CONTEXT:Being born small for gestational age (SGA) and growth hormone (GH) treatment are linked to disturbed glucose-insulin metabolism. OBJECTIVE:We investigated how GH treatment affects glucose-insulin metabolism in children born SGA compared to children with isolated growth hormone deficiency (iGHD), obesity and lean controls. METHODS:We analyzed glucose-insulin metabolism indices derived from oral glucose tolerance tests (Matsuda index, AUC insulin) and fasting parameters (fasting glucose, HOMA-IR) in 134 SGA patients without catch-up growth (CUG) receiving GH therapy (SGA-GHT), 27 untreated SGA patients with catch-up growth (SGA-CUG), 308 iGHD patients under GH treatment, 427 children with obesity, and 356 lean controls. We adjusted for sex, age, and BMI through matching and multivariable regression. RESULTS:Treatment-naïve SGA-GHT patients were more insulin-resistant than iGHD patients (higher insulin AUC [P = .002] and HOMA-IR [P < .001], lower Matsuda index [P < .001]) with levels approaching those of the obesity cohort. Under GH therapy, HbA1c was higher in SGA-GHT and iGHD patients (5.26% ± 0.35 vs 5.25% ± 0.25) than in lean controls (5.09% ± 0.27). Insulin resistance in SGA-GHT patients approached levels seen in obesity. Prediabetes prevalence was highest in SGA-GHT children (11.11%) compared to those with iGHD (1.59%) or obesity (3.13%). After stopping GH therapy, SGA-GHT patients retained elevated markers of prediabetes (4.65%) and insulin resistance compared to controls and iGHD patients, similar to children with obesity (6.38%). No overt type 2 diabetes was observed. CONCLUSION:SGA patients have an impaired glucose-insulin metabolism similar to that of children with obesity, which worsens under GH therapy. Close metabolic monitoring of GH-treated SGA patients is recommended.

BACKGROUND:Interpretation of blood leptin concentration in clinical practice and research is limited by a lack of comprehensive reference values. We aimed to establish reference ranges across the age and weight spectrum, taking into consideration important covariates age (0-75 years), pubertal status, and body weight status (normal to extreme obesity). METHOD:Data from 12 629 individuals across 16 European cohorts were pooled and extracted for weight, height, Tanner stage (TS), and serum leptin concentration via ELISA (Leptin ELISA kit). Generalized additive models for location, shape, and scale were used to render reference curves stratified by sex, TS, and weight status. RESULTS:In boys, serum leptin concentrations increased between ages 6 and 12, followed by a decline after age 12, while girls showed an increase until age 15, with body mass index (BMI) SD score (SDS) dependent trajectories thereafter. Leptin concentrations were generally higher in girls than boys, except in boys aged 9 to 15 years with a BMI-SDS of > 3. In adults, women consistently had higher leptin concentrations across all BMI categories. In men, leptin concentrations decreased until the mid-20s for a BMI of 30 kg/m2 and until age 50 for a BMI of 40 kg/m2, stabilizing thereafter. CONCLUSION:We present the first reference curves for leptin concentrations across the entire age and weight range. An online tool and an R package for calculating leptin z-scores that are specific to age, sex, TS, and BMI (or BMI-SDS) are now available for clinical and research use at https://leptin.science.

