Fertility preservation for female patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.

Comparison of cardiovascular risk factors between children and adolescents with classes III and IV obesity: findings from the APV cohort.

OBJECTIVE: Obesity is associated with many cardiovascular risk factors (CVRF) in childhood. There is an ongoing discussion whether there is a linear relationship between degree of overweight and deterioration of CVRFs justifying body mass index (BMI) cut-offs for treatment decisions. METHODS: We studied the impact of BMI-SDS on blood pressure, lipids, and glucose metabolism in 76,660 children (aged 5-25 years) subdivided in five groups: overweight (BMI-SDS 1.3 to <1.8), obesity class I (BMI-SDS 1.8 to <2.3), class II (BMI-SDS 2.3-2.8), class III (BMI-SDS > 2.8-3.3), and class IV (BMI-SDS > 3.3). Analyses were stratified by age and sex. RESULTS: We found a relationship between BMI-SDS and blood pressure, triglycerides, HDL cholesterol, liver enzymes, and the triglycerides-HDL-cholesterol ratio at any age and sex. Many of these associations lost significance when comparing children with obesity classes III and IV: In females < 14 years and males < 12 years triglycerides and glucose parameters did not differ significantly between classes IV and III obesity. Prevalence of dyslipidemia was significantly higher in class IV compared to class III obesity only in females ≥ 14 years and males ≥ 12 years but not in younger children. In girls < 14 years and in boys of any age, the prevalences of type 2 diabetes mellitus did not differ between classes III and IV obesity. CONCLUSIONS: Since a BMI above the highest BMI cut-off was not associated consistently with dyslipidemia and disturbed glucose metabolism in every age group both in boys and girls, measurements of CVRFs instead of BMI cut-off seem preferable to guide different treatment approaches in obesity such as medications or bariatric surgery.

Serum IGF1 and linear growth in children with congenital leptin deficiency before and after leptin substitution.

BACKGROUND: Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD). METHODS: In this cohort study we included eight pediatric patients (six males), age 0.9-14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin. RESULTS: All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS[Formula: see text]T0: -1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS[Formula: see text]T0: -1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆T0-12: 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDST0-12: 0.57 ± 0.06, p = 0.003) despite substantial weight loss. CONCLUSIONS: These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.

Trajectories of Body Mass Index from Childhood to Young Adulthood among Patients with Type 1 Diabetes-A Longitudinal Group-Based Modeling Approach Based on the DPV Registry.

OBJECTIVE: To identify distinct longitudinal patterns of body mass index (BMI) z score in type 1 diabetes from childhood to young adulthood and secondly to determine sex differences as well as associated clinical covariates. STUDY DESIGN: A total of 5665 patients with type 1 diabetes (51% male) with follow-up from 8 to 20 years of age from the multicenter diabetes prospective registry DPV were studied (baseline diabetes duration ≥1 years, BMI z score aggregated per year of life). Latent class growth modeling (SAS: PROC TRAJ) was applied to analyze BMI z score over time. RESULTS: Six distinct BMI z score trajectories were identified (group 1: 7% of patients, group 2: 22%, group 3: 20%, group 4: 16%, group 5: 25%, and group 6: 10%). Group 1, 2, 5, and 6 had an almost stable BMI z score, either in the low, near-normal, high stable, or chronic overweight range. Group 3 (60% girls) increased their BMI during puberty, whereas group 4 (65% boys) had a BMI decrease. Similar patterns were observed for girls only, whereas boys followed nearly stable trajectories without fluctuation over time. Between the near-normal and the other groups, significant differences (P < .05) in sex ratio, migration background, mental health, height z score, glycated hemoglobin A1c, diabetes treatment, dyslipidemia, hypertension, and smoking were observed. CONCLUSIONS: In youth with type 1 diabetes, a great heterogeneity of BMI z score trajectories exists that highlight the importance of personalized sex-specific intervention programs for subjects at risk for unfavorable BMI development.

