An alternative approach using hs-CRP levels and age of onset in diagnostics of HNF1A-MODY.

AIMS: The aim is to identify people with HNF1A-MODY among individuals in diabetic cohort solely based on low hs-CRP serum level and early diabetes onset. METHODS: In 3537 participants, we analyzed the hs-CRP levels. We analyzed the HNF1A gene in 50 participants (1.4% of the cohort) with type 1 or type 2 diabetes who had hs-CRP ≤0.25 mg/L and were diagnosed with diabetes mellitus (DM) at the age of 8-40 years. We functionally characterized two identified missense variants. RESULTS: Three participants had a rare variant in the HNF1A gene, two of which we classified as likely pathogenic: c.1369_1384dup (p.Val462Aspfs*92) and c.737T>G (p.Val246Gly), and one as likely benign: c.1573A>T (p.Thr525Ser). Our functional studies revealed that p.Val246Gly decreased HNF1α transactivation activity to ~59% and the DNA binding ability to ~16% of the wild-type, while p.Thr525Ser variant showed no effect on transactivation activity, DNA binding, nor nuclear localization. Based on the two identified HNF1A-MODY patients among 3537 people with diabetes, we estimate 0.057% as the minimal HNF1A-MODY prevalence in Slovakia. A positive predictive value of hs-CRP ≤0.25 mg/L for finding HNF1A-MODY individuals was 4.0% (95% CI 0.7%, 13.5%). CONCLUSIONS: Hs-CRP value and age of DM onset could be an alternative approach to current diagnostic criteria with a potential to increase the diagnostic rate of HNF1A-MODY.

Genetic testing is necessary for correct diagnosis and treatment in patients with isolated methylmalonic aciduria: a case report.

BACKGROUND: Isolated methylmalonic aciduria can be caused by pathogenic mutations in the gene for methylmalonyl-CoA mutase or in the genes encoding enzymes involved in the intracellular metabolism of cobalamin. Some of these mutations may be cobalamin responsive. The type of methylmalonic aciduria cannot always be assumed from clinical manifestation and the responsiveness to cobalamin has to be assessed for appropriate cobalamin administration, or to avoid unnecessary treatment. The cases presented herein highlight the importance of genetic testing in methylmalonic aciduria cases and the need for standardisation of the in vivo cobalamin-responsiveness assessment. CASE PRESENTATION: We describe two patients who presented in the first week of life with rapid neurological deterioration caused by metabolic acidosis with severe hyperammonaemia requiring extracorporeal elimination in addition to protein restriction, energy support, carnitine, and vitamin B12 treatment. The severity of the clinical symptoms and high methylmalonic acid concentrations in the urine (>30,000 µmol/mmol of creatinine) without hyperhomocysteinaemia in both of our patients suggested isolated methylmalonic aciduria. Based on the neonatal manifestation and the high methylmalonic acid urine levels, we assumed the cobalamin non-responsive form. The in vivo test of responsiveness to cobalamin was performed in both patients. Patient 1 was evaluated as non-responsive; thus, intensive treatment with vitamin B12 was not used. Patient 2 was responsive to cobalamin, but the dose was decreased to 1 mg i.m. every two weeks with daily oral treatment due to non-compliance. Genetic tests revealed bi-allelic mutations in the genes MMAB and MMAA in Patient 1 and 2, respectively. Based on these results, we were able to start intensive treatment with hydroxocobalamin in both patients. After the treatment intensification, there was no acute crisis requiring hospitalisation in Patient 1, and the urine methylmalonic acid levels further decreased in Patient 2. CONCLUSIONS: Despite carrying out the in vivo test of responsiveness to cobalamin in both patients, only the results of molecular genetic tests led us to the correct diagnosis and enabled intensive treatment with hydroxocobalamin. The combination of the standardized in vivo test of cobalamin responsiveness and genetic testing is needed for accurate diagnosis and appropriate treatment of isolated methylmalonic aciduria.

Comparison of diabetes phenotype in children and their mothers with permanent neonatal diabetes mellitus carrying the same KCNJ11 variants.