Introduction and Objective: The course of type 2 diabetes is more severe in children with obesity than in adults. Early identification of children at high risk for diabetes is crucial but specific pediatric criteria are lacking. Methods: We established age- and puberty-specific reference values for seven indexes of insulin response during OGTT in 530 healthy participants (1408 observations) aged 6-30 years. Using these cut-offs, we assessed the prevalence and longitudinal stability of insulin resistance in 1876 children with obesity (2846 observations) and analyzed its predictive value for diabetes onset through survival analyses. Results: In patients with obesity, insulin resistance was present in half of preschool children (6-8 years) and remained high into early adulthood with two-thirds affected at 18-30 years. Indexes of insulin resistance/hyperinsulinemia outside the reference range remained more stable during subsequent testing (86-89%) compared to classical glucose metabolism markers (e.g. 2-hour glucose: 30.0%, fasting glucose: 49.3%, HbA1c: 36.4%). Children with insulin resistance had a 4-fold increased diabetes risk over 20 years, with OGTT indexes outperforming fasting indexes (HRs for ISIMatsuda 4.05 (95% CI 1.83 - 8.93); HOMA-IR 2.56 (95% CI 1.25 - 5.24)). Using our new cut-offs, we identified twice as many future diabetes manifestations at baseline compared to conventional prediabetes markers (82.4% with pathological ISIMatsuda vs. 39.2% with impaired glucose tolerance). Findings were validated in independent cohorts from Berlin (Germany), Salzburg (Austria), and Uppsala (Sweden). Conclusion: OGTT-derived reference values enable earlier and more sensitive detection of children at high risk for diabetes than conventional diabetes markers and fasting indexes. Children with obesity and hyperinsulinemia require close monitoring and rigorous treatment to prevent diabetes. R. Stein: Other Relationship; Novo Nordisk, Rhythm Pharmaceuticals, Inc. E. Wenzel: None. H. Enders-Seidlitz: None. D. Weghuber: Advisory Panel; Novo Nordisk A/S. Consultant; Novo Nordisk A/S. Advisory Panel; Eli Lilly and Company, Rhythm Pharmaceuticals, Inc. M.W. Stumvoll: None. M. Blüher: Advisory Panel; AstraZeneca. Speaker's Bureau; Amgen Inc. Advisory Panel; Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Eli Lilly and Company, Novo Nordisk, Nestlé Health Science, Sanofi-Aventis Deutschland GmbH. A. Körner: Advisory Panel; Novo Nordisk. Speaker's Bureau; Merck & Co., Inc, Novo Nordisk. German Research Foundation (DFG), SFB1052/CRC1052 (209933838); European Society for Paediatric Endocrinology

BACKGROUND/OBJECTIVES:Obesity poses a major public health concern. Although BMI heritability is estimated at 40-80%, genetic diagnostics remain challenging. This study aims to (i) assess the diagnostic yield of monogenic obesity in a large patient sample using exome-wide data, (ii) identify predictors to improve genetic testing criteria, and (iii) evaluate whether the identified genes are included in public obesity gene panels. SUBJECTS/METHODS:We reviewed the genetic test results of 521 patients with obesity. 84.7% underwent whole-exome analysis, 15.3% were analyzed using a multi-thousand-gene panel. RESULTS:Monogenic obesity was diagnosed in 5.8% of patients, while 7.1% carried a potentially obesogenic variant. Diagnostic yield was higher in children (6.3%) and patients with syndromic obesity (7.0%). Surprisingly, diagnostic yield was lower in severe obesity cases. 40% of patients with monogenic obesity carried variants in genes not included in current obesity panels. CONCLUSION:Overall, 12.9% of patients had monogenic obesity or a potentially obesogenic variant. These findings suggest that genetic testing should not be limited to patients with extreme obesity. Current obesity panels miss crucial syndromic genes, demonstrating a need for more comprehensive panels and the superiority of whole-exome sequencing in obesity.