Sleep and glycemic control in adolescents with type 1 diabetes.

BACKGROUND: Increasing evidence link sleep curtailment and circadian misalignment with adverse metabolic outcome. Adolescents might be most affected, given their late sleep timing and early school and work start times. OBJECTIVE: Our aim was to examine the impact of poor sleeping habits on glycemic control in adolescents with type 1 diabetes. SUBJECTS AND METHODS: This was a non-interventional multicenter study across Germany recruiting pubertally mature adolescents with type 1 diabetes. Medical records were used to collect information on diabetes duration, treatment, and complications. Participants self-reported sleep quality, timing, chronotype, and social jetlag-a measure of circadian misalignment. Hemoglobin A1c (HbA1c) was determined at the time of questionnaire response. We used multivariable linear regression models to examine associations between sleep and glycemic control. RESULTS: A total of 191 patients aged 16.5 years (mean HbA1c 8.0% [64 mmol/mol]) were included in this study. In multivariable adjusted analyses, sleep quality was significantly associated with HbA1c (mean difference; ß = -0.07, P = .05). Stratified analysis indicated that this association might be stronger in boys and also in children with migration background. In contrast, neither sleep duration, sleep debt, chronotype, nor social jetlag was associated with HbA1c . Secondary analyses showed that social jetlag was significantly associated with levels of insulin requirements (mean difference; ß = 0.035, P = .03). CONCLUSIONS: Our study suggests that poor sleep quality is associated with increased HbA1c in adolescents with type 1 diabetes and that higher levels of circadian misalignment are associated with increased insulin requirements. If replicated, our results indicate a clinical relevance of sleep habits in adolescents with type 1 diabetes.

Low association between fasting and OGTT stimulated glucose levels with HbA1c in overweight children and adolescents.

BACKGROUND: Diabetes and prediabetes are defined based on different methods such as fasting glucose, glucose at 2-hour in oral glucose tolerance test (OGTT), and glycated hemoglobin A1c (HbA1c). These parameters probably describe different deteriorations in glucose metabolism limiting the exchange between each other in definitions of diabetes. OBJECTIVE: To investigate the relationship between OGTT and HbA1c in overweight and obese children and adolescents living in Germany. METHODS: Study population: Overweight and obese children and adolescents (n = 4848; 2668 female) aged 7 to 17 years without known diabetes. The study population was stratified into the following subgroups: normal glucose tolerance, prediabetes, diabetes according to OGTT and/or HbA1c categories, confirmed diagnosis of diabetes. RESULTS: In the entire study group fasting plasma glucose (FPG) correlated weakly to 2-hour glucose (r = 0.26), FPG correlated weakly to HbA1c (r = 0.18), and 2-hour glucose correlated weakly to HbA1c (r = 0.17, all P < .001). Patients with confirmed diabetes showed a very high correlation between FPG and 2-hour glucose (r = 0.73, n = 50). Moderate correlations could be found for patients with impaired fasting glucose (2-hour glucose vs HbA1c: r = 0.30, n = 436), for patients with diabetes according to OGTT and/or HbA1c (FPG vs 2-hour glucose: r = 0.43; 2-hour glucose vs HbA1c: r = -0.30, n = 115) and for patients with confirmed diabetes (2-hour glucose vs HbA1c: r = -0.47, all P < .001). CONCLUSIONS: Because FPG, 2-hour glucose, and HbA1c correlated only weakly we propose that these parameters, particularly in the normal range, might reflect distinct aspects of carbohydrate metabolism.

Diabetes screening in overweight and obese children and adolescents: choosing the right test.