Objective. Mutations of the KCNJ11 gene are the most common cause of the permanent neonatal diabetes mellitus (PNDM). Majority of people with KNCJ11-PNDM have a de-novo mutation. We aimed to compare diabetes phenotype in two children and their mothers with PNDM carrying the same sulfonylurea-sensitive KCNJ11 variants.Methods. We have compared glibenclamide (sulfonylurea) dose, C-peptide, and HbA1c serum levels in two children and their mothers with PNDM up to 5.5-year follow-up. All of them were carrying a heterozygous activating KCNJ11 pathogenic variant (p.R201H in Family 1 or p.H46Y in Family 2). The mothers were initially treated with insulin and successfully switched to sulfonylurea at the age of 24 and 11 years, respectively. Both children were treated with sulfonylurea since the diagnosis of PNDM.Results. Glibenclamide dose was similar in both children (0.02-0.03 mg/kg/day), but lower compared to their mothers (0.1-0.4 mg/kg/day) (p<0.002). Fasting serum C-peptide levels were also lower in children (70-210 pmol/l) than in their mothers (263-720 pmol/l) (p<0.002), but no significant differences were observed in postprandial C-peptide levels. HbA1c was lower only in the son of SVK4 (Family 2) compared to his mother, as she had poor adherence to the sulfonylurea therapy during the first years after the sulfonylurea switch.Conclusions. Evaluation of the treatment in people with sulfonylurea-sensitive KNCJ11-PNDM should respect the age of patients together with the type of mutation and duration of diabetes at therapy start and may differ within one family.

Novel insights into genetics and clinics of the HNF1A-MODY.

MODY (Maturity Onset Diabetes of the Young) is a type of diabetes resulting from a pathogenic effect of gene mutations. Up to date, 13 MODY genes are known. Gene HNF1A is one of the most common causes of MODY diabetes (HNF1A-MODY; MODY3). This gene is polymorphic and more than 1200 pathogenic and non-pathogenic HNF1A variants were described in its UTRs, exons and introns. For HNF1A-MODY, not just gene but also phenotype heterogeneity is typical. Although there are some clinical instructions, HNF1A-MODY patients often do not meet every diagnostic criteria or they are still misdiagnosed as type 1 and type 2 diabetics. There is a constant effort to find suitable biomarkers to help with in distinguishing of MODY3 from Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). DNA sequencing is still necessary for unambiguous confirmation of clinical suspicion of MODY. NGS (Next Generation Sequencing) methods brought discoveries of multiple new gene variants and new instructions for their pathogenicity classification were required. The most actual problem is classification of variants with uncertain significance (VUS) which is a stumbling-block for clinical interpretation. Since MODY is a hereditary disease, DNA analysis of family members is helpful or even crucial. This review is updated summary about HNF1A-MODY genetics, pathophysiology, clinics functional studies and variant classification.

EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.

Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2γ function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms.

[Actual trends in diagnostics and treatment of congenital hyperinsulinism]. / Súcasné trendy v diagnostike a liecbe kongenitálneho hyperinzulinizmu.

Congenital hyperinsulinism (CHI) is the most common cause of severe persistent hypoglycemia in neonates and infants. Early diagnosis and effective treatment (based on the principles of pharmacogenetics) play the key role for the prognosis. The DNA anlysis, which can identify mutation in one of the 11 genes causing MODY, is crutial in the diagnostics. Moreover, The genotype determines also the optimal therapy approach (medicaments, diet or rarely surgery). There was a large progress of novel medicaments treating particularly most severe (diazoxide-resistant) forms of CHI.Key words: congenital hyperinsulinism - diazoxid - DNA analysis - hypoglycemia - somatostatine analogues.

De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed.

AIMS/HYPOTHESIS: MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A). METHODS: Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing. RESULTS: Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo. CONCLUSIONS/INTERPRETATION: In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.

Complete remission in children and adolescents with type 1 diabetes mellitus-prevalence and factors.

