Primoz Kotnik

RBP4: a controversial adipokine

Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4s role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine.

Improved Metabolic Control in Pediatric Patients with Type 1 Diabetes: A Nationwide Prospective 12-Year Time Trends Analysis

BACKGROUND This study estimated temporal trends of metabolic control over 12 years in a national cohort of childhood-onset type 1 diabetes. SUBJECTS AND METHODS Data from the prospective childhood-onset diabetes register, which included 886 case subjects from 0 to 17.99 years of age at diagnosis and at least 1 year of follow-up until the age of 22.99 years, were analyzed using multivariable linear and logistic regression models in the observational period between 2000 and 2011. RESULTS Hemoglobin A1c (HbA1c) significantly decreased over 12 years, from 78 mmol/mol (interquartile range [IQR], 68-88 mmol/mol) (9.26% [IQR, 8.41-10.24%]) in the year 2000 to 61 mmol/mol (IQR, 55-67 mmol/mol) (7.75% [IQR, 7.20-8.30%]) in the year 2011 (P<0.001). HbA1c was significantly associated with age, treatment modality, and duration of diabetes (P<0.001), with females having on average 1.02% higher HbA1c (P=0.01; 95% confidence interval [CI] 1.005-1.035). The overall use of insulin pumps was 74%. The incidence rate of severe acute complications was low: 1.07 per 100 patient-years for severe diabetic ketoacidosis (95% CI 0.81-1.40) and 1.21 per 100 patient-years for severe (requiring intravenous or intramuscular therapy) hypoglycemia (95% CI 0.81-1.40). CONCLUSIONS The metabolic control of the entire nationwide pediatric type 1 diabetes population significantly improved during the 12-year observational period with a low rate of severe acute complications events. The improvement was associated with the treatment modality. Additional efforts and solutions are necessary to further improve metabolic control and the quality of life of young people with type 1 diabetes.

Functional Significance and Predictive Value of MicroRNAs in Pediatric Obesity: Tiny Molecules with Huge Impact?

Obesity is a major health concern. While some children develop comorbidities such as insulin resistance and low-grade systemic inflammation upon weight gain, others stay metabolically healthy. There is an urgent need for clinically relevant markers with prognostic value related to disease development and intervention success. MicroRNAs (miRNAs) are established biomarkers for several disease states. Herein, we give a brief overview of miRNA biogenesis and function and the potential role of circulating miRNA in the context of pediatric obesity.

Interleukin-1β downregulates RBP4 secretion in human adipocytes.

Aims/hypothesis The excessive accumulation of adipose tissue in the obese state is linked to an altered secretion profile of adipocytes, chronic low-grade inflammation and metabolic complications. RBP4 has been implicated in these alterations, especially insulin resistance. The aim of the present study was to determine if a local inflammatory micro-environment in adipose tissue regulates RBP4 expression and secretion. Methods Human SGBS and primary adipocytes cultured with conditioned media from human THP-1 macrophages were used as an in vitro model for adipose inflammation. Adipocytes were exposed to recombinant TNF-α, IL-1β, IL-6 or IL-8. In addition, coexpression of IL-1β and RBP4 was measured in adipose tissue samples from 18 healthy females. RBP4 expression was studied by quantitative PCR and ELISA. Results RBP4 mRNA expression and secretion was significantly reduced upon incubation with macrophage-conditioned media in SGBS adipocytes and human primary adipocytes. Out of several factors studied we identified IL-1β as a new factor regulating RBP4. IL-1β significantly downregulated RBP4 mRNA and secretion in a time- and dose-dependent manner. IL-1β mediated its inhibitory effects on RBP4 expression via IL-1 receptor and NF-κB, as incubation with the IL-1 receptor blocking antibody and the NF-κB inhibitors CAPE and SC-514 reversed its effect. Most interestingly, RBP4 mRNA was negatively correlated with IL-1β mRNA in subcutaneous adipose tissue. Conclusions Adipose tissue inflammation as found in the obese state might lead to a downregulation in local RBP4 levels. IL-1β was identified as a major factor contributing to the decrease in RBP4. The increase in circulating RBP4 that often precedes the development of systemic insulin resistance is most likely unrelated to inflammatory processes in adipose tissue.

Noonan syndrome and Turner syndrome patients respond similarly to 4 years' growth-hormone therapy: longitudinal analysis of growth-hormone-naïve patients enrolled in the NordiNet® International Outcome Study and the ANSWER Program.