Type 2 diabetes can occur without any symptoms, and health problems associated with the disease are serious. Screening tests allowing an early diagnosis are desirable. However, optimal screening tests for diabetes in obese youth are discussed controversially. We performed an observational multicenter analysis including 4848 (2668 female) overweight and obese children aged 7 to 17 years without previously known diabetes. Using HbA1c and OGTT as diagnostic criteria, 2.4% (n = 115, 55 female) could be classified as having diabetes. Within this group, 68.7% had HbA1c levels ≥48 mmol/mol (≥6.5%). FPG ≥126 mg/dl (≥7.0 mmol/l) and/or 2-h glucose levels ≥200 mg/dl (≥11.1 mmol/l) were found in 46.1%. Out of the 115 cases fulfilling the OGTT and/or HbA1c criteria for diabetes, diabetes was confirmed in 43.5%. For FPG, the ROC analysis revealed an optimal threshold of 98 mg/dl (5.4 mmol/l) (sensitivity 70%, specificity 88%). For HbA1c, the best cut-off value was 42 mmol/mol (6.0%) (sensitivity 94%, specificity 93%). CONCLUSIONS: HbA1c seems to be more reliable than OGTT for diabetes screening in overweight and obese children and adolescents. The optimal HbA1c threshold for identifying patients with diabetes was found to be 42 mmol/mol (6.0%). What is Known: • The prevalence of obesity is increasing and health problems related to type 2 DM can be serious. However, an optimal screening test for diabetes in obese youth seems to be controversial in the literature. What is New: • In our study, the ROC analysis revealed for FPG an optimal threshold of 98 mg/dl (5.4 mmol/l, sensitivity 70%, specificity 88%) and for HbA1c a best cut-off value of 42 mmol/mol (6.0%, sensitivity 94%, specificity 93%) to detect diabetes. Thus, in overweight and obese children and adolescents, HbA1c seems to be a more reliable screening tool than OGTT.

Mild Hypothermia in a Child with Low-Dose Risperidone.

Risperidone is a widely used, second-generation antipsychotic approved for treating schizophrenia as well as for treating aggression in children and adolescents with mental retardation. The substance has a well-established risk profile including alterations of body temperature. Apart from hyperthermia with and without full-blown malignant neuroleptic syndrome, low body temperatures (hypothermia) have also been reported anecdotally, usually appearing in the context of comedication. Here, we report a case of hypothermia associated with a low-dose risperidone monotherapy in a child.

Prehepatic secretion and disposal of insulin in obese adolescents as estimated by three-hour, eight-sample oral glucose tolerance tests.

The body compensates for early-stage insulin resistance by increasing insulin secretion. A reliable and easy-to-use mathematical assessment of insulin secretion and disposal could be a valuable tool for identifying patients at risk for the development of type 2 diabetes. Because the pathophysiology of insulin resistance is incompletely understood, assessing insulin metabolism with minimal assumptions regarding its metabolic regulation is a major challenge. To assess insulin secretion and indexes of insulin disposal, our marginalized and regularized absorption approach (MRA) was applied to a sparse sampling oral glucose tolerance test (OGTT) protocol measuring the insulin and C-peptide concentrations. Identifiability and potential bias of metabolic parameters were estimated from published data with dense sampling. The MRA was applied to OGTT data from 135 obese adolescents to demonstrate its clinical applicability. Individual prehepatic basal and dynamic insulin secretion and clearance levels were determined with a precision and accuracy greater than 10% of the nominal value. The intersubject variability in these parameters was approximately four times higher than the intrasubject variability, and there was a strong negative correlation between prehepatic secretion and plasma clearance of insulin. MRA-based analysis provides reliable estimates of insulin secretion and clearance, thereby enabling detailed glucose homeostasis characterization based on restricted datasets that are obtainable during routine patient care.

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.

A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

Depression, metabolic control, and antidepressant medication in young patients with type 1 diabetes.