Little is known about complete remission in Type 1 diabetes mellitus (T1D) with the discontinuance of insulin treatment for a period of time. In this retrospective study we analysed the frequency and factors of onset and duration of 1. remission and 2. complete remission in children and adolescents with T1D from the Children Diabetes Centre in Bratislava, Slovakia. A total of 529 individuals with T1D, aged < 19 years (8.5 ± 4.3 years) at diabetes onset were included in the study. Remission was defined by HbA1c < 7.0% (53 mmol/mol) and an insulin daily dose < 0.5 IU/kg (and 0 IU/kg for complete remission). Remission occurred in 210 (39.7%) participants, and 15 of them had complete remission (2.8% from all participants). We have identified a new independent factor of complete remission onset (higher C-peptide). Complete remitters had a longer duration of remission compared with other remitters and also differed in lower HbA1c levels. No association was seen with autoantibodies or genetic risk score for T1D. Thus, not only partial but also complete remission is influenced by factors pointing toward an early diagnosis of T1D, which is important for better patient outcome.

Thyroid hormone levels and BMI-SDS changes in adolescents with obesity.

Background: Thyroid hormones play an important role in energy metabolism and weight control, explained mostly by inducing thermogenesis and increasing basal metabolic rate. It has recently been shown that FT4 levels are associated with food preferences, which might also play a role in modulating body weight. The aim of this longitudinal follow-up study was to analyze the relationship of thyroid hormones levels (FT4, TSH) at baseline with weight/BMI-SDS changes in children and adolescents with obesity. Methods: Three hundred seventy-seven children and adolescents have been enrolled to this study and followed up without a systematic intervention program for 5.59 ± 1.85months. Children and adolescents were divided into three subgroups: 1) 144 adolescents with obesity (15-19 years), 2) 213 children with obesity (10-14.9 years), and 3) 20 lean adolescents (15-19 years). Thyroid hormones were measured at the baseline, and anthropometry was performed at the baseline and during the follow-up. For further analyses, participants were divided according to the BMI-SDS change into two groups: 1. with BMI-SDS decrease, and 2. with BMI-SDS increase. Results: Adolescents with obesity from the BMI-SDS decrease group had significantly lower baseline serum levels of TSH compared to the BMI-SDS increase group (2.4 ± 1.0 vs. 3.2 ± 2.0mIU/l; p=0.005). Similar difference was found for FT4 levels (14.7 ± 2.2 in the BMI-SDS decrease group vs. 15.5 ± 2.7pmol/l in the BMI-SDS increase group, p=0.048). Moreover, the BMI-SDS decrease was present in significantly higher percentage of adolescents with obesity with lower than median TSH level compared to those with higher than median TSH level at baseline (61.1% vs 38.6%, p=0.011). Likewise, the BMI-SDS decrease was present in significantly higher percentage of adolescent females with obesity and lower than median FT4 compared to those with higher than median FT4 level at baseline (70.6% vs. 23.5%, p<0.001). No associations of baseline thyroid hormones with the BMI-SDS change were observed in children with obesity or lean adolescents. Conclusion: Adolescents with obesity and increased BMI-SDS during the follow-up had significantly higher baseline levels of both TSH and FT4 compared to BMI-SDS decrease group. These results support the previous findings that higher FT4 in individuals with obesity may influence weight gain.

Fasting indices of glucose-insulin-metabolism across life span and prediction of glycemic deterioration in children with obesity from new diagnostic cut-offs.

