI-SDS was higher at treatment termination than initiation (P = 0.025). Median ages at menarche of the CPP and EFP groups were 11.8 and 12.0 years. Menstrual irregularities were reported in 20.3% of girls with CPP and in 18.7% of those with EFP. Adverse effects to treatment were reported in 3.5% and 3.9% of girls with CPP and EFP, respectively. CONCLUSIONS: In this large cohort, GnRHa treatment in girls with EFP was effective without significant adverse effects as in those with CPP. A randomized controlled trial is required to examine the psychological impact of GnRHa treatment of variant early puberty. IMPACT STATEMENT: Gonadotropin-releasing hormone analog (GnRHa) is the standard treatment for central precocious puberty (CPP). We assessed efficacy and safety of GnRHa treatment in girls with early fast puberty (EFP), characterized by pubertal signs between ages 8-9 years with fast pubertal signs advancement and accelerated growth and bone maturation and in girls with CPP. We found in this large cohort that GnRHa treatment in girls with EFP was effective and safe as in those with CPP. A prospective randomized controlled trial is required to examine the psychological impact of GnRHa treatment of variant early puberty.

Hypoglycemia in Children Referred to a Tertiary Care Pediatric Endocrine Clinic: Age-Dependent Etiological Variations.

INTRODUCTION: Diagnosing hypoglycemia in infants and children presents significant challenges. Our objective was to elucidate the diagnoses and clinical features of children with hypoglycemia referred to a pediatric endocrine tertiary clinic. METHODS: Retrospective study of 154 children (0-18 years old) presenting with hypoglycemia, during 1992-2018. RESULTS: The cohort was divided by clinical diagnosis into six groups: ketotic hypoglycemia (n=45, 29.2%), congenital hyperinsulinemic hypoglycemia (n=35, 22.7%), transient hyperinsulinemic hypoglycemia (n=28, 18.2%), metabolic disorder (n=14, 9.1%), systemic disease/syndrome (n=15, 9.7%), and hormone deficiencies (n=8, 5.2%). Two patients had insulinoma and in 7 (4.5%) no diagnosis was elucidated. At diagnosis, 58 (37.7%) were <1 month old, 23 (14.9%) aged 1-12 months, 58 (37.7%) aged 1-6 years, and 15 (9.7%) aged 6-18 years. Hypoglycemia etiology varied among neonates, infants, and children. In eight patients hypoglycemia was asymptomatic. Of 47 patients who completed a diagnostic fast, 31 became hypoglycemic, yet a significant added value for diagnosis was only found in 14 (29.8%) patients. CONCLUSIONS: Hypoglycemia etiology in children is heterogeneous and varies by age. Any hypoglycemia measured in a child should be seriously evaluated as 7% are asymptomatic. Work-up should be tailored based on age, and clinical, biochemical, and imaging findings. Despite extensive work-up, in a significant number of patients the mechanism underlying pediatric hypoglycemia remains an enigma. This emphasizes the unmet needs and challenges in studying pediatric hypoglycemia.

Ubiquitin Proteasome System Role in Diabetes-Induced Cardiomyopathy.

This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart complications. db/db mice heart tissues were compared with WT mice tissues using RNA sequencing, qRT-PCR, and protein analysis to identify cardiac UPS modifications associated with diabetes. The findings unveiled a distinctive gene profile in the hearts of db/db mice with decreased levels of nppb mRNA and increased levels of Myh7, indicating potential cardiac dysfunction. The mRNA levels of USP18 (deubiquitinating enzyme), PSMB8, and PSMB9 (proteasome ß-subunits) were down-regulated in db/db mice, while the mRNA levels of RNF167 (E3 ligase) were increased. Corresponding LMP2 and LMP7 proteins were down-regulated in db/db mice, and RNF167 was elevated in Adult diabetic mice. The reduced expression of LMP2 and LMP7, along with increased RNF167 expression, may contribute to the future cardiac deterioration commonly observed in diabetes. This study enhances our understanding of UPS imbalances in the hearts of diabetic mice and raises questions about the interplay between the UPS and other cellular processes, such as autophagy. Further exploration in this area could provide valuable insights into the mechanisms underlying diabetic heart complications and potential therapeutic targets.

Disordered eating behaviours in adolescents with type 1 diabetes can be influenced by their weight at diagnosis and rapid weight gain subsequently.

AIMS: To assess the prevalence and disease-related risk factors for disordered eating behaviours among adolescents with type 1 diabetes and also to search for risk factors at disease diagnosis that can predict the development of disordered eating behaviours. METHODS: A retrospective observational study of 291 adolescents aged 15-19 years with type 1 diabetes who completed the Diabetes Eating Problem Survey-Revised (DEPS-R) as is routine in our diabetes clinic. The prevalence of disordered eating behaviours and risk factors for their development was assessed. RESULTS: In 84 (28.9%) adolescents, disordered eating behaviours were found. Disordered eating behaviours were positively associated with female sex (ß = 3.01 [SE = 0.97], p = 0.002), higher BMI-Z score (ß = 2.08 [SE = 0.49], p < 0.001), higher HbA1c (ß = 0.19 [SE = 0.03], p < 0.001) and treatment with multiple daily injections of insulin (ß = 2.19 [SE = 1.02], p = 0.032). At type 1 diabetes diagnosis, higher BMI-Z score (ß = 1.54 [SE = 0.63], p = 0.016) for those diagnosed before age 13 years and increased weight gain at 3 months post-diagnosis (ß = 0.88 [SE = 0.25], p = 0.001) in females diagnosed at age 13 years or older were found to be risk factors for disordered eating behaviours. CONCLUSIONS: Disordered eating behaviours are common among adolescents with type 1 diabetes and are associated with various parameters, including BMI at diagnosis and the rate of weight gain at 3 months post-diagnosis in females. Our findings highlight the need for early preventive efforts for disordered eating behaviours and interventions to avoid late diabetes complications.