OBJECTIVE: Recent literature suggests an association between type 1 diabetes (T1D) and depression. So far, most studies explored this link in adult populations, with few data being available on diabetes and depression from minors and young adults. This study aimed to look for associations between symptoms of depression/antidepressant treatment and metabolic outcomes of T1D. METHODS: We conducted an observational study using the German diabetes database (Diabetes-Patienten-Verlaufsdokumentation--DPV) and searched for patients up to the age of 25 yr, with depressive symptoms and/or receiving antidepressant medication. RESULTS: Of 53 986 T1D patients below the age of 25 yr, antidepressant medication and/or depressive symptoms were reported in 419 (0.78%). After adjustment for age, gender, diabetes duration and center heterogeneity, minors and young adults with depressive symptoms showed worse outcome parameters such as a higher rate of severe hypoglycemia (0.56 vs. 0.20/patient year, p = 0.005) and more episodes of diabetic ketoacidosis (0.20 vs. 0.07/patient year, p < 0.001). Hemoglobin A1c (HbA1c) was higher in the depression group (74.50 vs. 67.58 mmol/mol, p < 0.001) and young patients with T1D and depression showed longer duration of inpatient treatment (7.04 vs. 3.10 hospital days/patient year, p < 0.001) and more frequent admissions to hospital care (0.63 vs. 0.32/patient year, p < 0.001). Antidepressant medication was recorded in 52.3% of the depressed patients, with selective serotonin reuptake inhibitors (SSRIs) being the most widely described class of antidepressants (29.1%). CONCLUSIONS: Our findings demonstrate an adverse treatment outcome for young patients with T1D and comorbid depressive symptoms underlining an urgent need for collaborative mental and somatic health care for patients with T1D and depression.

Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common disorders of the liver worldwide. Recently, a correlation between thyroid dysfunction and NAFLD has been discussed. Objective of the present study was to investigate the association between thyroid dysfunction and hepatic steatosis. METHODS: Data from 2,445 subjects (51.7% females) aged 18 to 65 years participating in a population-based cross-sectional study were assessed based on a standardized questionnaire and documentation of physical, biochemical and ultrasonographic findings. After application of exclusion criteria, a total of 1,276 subjects were included in the study collective. The influence of potential factors on the development of hepatic steatosis was assessed using multivariate logistic regression. RESULTS: The prevalence of hepatic steatosis in the study collective was 27.4% (n = 349). The serum thyroxin (TT4) concentration in subjects with hepatic steatosis was reduced (p =0.0004). Adjusting for age, or BMI, there was an increased prevalence of hepatic steatosis in subjects with reduced TT4 concentrations (p = 0.0143; p = < .0001). CONCLUSIONS: The findings of the present study confirm an association between both subclinical and clinical hypothyroidism and hepatic steatosis.

Effectiveness of structured, multidisciplinary long-term care for pediatric cancer survivors: protocol of the multicenter, randomized-controlled AELKI study.

BACKGROUND: In Germany, around 2.250 children and adolescents are diagnosed with cancer each year. Despite generally positive long-term survival rates, many patients must cope with late effects of the disease and its treatment. This highlights the need for a well-structured, long-term approach addressing both physical and mental health issues. Currently, the German healthcare system lacks such comprehensive structures. Our study aims to evaluate the effectiveness of a structured, multidisciplinary long-term approach compared to conventional "treatment as usual" (TAU). METHODS: A prospective, multicenter study with ten pediatric university clinics in Germany will be conducted. The cluster-randomization takes place at the clinic level. Children and adolescents who completed their cancer treatment at least five years ago and their parents will be eligible to participate. While the control group (CG) receives TAU, the intervention group (IG) participates in a structured program. This program includes risk-based medical treatment and psychosocial interventions tailored to each patient's individual needs within a two-month timeframe. The primary outcome is the improvement of self-efficacy. Secondary outcomes are satisfaction with health care, improvement of health-related quality of life (HRQoL), reduction of mental health problems, and improvement of transition readiness. DISCUSSION: This approach has the potential to optimize the health care for individuals who survived cancer during childhood or adolescence. It addresses the challenges of overuse, underuse, and misuse of health care resources. By considering both medical and psychosocial factors and promoting increased self-efficacy, independent from parental involvement, it may facilitate a smoother transition to adult medicine and enhance adherence to lifelong aftercare. If proven successful, this approach will contribute to the integration of multidisciplinary strategies into standard healthcare practice. TRIAL REGISTRATION: German Clinical Trials Register DRKS00029269. Registered on December 23, 2022.