Background: Fasting indices of glucose-insulin-metabolism are an easy and affordable tool to assess insulin resistance. We aimed to establish reference ranges for fasting insulin indices that reflect age-dependent variation over the entire life span and subsequently test their clinical application regarding the prediction of glycemic deterioration in children. Methods: We calculated age- and puberty-dependent reference values for HOMA-IR, HOMA2-IR, HOMA-ß, McAuley index, fasting insulin, and fasting glucose from 6994 observations of 5512 non-obese healthy subjects aged 5-80 years. Applying those references, we determined the prevalence of insulin resistance among 2538 subjects with obesity. Furthermore, we investigated the intraindividual stability and the predictive values for future dysglycemia of these fasting indices in 516 children and adolescents with obesity up to 19 years of follow-up. We validated the results in three independent cohorts. Findings: There was a strong age-dependent variation of all indices throughout the life span, including prolonged recovery of pubertal insulin resistance and a subsequent continuous increase throughout adulthood. Already from age 5 years onwards, >40% of children with obesity presented with elevated parameters of insulin resistance. Applying newly developed reference ranges, insulin resistance among children with obesity doubled the risk for future glycemic deterioration (HOMA-IR HR 1.88 (95% CI 1.1-3.21)), fasting insulin HR 1.89 (95% CI 1.11-3.23). In contrast, fasting glucose alone was not predictive for emerging dysglycemia in children with obesity (HR 1.03 (95% CI 0.62-1.71)). The new insulin-based thresholds were superior to fasting glucose and HbA1c in detecting children eventually manifesting with dysglycemia in prospective analyses. Interpretation: The variation of fasting glucose-insulin-metabolism across the life span necessitates age-specific reference ranges. The improved prediction of future glycemic deterioration by indices based on fasting insulin beyond simple glucose measures alone could help to stratify risk characteristics of children with obesity in order to guide patient-tailored prevention and intervention approaches. Funding: German Research Foundation (DFG)-through SFB 1052, project number 209933838, subproject C5; Federal Ministry of Education and Research, Germany; European Union-European Regional Development Fund; Free State of Saxony. The German Diabetes Association, the CarbHealth consortium (01EA1908B). EU-IMI2-Consortium SOPHIA (grant agreement No 875534), German Center for Diabetes Research (DZD), grant number 82DZD14E03.

The Bright Side of Skin Autofluorescence Determination in Children and Adolescents with Newly Diagnosed Type 1 Diabetes Mellitus: A Potential Predictor of Remission?

Skin autofluorescence (SAF) is a noninvasive method reflecting tissue accumulation of advanced glycation end products (AGEs). We investigated whether, in newly diagnosed children and adolescents with type 1 diabetes (T1D), this surrogate marker of long-term glycemia is associated with markers of the early manifestation phase, residual secretion capacity of the ß-cells, and the occurrence of remission. SAF was measured in 114 children and adolescents (age: 8.0 ± 4.5 years, 44% girls) at the time of T1D diagnosis, and related to HbA1c, C-peptide, diabetic ketoacidosis, and remission. 56 patients were followed up for 1 year. Seventy-four sex- and age-matched healthy individuals served as controls. SAF was higher in the T1D group compared with controls (1.0 ± 0.2 vs. 0.9 ± 0.2, p < 0.001). At the time of diagnosis, SAF correlated with HbA1c (r = 0.285, p = 0.002), was similar in patients with and without ketoacidosis, and was lower in the remitters compared with non-remitters (0.95 ± 0.18 vs. 1.04 ± 0.26, p = 0.027). Unlike HbA1c, SAF was an independent predictor of remission (∆R2 = 0.051, p = 0.004). Former studies consider SAF in diabetic patients as a tool to identify individuals at an increased risk of chronic complications. Here we show that determination of SAF at the time of T1D diagnosis might potentially predict remission, at least in children.

Food preferences and thyroid hormones in children and adolescents with obesity.

Background: Thyroid hormones profoundly affect energy metabolism but their interrelation with food preference, which might contribute to childhood obesity development, are much less understood. In this study, we investigated if thyroid hormone levels are associated with specific modulation of food preference and potentially linked to the level of obesity in children and adolescents. Methods: Interrelations between food preference and peripheral thyroid activity were examined in a population of 99 non-obese and 101 obese children and adolescents (12.8 ± 3.6 years of age, 111/89 F/M) randomly selected from the patients of the Obesity and Metabolic Disease Out-patient Research Unit at National Institute for Children's Diseases in Bratislava in a period between December 2017 and March 2020. Results: Children and adolescents with obesity had a lower preference for food rich in high sucrose and high-complex carbohydrates, while the preference for protein and fat-containing food and that for dietary fibers did not differ between obese and nonobese. In adolescents with obesity, free thyroxine (FT4) correlated positively with the preference for a high protein and high fat-rich diet, irrespective of the fatty acid unsaturation level. Moreover, FT4 correlated negatively with the preference for dietary fibers, which has been also exclusively found in obese adolescents. Individuals with obesity with higher FT4 levels had higher systemic levels of AST and ALT than the population with lower FT4. Multiple regression analysis with age, sex, BMI-SDS, and FT4 as covariates revealed that FT4 and male gender are the major predictors of variability in the preference for a diet high in protein, fat, and monounsaturated fatty acids. FT4 was the sole predictor of the preference for a diet containing saturated and polyunsaturated fatty acids as well as for a diet low in fiber. Conclusion: The link between free thyroxin levels and dietary preference for food rich in fat and protein is present exclusively in individuals with obesity. Higher serum FT4 was linked with elevated AST and ALT in children and adolescents with obesity, and FT4 was the best predictor for preference for food rich in fat and low in fiber. This may indicate that FT4 could contribute to the development of childhood obesity and its complications by modulating food preference.