BackgroundTurner syndrome (TS) and Noonan syndrome (NS) are distinct syndromes associated with short stature and other similar phenotypic features. We compared the responses to growth hormone (GH) therapy of TS and NS patients enrolled in the NordiNet® International Outcome Study (IOS) or the American Norditropin Studies: Web-Enabled Research (ANSWER) Program, which collect information on GH therapy in clinical practice.MethodsRepeated-measures regression analysis was performed on change in height standard deviation score (HSDS) and target-height-corrected HSDS, based on national normal references and treatment-naïve disease-specific references. Models were adjusted for baseline age and HSDS, and average GH dose. The study population was paediatric patients with TS and NS in the NordiNet® IOS and ANSWER Program. Longitudinal growth responses over 4 years were evaluated.ResultsIn 30 NS patients (24 males; baseline age 8.39 ± 3.45 years) and 294 TS patients (7.81 ± 3.22 years), 4-year adjusted ΔHSDS were +1.14 ± 0.13 and +1.03 ± 0.04, respectively (national references). Based on untreated, disease-specific references, 4-year adjusted ΔHSDS for NS and TS were +1.48 ± 0.10 and +1.79 ± 0.04. The analyses showed a significant increase in HSDS over time for both NS and TS (P < 0.0001). ΔHSDS in NS was higher with younger baseline age; ΔHSDS in TS was higher for patients with younger baseline age and higher GH dose.ConclusionsNS and TS patients responded well and similarly over 4 years of GH treatment.

ESPE Position Statement for Paediatric Endocrinology Subspecialty

Paediatric Endocrinology, under the leaderships of Lawson Wilkins in the US and of Andrea Prader in Europe, started to take shape as a subspecialty in the 1960s. Since that time, paediatric endocrinology has developed at a tremendous speed, especially during the last 30 years, in line with increasing knowledge in the field of genetics and other basic sciences, as well as improved medications and technical facilities. Endocrine conditions encountered in childhood are diverse and show a wide spectrum that is in many aspects substantially different from endocrine diseases in adults and the elderly. Children are simply not little adults. Handling of paediatric endocrine disorders requires the special attention of medical specialists with significant background training in paediatrics, to understand all aspects of human growth and development, along with specialised training in paediatric endocrinology. Developmental issues, including sex differentiation, body growth, skeletal development, pubertal maturation, and neuropsychological development from the intrauterine period to adolescence and young adulthood, are specific paediatric issues that cannot be fully understood and managed without paediatric training as the basic medical background. Recognising, classifying, diagnosing, and managing disorders of growth and development are specific tasks for fully trained paediatric endocrinologists. At the European Academy of Paediatrics (EAP), a subsection of the European Union of Medical Specialists (UEMS; formerly CESP), each paediatric subspecialty is represented by a liaison officer within the Tertiary Care Working Group (TCWG). The EAP has its own legislation/constitution (Belgian/ EU law) representing the central unifying platform for paediatric training in Europe. One of the major goals of the liaison officers is to update the current syllabus and accreditation procedures for their subspecialty, aiming at harmonisation of paediatric training throughout Europe. ESPE has recently, in 2014, revised its training program and this was approved by the General AsPublished online: July 6, 2016 HORMONE RESEARCH IN PÆDIATRICS

Stabilization of Overweight and Obesity in Slovenian Adolescents and Increased Risk in Those Entering Non-Grammar Secondary Schools

Background/Aim: To estimate overweight and obesity prevalence trends in Slovenian adolescents entering secondary schools in the years 2004, 2009 and 2014 and differences in the prevalence between different types of secondary schools. Methods: Data from 17,538 adolescents entering secondary schools (mean age ± standard deviation 15.4 ± 0.5 years) collected during obligatory medical examination in years 2004, 2009 and 2014 was analyzed. Overweight and obesity were defined using International Obesity Task Force criteria. Results: In 2004-2009 overweight and obesity prevalence increased, especially in males and stabilized thereafter (2009-2014) in both genders. It was significantly higher (p < 0.0001) in those attending secondary vocational and technical/professional versus grammar schools (2009; 28.7 vs. 16.8% overweight females and 31.6 vs. 22.3% overweight males; 2014: 29.7 vs. 17.9% overweight females and 33.6 vs. 20.4% overweight males). Conclusions: Overweight and obesity prevalence in Slovenian adolescents entering secondary schools stabilized recently. Adolescents attending secondary vocational and technical/professional schools are at an increased risk of overweight and obesity.

Early growth hormone treatment start in childhood growth hormone deficiency improves near adult height: analysis from NordiNet® International Outcome Study

Objective To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD). Design NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting. Methods Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS). Results Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start. Conclusions Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.

Lack of association of common allelic variants in the thyroglobulin gene with Hashimoto's thyroiditis in young subjects with type 1 diabetes.