Estimation of parameters for the elimination of an orally administered test substance with unknown absorption.

Assessment of the elimination of an oral test dose based on plasma concentration values requires correction for the effect of gastric release and absorption. Irregular uptake processes should be described 'model independently', which requires estimation of a large number of absorption parameters. To limit the associated computational effort a new approach is developed with a reduced number of unknown parameters. A marginalized and regularized absorption approach (MRA) is defined, which uses for the uptake just one parameter to control rigidity of the uptake curve. For validation, elimination and absorption were reproduced using published IVIVC data and a synthetic data set for comparison with approaches using a 'model-free'--staircase function or mechanistic models to describe absorption. MRA performed almost as accurate as well specified mechanistic models, which gave the best reproduction. MRA demonstrated a 50fold increase in computational efficiency compared to other approaches. The absorption estimated for the IVIVC study demonstrated an in vivo-in vitro correlation comparable to published values. The newly developed MRA approach can be used to efficiently and accurately estimate elimination and absorption with a restricted number of adaptive parameters and with automatic adjustment of the complexity of the uptake.

Could setmelanotide be the game-changer for acquired hypothalamic obesity?

Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health problems and premature mortality. Treatment for acquired hypothalamic obesity has thus far been disappointing. Several interventions were reported to be partially successful, including dextro-amphetamine and GLP-1R agonists, although results in acquired hypothalamic obesity are conflicting. Disruption of signaling through the melanocortin-4 receptor (MC4R) pathway results in hyperphagia and severe early-onset hypothalamic obesity. Recently, the MC4R agonist setmelanotide has shown promising results in children with genetic forms of hypothalamic obesity; POMC, PCSK1 and LEPR. Patient quotes such as "we have our family life back" illustrate the magnitude of the effect. Targeted hormone replacement therapy with a MC4R agonist for acquired hypothalamic obesity could be a game-changer. Preliminary results of setmelanotide treatment in 14, mostly pediatric, patients with acquired hypothalamic obesity are promising. The FDA has recommended that a prospective, randomized, blinded trial be conducted over a 12 months treatment period, comparable to pivotal trials for other obesity drugs. It may be discussed whether setmelanotide should be regarded as an obesity drug or whether it may be envisioned as an agent for hypothalamic substitution therapy. In this commentary we discuss the trial that is currently recruiting patients with acquired hypothalamic obesity.

Spectrum of diabetes mellitus in patients with Shwachman-Diamond syndrome: case report and review of the literature.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare congenital disorder caused by mutations in the SBDS gene and characterized by exocrine pancreatic deficiency, hematologic dysfunction, and skeletal growth failure. Although the hematologic features and characteristics of the somatic disorders commonly associated with SDS are well known, emerging data from case reports and patient registries suggest that SDS may also be associated with an increased risk of diabetes mellitus. However, currently available data on SDS-associated diabetes are limited and do not allow conclusions regarding prevalence and incidence rates, clinical course, and outcomes. CASE PRESENTATION: Here we report the case of a 5-year-old girl with SDS who underwent bone marrow transplantation at the age of 3 months and developed autoantibody-positive type 1 diabetes mellitus at the age of 1.8 years. The manifestation and course of diabetes development were mild, complicated by concurrent spontaneous episodes of hypoglycemia even before the onset of antidiabetic treatment. Currently, adequate metabolic control can be achieved by dietary intervention. CONCLUSIONS: Considering that the SBDS protein regulates mitosis and ribosomal biosynthesis and that its suppression may cause immunologic instability and chronic inflammation, this case provides insight into the phenotype of rare Shwachman-Diamond syndrome-associated diabetes mellitus, which may be characterized by significant age-dependent differences in clinical course.