Associations of GHR, IGF-1 and IGFBP-3 expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children.

Components of the growth hormone (GH) axis, such as insulin-like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP-3), GH receptor (GHR) and GH-binding protein (GHBP), regulate growth and metabolic pathways. Here, we asked if serum levels of these factors are altered with overweight/obesity and if this is related to adipose tissue (AT) expression and/or increased fat mass. Furthermore, we hypothesized that expression of GHR, IGF-1 and IGFBP-3 is associated with AT function. Serum GHBP levels were increased in children with overweight/obesity throughout childhood, while for IGF-1 levels and the IGF-1/IGFBP-3 molar ratio obesity-related elevations were detectable until early puberty. Circulating levels did not correlate with AT expression of these factors, which was decreased with overweight/obesity. Independent from obesity, expression of GHR, IGF-1 and IGFBP-3 was related to AT dysfunction,and increased insulin levels. Serum GHBP was associated with liver fat percentage and transaminase levels. We conclude that obesity-related elevations in serum GHBP and IGF-1 are unlikely to be caused by increased AT mass and elevations in GHBP are more closely related to liver status in children. The diminished AT expression of these factors with childhood obesity may contribute to early AT dysfunction and a deterioration of the metabolic state.

Fucosylated AGP glycopeptides as biomarkers of HNF1A-Maturity onset diabetes of the young.

AIMS: We previously demonstrated that antennary fucosylated N-glycans on plasma proteins are regulated by HNF1A and can identify cases of Maturity-Onset Diabetes of the Young caused by HNF1A variants (HNF1A-MODY). Based on literature data, we further postulated that N-glycans with best diagnostic value mostly originate from alpha-1-acid glycoprotein (AGP). In this study we analyzed fucosylation of AGP in subjects with HNF1A-MODY and other types of diabetes aiming to evaluate its diagnostic potential. METHODS: A recently developed LC-MS method for AGP N-glycopeptide analysis was utilized in two independent cohorts: a) 466 subjects with different diabetes subtypes to test the fucosylation differences, b) 98 selected individuals to test the discriminative potential for pathogenic HNF1A variants. RESULTS: Our results showed significant reduction in AGP fucosylation associated to HNF1A-MODY when compared to other diabetes subtypes. Additionally, ROC curve analysis confirmed significant discriminatory potential of individual fucosylated AGP glycopeptides, where the best performing glycopeptide had an AUC of 0.94 (95% CI 0.90-0.99). CONCLUSIONS: A glycopeptide based diagnostic tool would be beneficial for patient stratification by providing information about the functionality of HNF1A. It could assist the interpretation of DNA sequencing results and be a useful addition to the differential diagnostic process.

Dynamic alterations in linear growth and endocrine parameters in children with obesity and height reference values.