Introduction: Research on severe obesity (SO) is scarce and often contradictory. As higher weight status persists into adulthood, we aimed to analyze long-term trends in the prevalence of SO in children and adolescents in Germany using a large real-world data set. Furthermore, we analyzed subgroup differences and assessed how the COVID-19 pandemic affected weight status. METHODS:We analyzed data from the CrescNet auxological network, including 1,495,401 clinical visits by 4- to 16-year-old children (2002-2023). Weight trends were examined with a focus on SO using logistic regression, stratified by sex and age. Effects are reported as odds ratio per 5 years (OR5) pre-pandemic and as OR for consecutive years during the pandemic. Quantile regression assessed trends of the 50th, 90th, 97th, and 99th percentiles of excess weight. RESULTS:Pre-pandemic, SO remained stable or declined in children under 12 until 2010: OR5: 0.8-1, p < 0.001) but rose significantly afterward (OR5: 1.1-1.2, p < 0.001). Children between 12 and 16 years of age showed a continuous increase, especially boys (boys12-16: OR5: 1.3, girls12-16: OR5: 1.1, p < 0.001). During the pandemic, SO peaked in 2021 across all groups (OR21 vs. 19: 1.3-1.7, p < 0.001). By 2023, younger children had returned to pre-pandemic levels, while older children, particularly 8- to 16-year-old girls, remained at higher weights (OR23 vs. 19: 1.2-1.5, p < 0.001-0.002). Weight gain was most prominent in SO groups but could also be seen in pre-pandemic and pandemic overweight and obesity subgroups, generally decreasing toward the end of the pandemic. CONCLUSION:SO has increased over the last 2 decades, with the COVID-19 pandemic accelerating this trend, particularly in adolescents. While younger children recovered by 2023, excess weight in older children, especially girls, continues to escalate. .

Übergewicht und Adipositas bei Kindern sind weltweit ein wachsendes Problem. In Deutschland betrifft dies etwa 15

Even though the transition from adolescence to adulthood is a vulnerable and crucial period for young individuals with chronic conditions, it remains poorly studied in obesity. We comprehensively characterized the transition of children with overweight/obesity from childhood to adult care. Data from an adulthood follow-up of the Leipzig childhood obesity cohort (N = 209, mean age at follow-up 24.9 years) were analyzed and related to the respective childhood data. Assessments comprised anthropometrics, oral glucose tolerance testing, carotid ultrasonography, 24 h blood pressure monitoring, liver elastography and questionnaires on psychosocial background, quality of life and transition process. Here we show that childhood onset overweight/obesity persists in 93.3

Background and Objectives Growth-hormone deficiency and being born small for gestational age (SGA) are associated with the development of a disturbed glucose-insulin metabolism. We aimed to investigate whether SGA patients have a higher risk of developing an impaired glucose-insulin metabolism in comparison to children with an isolated growth-hormone deficiency (iGHD), to children with obesity and a healthy control group.

Zusammenfassung Kinder und Jugendliche mit extremer und/oder genetischer Adipositas benötigen aufgrund des chronisch-rezidivierenden und progressiven Charakters der Adipositas eine langfristige und kontinuierliche Betreuung und Behandlung. Ziel dieser Arbeit ist es, ein strukturiertes Versorgungs- und Behandlungskonzept für Kinder und Jugendliche mit extremer und/oder genetischer Adipositas vorzustellen, welches den speziellen Anforderungen und Bedürfnissen dieser Patientengruppe entspricht. Kinder und Jugendliche mit extremer und/oder genetischer Adipositas sollten strukturiert und kontinuierlich nach dem „Chronic Care Model“ in spezialisierten Behandlungszentren in enger Zusammenarbeit mit niedergelassenen Arztpraxen versorgt und behandelt werden. Das Wissen über die zugrundeliegenden molekularbiologischen Mechanismen der Regulation von Hunger und Sättigung, des Körpergewichts und letztlich der Entstehung der Adipositas ermöglichen einen personalisierten Behandlungsansatz. Individualisierte, multimodale Behandlungsansätze sind die Grundlage für eine langfristige und effektive Behandlung der Adipositas bei Kindern und Jugendlichen mit extremer und/oder genetischer Adipositas. Neue pharmakologische Therapiemöglichkeiten, wie Inkretin-basierte Medikamente für Jugendliche mit extremer Adipositas oder speziell entwickelte Mechanismus-basierte Medikamente für Personen mit genetischer Adipositas, stellen einen bedeutenden Fortschritt im chronischen Gewichtsmanagement und eine effektive Ergänzung zu individuellen, multimodalen Lebensstilinterventionen dar.