A Whey-Based Diet Can Ameliorate the Effects of LPS-Induced Growth Attenuation in Young Rats.

Chronic inflammation in childhood is associated with impaired growth. In the current study, a lipopolysaccharide (LPS) model of inflammation in young rats was used to study the efficacy of whey-based as compared to soy-based diets to ameliorate growth attenuation. Young rats were injected with LPS and fed normal chow or diets containing whey or soy as the sole protein source during treatment, or during the recovery period in a separate set of experiments. The body and spleen weight, food consumption, humerus length, and EGP height and structure were evaluated. Inflammatory markers in the spleen and markers of differentiation in the EGP were assessed using qPCR. The LPS led to a significant increase in the spleen weight and a decrease in the EGP height. Whey, but not soy, protected the animals from both effects. In the recovery model, whey led to increased EGP height at both 3 and 16 d post treatment. The most affected region in the EGP was the hypertrophic zone (HZ), which was significantly shortened by the LPS treatment but enlarged by whey. In conclusion, LPS affected the spleen weight and EGP height and had a specific effect on the HZ. Nutrition with whey protein appeared to protect the rats from the LPS-induced growth attenuation.

Fear of hyperglycaemia in parents of children with type 1 diabetes mellitus - A multi-centre multinational study.

AIMS: Study aims: (1) developing and validating a novel questionnaire for measuring fear of hyperglycaemia among parents of children with type 1 diabetes (T1D) - the Hyperglycaemia Fear Survey - Parent version (FoHyper-P); (2) investigating correlations between parental fear of hyperglycaemia and objective measures of glycaemic control. METHODS: A multi-centre, multinational study of 152 parents of children with T1D was conducted in three large diabetes clinics from Israel, Poland, and Greece. Inclusion criteria were parents of children aged 6-16 years, at least 6 months from diagnosis, at least 3 months of CGM use and parental involvement in care. Parents filled the FoHyper-P and the Hypoglycaemia Fear Survey - Parent Version (HFS-P). Patient data were obtained via electronic medical records and informative questionnaires. Bonferroni correction was performed to counteract multiple comparisons. RESULTS: Significant strong-moderate correlations were found between FoHyper-P and HFS-P including total questionnaires scoring (r = 0.747, pBonf < 0.001), worries subscales (r = 0.735, pBonf <0.001), and behaviour subscales (r = 0.532, pBonf <0.001). Using linear regression models, we found a positive association between the worry subscale and HbA1C. Weak correlations (p < 0.05, not significant after Bonferroni correction) were found between time in range, time above range and parental fear of hyperglycaemia as well as between worry subscales and a higher HbA1C in the past year, percent of hyperglycaemia and lower TIR. CONCLUSIONS: The FoHyper-P is a novel, validated tool for assessing parental fear of hyperglycaemia. Integrating it into clinical practice addresses an underestimated aspect of parental diabetes management, enabling better care for children with T1D.

The Physiology and Mechanisms of Growth.

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Compromised Adult Height in Females with Non-Classical Congenital Adrenal Hyperplasia Diagnosed in Childhood.

INTRODUCTION: Data on adult height (AHt) in individuals with non-classical congenital adrenal hyperplasia (NCCAH) are inconsistent. METHODS: We conducted a retrospective study of 109 females diagnosed with NCCAH at age <18 years who reached AHt. We studied AHt compared to target height (THt) and the correlation of AHt with clinical parameters. RESULTS: The mean age at diagnosis was 9.7 ± 4.4 years; the mean follow-up was 10.9 ± 6.3 years. Hydrocortisone treatment (11.0 ± 5.0 mg/m2) was initiated at age 9.7 ± 4.0 years. Bone age was more advanced in girls who presented with central precocious puberty or early puberty (CPP/EP) (n = 43) than with timely puberty. AHt-standard deviation score (SDS) was lower than Ht-SDS at diagnosis (-0.8 ± 1.0 vs. +0.2 ± 1.3; p < 0.001) and -0.3 SDS shorter than THt (p < 0.001). Height, weight, and body mass index-SDS at last visits were similar between patients treated with glucocorticoids (n = 92) and those never treated (n = 17). AHt was comparable between patients with timely puberty and with CPP/EP, with no difference between those treated or not by GnRH analogue. AHt was similar between patients who were fully pubertal (Tanner 5), pre-pubertal (Tanner 1), and pubertal (Tanner 2-4) at diagnosis (158.0 ± 7.6, 158.1 ± 6.1, and 157.5 ± 6.5, respectively; p = 0.9). AHt-SDS was correlated with THt (R = 0.67, p < 0.001) and Ht-SDS at diagnosis (R = 0.7, p < 0.001) but not with age at diagnosis (R = -0.05, p = 0.6), the extent of bone age advancement (R = -0.04, p = 0.72), glucocorticoid treatment duration (R = -0.11, p = 0.34), or dose (R = -0.04, p = 0.70). CONCLUSION: AHt of females diagnosed with NCCAH in childhood was lower than their THt. Glucocorticoid treatment duration and dose, pubertal status at diagnosis, and having CPP or EP were not correlated with AHt.