BACKGROUND: Obesity can affect linear growth of children but there is uncertainty regarding the dynamics and potential causes. METHODS: In the population-based LIFE Child and the obesity-enriched Leipzig Obesity Childhood cohorts (8,629 children, 37,493 measurements), recruited from 1999 to 2018 in Germany, we compared height, growth, and endocrine parameters between normal-weight and children with obesity (0-20 years). Derived from the independent German CrescNet registry (12,703 children) we generated height reference values specific for children with obesity (data collected from 1999 to 2020). FINDINGS: Children with obesity were significantly taller than normal-weight peers, differing at maximum by 7·6 cm (1·4 height, standard deviation scores or SDS) at age 6-8 years. Already at birth, children with obesity were slightly taller and thereafter had increased growth velocities by up to 1·2 cm/year. This growth acceleration was unrelated to parental height, but was accompanied by increased levels of insulin-like growth factor-1 (IGF-1), insulin and leptin. During puberty, children with obesity showed a catch-down in height SDS. The reduction in pubertal growth velocity by up to 25% coincided with a decrease in levels of IGF-1 (by 17%) and testosterone (by 62%) in boys and estradiol (by 37%) in girls. We confirmed these alterations in growth in the independent CrescNet cohort and furthermore provide height reference values for children with obesity for open access. INTERPRETATION: Dynamics of linear growth are altered distinctively in different developmental phases in children with obesity. Early emergence before other profound comorbidities implies predisposition, environmental, and/or endocrine factors affecting growth in early life. Height reference values for children with obesity may enhance the precision of clinical health surveillance. FUNDING: German Research Foundation, German Diabetes Association, EU, ESF, ERDF, State of Saxony, ESPE, Hexal, Novo Nordisk, Pfizer Pharma.

The Bone Markers Sclerostin, Osteoprotegerin, and Bone-Specific Alkaline Phosphatase Are Related to Insulin Resistance in Children and Adolescents, Independent of Their Association with Growth and Obesity.

BACKGROUND/AIMS: Sclerostin, osteoprotegerin, and bone-specific alkaline phosphatase (B-ALP), which are primarily related to bone metabolism, have been linked with insulin resistance in adults. We aimed to evaluate the association of these markers with growth, obesity, and parameters of insulin resistance in lean and obese children and adolescents. METHODS: We measured sclerostin, osteoprotegerin, and B-ALP in fasting and oral glucose tolerance test (oGTT) serum samples from 1,325 children and adolescents, and during 24-h profiles and after exercise and glucose exposure in young adults. RESULTS: In addition to the positive relationship with height standard deviation scores (SDS), sclerostin (r = 0.035, p < 0.001) and B-ALP (r = 0.06, p = 0.028) increased, whereas osteoprotegerin (r = -0.098, p < 0.001) decreased with BMI SDS. Furthermore, B-ALP correlated with fasting- and oGTT-derived markers of glucose and insulin metabolism suggestive of insulin resistance. To evaluate potential confounding diurnal variation of bone markers, we performed 24-h profiles. B-ALP and osteoprotegerin had lower night-time levels. Exercise acutely and transiently increased B-ALP and osteoprotegerin levels, but glucose ingestion had no effect. CONCLUSIONS: Besides their association with growth, sclerostin and osteoprotegerin levels are altered in childhood obesity. Particularly B-ALP was related to insulin resistance indices. Our findings accent the link between bone, growth, and insulin resistance.

Risk factors of post-surgery complications in children with thyroid cancer.

INTRODUCTION: Thyroid cancer in children is a hot topic because of the large clinical heterogeneity and the risk of severe complications. We aimed to study 1. The frequency, 2. Etiology, and 3. Risk factors of post-surgery complications of thyroid cancer. MATERIAL AND METHODS: A retrospective analysis including risk factors for post-surgery complications of patients treated for thyroid malignancies in years 2006-2018 was performed. RESULTS: Over a period of 12 years 22 patients with thyroid malignancy (68% female; 12.6 ±â€¯4.0 years of age, median follow-up 6 years) were identified. Histologically, 12 (55%) patients had papillary carcinoma. Six patients (27.3%) had multiple endocrine neoplasia type 2 (MEN2) syndrome, 3 (13.7%) patients had medullary carcinoma and 1 patient had follicular carcinoma. Neck lymph node metastases were diagnosed in 8 (36.4%), distant metastases in 6 (27.3%), and both locations were involved in 4 (18.2%) patients. Six (27.3%) children had surgical complications: 1 child had unilateral vocal cord paralysis and transient hypoparathyroidism and 5 had transient hypoparathyroidism. The higher risk of surgery complications in forward stepwise logistic regression was associated in with distant metastases (R2 = 0.584, OR 52.63, p = 0.010). CONCLUSIONS: Postoperative complications were significantly associated with presence of distant metastases. Favorable results were observed in with children with MEN2 syndrome.