Background/Aim: Four SNPs (E10SNP24, E10SNP158, E12SNP, E33SNP) in the Tg gene are suspected to be involved in the development of autoimmune thyroid diseases. The aim of the study was to determine whether these variants play a role in the development of Hashimoto’s thyroiditis in young subjects with type 1 diabetes, in whom autoimmune thyroid diseases are significantly more common than in the general population. Subjects and Methods: Seventy-six subjects with type 1 diabetes and Hashimoto’s thyroiditis and 110 subjects with only type 1 diabetes were studied. Hashimoto’s thyroiditis was determined according to the clinical, biochemical and ultrasonographic criteria. SNPs were determined by the TaqMan SNP method. Results: In young subjects with type 1 diabetes, no association between any of the tested SNPs or their combinations and Hashimoto‘s thyroiditis was found. Conclusions: This is the first study to investigate the association of SNPs located inside the coding region of the Tg gene with the development of Hashimoto’s thyroiditis in subjects with type 1 diabetes. The lack of an association is in concordance with a study where marker Tgms2, located inside intron 27, was not associated with joint susceptibility for autoimmune thyroid disease and type 1 diabetes.

Association of Average Telomere Length with Body-Mass Index and Vitamin D Status in Juvenile Population with Type 1 Diabetes / Povezava Povprečnih Dolžin Telomerov Z Indeksom Telesne Teže in Vitaminom D Pri Mladostnikih S Sladkorno Boleznijo Tipa 1

Abstract Background. Type 1 diabetes (T1D) is an autoimmune chronic disease where hyperglycemia, increased risk of oxidative stress, advanced glycation end-products and other genetic and environmental factors lead to T1D complications. Shorter telomeres are associated with hyperglycemic levels and lower serum vitamin D levels. Methods. Average telomere length (ATL) in whole blood DNA samples was assessed with qPCR method in 53 Slovenian T1D children/adolescents (median age 8.7 years, 1:1.3 male/female ratio). Body mass index standard deviation score (BMI-SDS), glycated haemoglobin and serum level of vitamin D metabolite (25-(OH)-D3) and the age at the onset of T1D were collected from the available medical documentation. Results. Results indicate shorter ATL in subjects with higher BMI-SDS when compared to those with longer ATL (0.455 ± 0.438, -0.63 ± 0.295; p=0.049). Subjects with higher BMI-SDS had lower serum vitamin D levels when compared to those with lower BMI-SDS (40.66 ± 3.07 vs. 52.86 ± 4.85 nmol/L; p=0.045). Vitamin D serum levels did not significantly differ between subjects with longer/shorter ATL. Conclusion. T1D children/adolescents with shorter ATL tend to have higher BMI-SDS. Lower serum vitamin D levels were associated with higher BMI-SDS, while associations between vitamin D serum levels, age at the onset of T1D, glycated haemoglobin and ATL were not observed. Additional studies with more participants are required to clarify the role of the telomere dynamics in T1D aetiology and development of complications. Izvleček Izhodišče. Sladkorna bolezen tipa 1 (SBT1) je kronična avtoimunska bolezen, pri kateri hiperglikemija ter zvišana raven oksidativnega stresa in končnih produktov glikacije skupaj z genetskimi in okoljskimi dejavniki privedeta do nastanka diabetičnih zapletov. Krajše dolžine telomerov so povezane s hiperglikemičnimi epizodami in nižjimi serumskimi vrednostmi vitamina D. Metode. Z metodo qPCR smo iz vzorcev DNK periferne krvi določili povprečne dolžine telomerov 53 slovenskim bolnikom s SBT1 (povprečna starost 8,7 leta, razmerje med dečki in deklicami 1:1,3). Indeks standardnega odklona indeksa telesne teže (BMI-SDS), vrednosti serumskega metabolita vitamina D - 25-hidroksikalcifediola (25-(OH)-D3), glikiran hemoglobin in starost preiskovancev ob izbruhu bolezni smo pridobili iz razpoložljive medicinske dokumentacije. Rezultati. Rezultati nakazujejo krajše dolžine telomerov pri bolnikih z višjimi vrednostmi BMI-SDS (0,455 ± 0,438, -0,63± 0,295; p=0,049). Preiskovanci z višjimi vrednostmi BMI-SDS so imeli nižje vrednosti 25-(OH)-D3 kot preiskovanci z nižjimi vrednostmi BMI-SDS (40,66 ± 3,07 proti 52,86 ± 4,85 nmol/L; p=0,045). Vrednosti 25-(OH)-D3 niso statistično značilno različne pri preiskovancih z višjimi oziroma nižjimi povprečnimi dolžinami telomerov. Zaključki. Otroci in mladostniki s SBT1 s krajšimi dolžinami telomerov imajo nekoliko višje vrednosti BMI-SDS. Nižje vrednosti 25-(OH)-D3 so povezane z višjim BMI-SDS. Povezav med serumskimi vrednostmi 25-(OH)-D3, starostjo bolnikov ob izbruhu bolezni, glikiranim hemoglobinom in povprečnimi dolžinami telomerov nismo zaznali. Za razjasnitev vloge telomerov v etiologiji, patogenezi in nastanku zapletov SBT1 bodo potrebne nadaljnje raziskave z večjim številom preiskovancev.