Hintergrund und Fragestellung: Der Verlauf von Typ-2-Diabetes ist bei Kindern schwerwiegender als bei Erwachsenen. Ziel dieser Arbeit ist es, geeignete Insulinresistenzmarker und entsprechende Cut-offs zu identifizieren, um Kinder mit hohem Diabetesrisiko frühzeitig zu erkennen.

Abstract Disclosure: K. Landgraf: None. E.T. Kempf: None. R. Stein: None. M. Hanschkow: None. Y. Tseng: None. T. Schöneberg: None. E. Zeggini: None. M. Blüher: None. A. Körner: None. Here we identified and characterized a heterozygous tandem duplication at the ASIP (agouti-signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female index patient with extreme childhood obesity.From an adipose tissue sample of the patient, we observed pronounced and sustained differentiation potential of stroma-vascular fraction (SVF) cells into adipocytes in the patient compared to normal control cells. We further found reduced mitochondrial maximum respiration, spare capacity, and proton leak in the patient’s SVF cells as proxies for reduced energy expenditure. By transcriptome screen, we identified overexpression of one single gene, ASIP. We found and functionally confirmed a chromosomal rearrangement at the ASIP locus, that places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase (ITCH) promoter. The patient's phenotype of early-onset obesity, overgrowth, red hair, and hyperinsulinemia is concordant with that of mutant, so called agouti mice ubiquitously expressing the homolog nonagouti. Physiologically, ASIP antagonises the melanocortin 1 receptor (MC1R) in the skin. Due to its homology to the hypothalamic regulator of eating behaviour agouti-related protein (AGRP), we hypothesize that ectopic ASIP similarly influences eating behaviour via repressing melanocyte-stimulating hormone-mediated activation of MC4R and that the mutation might therefore represent a novel monogenic cause for severe childhood obesity. We show that the tandem duplication results in the ectopic generation of ASIP in patient-derived native stroma-vascular fraction (SVF) cells, adipocytes and blood cells as well as in induced pluripotent stem cells (iPSCs) generated from SVF cells of the patient, thus indicating ubiquitous ectopic ASIP expression. This overexpression persisted after differentiation of iPSCs into the three germ layers, mesoderm, ectoderm and endoderm, and after differentiation into hypothalamic-like neurons. Furthermore, we observed that ASIP causes a reduction of MC4R activity in vitro supporting the hypothesis that the obesity phenotype of our patient is caused by ectopic ASIP acting at the MC4R in the hypothalamus. Since the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig childhood obesity cohort of 1745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity and might be potentially treatable with melanocortin 4 receptor agonists. Presentation: Thursday, June 15, 2023

ZUSAMMENFASSUNGKinder mit vermeintlichen Wachstumsstörungen werden häufig in Kinderarztpraxen vorgestellt. Zur Diagnosefindung sind Anamnese, körperliche Untersuchung und Beurteilung des Wachstumsverlaufs unabdingbar. Neben physiologischen Wachstumsformen, die die biologische Varianz in der Bevölkerung widerspiegeln, kommen einige Pathologien infrage. Pathologische Wachstumsstörungen sind vor allem über eine veränderte Wachstumsgeschwindigkeit mit Abweichen von den ursprünglichen Perzentilen definiert. Hier seien unter anderem ein sekundärer Kleinwuchs bei chronischer Erkrankung, syndromaler Kleinwuchs, Kleinwuchs nach intrauteriner Wachstumsverzögerung und Wachstumshormonmangel genannt. Die Diagnosestellung ist häufig nicht einfach und erfordert einige Verlaufskontrollen und/oder endokrinologische Stimulationstests. Die Wachstumshormontherapie wird nicht nur bei Wachstumshormonmangel, sondern auch bei anderen Erkrankungen eingesetzt, verlangt jedoch eine gewissenhafte Indikationsstellung.

Here we report a heterozygous tandem duplication at the ASIP (agouti signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female patient with extreme childhood obesity. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons. The patient’s phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient. As the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig Childhood Obesity cohort of 1,745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.