Testosterone imbalance may link depression and increased body weight in premenopausal women.

Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance.

Associations Between Anxiety, Body Mass Index, and Sex Hormones in Women.

Background: Several studies have shown a positive association between anxiety and obesity, particularly in women. We aimed to study whether sex hormone alterations related to obesity might play a role in this association. Patients and methods: Data for this study were obtained from a population-based cohort study (the LIFE-Adult-Study). A total of 3,124 adult women (970 premenopausal and 2,154 postmenopausal) were included into the analyses. The anxiety symptomatology was assessed using the GAD-7 questionnaire (cut-off ≥ 10 points). Sex hormones were measured from fasting serum samples. Results: We did not find significant differences in anxiety prevalence in premenopausal obese women compared with normal-weight controls (4.8% vs. 5.5%). Both obesity and anxiety symptomatology were separately associated with the same sex hormone alteration in premenopausal women: higher total testosterone level (0.97 ± 0.50 in obese vs. 0.86 ± 0.49 nmol/L in normal-weight women, p = 0.026 and 1.04 ± 0.59 in women with vs. 0.88 ± 0.49 nmol/L in women without anxiety symptomatology, p = 0.023). However, women with anxiety symptomatology had non-significantly higher estradiol levels than women without anxiety symptomatology (548.0 ± 507.6 vs. 426.2 ± 474.0 pmol/L), whereas obesity was associated with lower estradiol levels compared with those in normal-weight group (332.7 ± 386.5 vs. 470.8 ± 616.0 pmol/L). Women with anxiety symptomatology had also significantly higher testosterone and estradiol composition (p = 0.006). No associations of sex hormone levels and BMI with anxiety symptomatology in postmenopausal women were found. Conclusions: Although both obesity and anxiety symptomatology were separately associated with higher testosterone level, there was an opposite impact of anxiety and obesity on estradiol levels in premenopausal women. We did not find an evidence that the sex hormone alterations related to obesity are playing a significant role in anxiety symptomatology in premenopausal women. This could be the explanation why we did not find an association between obesity and anxiety. In postmenopausal women, other mechanisms seem to work than in the premenopausal group.

Serum Uric Acid Levels as an Indicator for Metabolically Unhealthy Obesity in Children and Adolescents.

BACKGROUND: Metabolically healthy obesity (MHO) refers to those individuals who do not show cardiometabolic abnormalities. Our aim was to identify potential clinical and metabolic indicators that may help to distinguish between metabolically healthy and unhealthy individuals amongst overweight and obese children and adolescents. METHODS: The study involved 246 overweight/obese and 212 normal-weight individuals enrolled in the LIFE Child study, aged between 6 and 18 years. Overweight/obese individuals without cardiovascular risk factors (fasting serum lipids, blood pressure, and glucose) were classified as MHO. Individuals meeting 1 or more criteria of cardiovascular risk factors were classified as metabolically unhealthy obesity (MUO). RESULTS: Among the 246 overweight/obese individuals, 173 (70%) were MHO and 73 (30%) were MUO. The MHO individuals were younger, more likely to be male, and had lower BMI SDS. In the logistic regression models, uric acid (UA) SDS (OR 1.61, 95% CI 1.1-2.6, p = 0.004), waist circumference SDS (OR 2.50, 95% CI 1.2-6.4, p = 0.017), and C-peptide (OR 4.05, 95% CI 3.5-91, p = 0.003) were significant indicators of MUO. CONCLUSION: Our results suggest that nearly one-third of overweight/obese children are already identified as MUO. Serum levels of UA can be used as an indicator of unhealthy obesity in youth, where lower levels of UA indicate a lower risk and higher levels suggest a higher risk of MUO. We note that the relevance of identifying potential indicators remains the first most important step in future clinical research.