Is COVID-19 to Blame? Trends of Incidence and Sex Ratio in Youth-Onset Type 2 Diabetes in Germany.

OBJECTIVE: We investigated the incidence of pediatric type 2 diabetes (T2D) in Germany during 2 years of the coronavirus disease 2019 (COVID-19) pandemic (2020-2021) compared with the control period 2011-2019. RESEARCH DESIGN AND METHODS: Data on T2D in children (aged 6 to <18 years) were obtained from the DPV (German Diabetes Prospective Follow-up) Registry. Poisson regression was used to estimate incidences for 2020 and 2021 based on data from 2011 to 2019, and these were compared with observed incidences in 2020 and 2021 by estimating incidence rate ratios (IRRs) with 95% CIs. RESULTS: Incidence of youth-onset T2D increased from 0.75 per 100,000 patient-years (PYs) in 2011 (95% CI 0.58, 0.93) to 1.25 per 100,000 PYs in 2019 (95% CI 1.02, 1.48), an annual increase of 6.8% (95% CI 4.1, 9.6). In 2020, T2D incidence increased to 1.49 per 100,000 PYs (95% CI 1.23, 1.81), which was not significantly higher than predicted (IRR 1.15; 95% CI 0.90, 1.48). In 2021, the observed incidence was significantly higher than expected (1.95; 95% CI 1.65, 2.31 vs. 1.38; 95% CI 1.13, 1.69 per 100,000 PYs; IRR 1.41; 95% CI 1.12, 1.77). Although there was no significant increase in incidence in girls in 2021, the observed incidence in boys (2.16; 95% CI 1.73, 2.70 per 100,000 PYs) significantly exceeded the predicted rate (IRR 1.55; 95% CI 1.14, 2.12), leading to a reversal of the sex ratio of pediatric T2D incidence. CONCLUSIONS: In Germany, incidence of pediatric T2D increased significantly in 2021. Adolescent boys were more affected by this increase, resulting in a reversal of the sex ratio of youth-onset T2D.

Lower Circulating Leptin Levels Are Related to Non-Alcoholic Fatty Liver Disease in Children With Obesity.

Background: While for individuals with obesity an association between hyperleptinemia and an increased risk of non-alcoholic fatty liver disease (NAFLD) is assumed, a leptin deficiency is also related to the development of NAFLD early in life in ob/ob mice, in patients with leptin deficiency due to biallelic likely pathogenic variants in the leptin gene, and in patients with lipodystrophy. Objectives: To investigate the association of circulating leptin levels in pre-pubertal children with obesity and steatosis hepatis. Methods: The cross-sectional study consisted data of n=97 (nmale=76) pre-pubertal children (11.8 ± 1.5 years) with obesity (BMIz: 2.4 ± 0.4). Fasting concentrations of cardiometabolic parameters were measured: insulin, c-peptide, glucose, triglyceride, cholesterol, HDL, LDL, AST, ALT, GGT, leptin. Steatosis hepatis was diagnosed by an ultrasound examination (mild, moderate or severe). Patients were categorized into two groups: low z-score of circulating leptin levels (≤25th percentile) vs. normal z-score of circulating leptin levels. Results: One-third of the children with obesity were diagnosed with steatosis hepatis (I°: 63.6%, II°/III°: 36.4%). Children with steatosis hepatis had significantly lower z-scores of circulating leptin levels compared to children with an unremarkable liver ultrasonography (-2.1 ± 0.8 vs. -0.7 ± 0.6). Z-scores of circulating leptin levels correlate negatively with degree of steatosis hepatis. Children with low z-scores of circulating leptin levels had significantly higher triglyceride, fasting insulin and c-peptide levels compared to children with normal z-scores of circulating leptin levels. Conclusion: Prepubertal children with NAFLD and obesity and partial leptin deficiency might be defined as a clinical subgroup.