Diurnal rythm of Nampt is gender and weight dependent.

RESEARCH AIM: Nicotinamide phosphoribosyltransferase (Nampt) is an adipocytokine that is elevated in obesity, type 2 diabetes and increased levels are associated with inflammatory processes. Nampt serum concentrations have been suggested to follow a diurnal rhythm peaking in the afternoon in lean males. However, no data exists regarding the effects of gender and body weight. MATERIAL AND METHODS: We measured Nampt serum levels over 24 h in a cohort of healthy individuals living with either normal weight or obesity. Furthermore, effects of meals, oral glucose tolerance test and physical exercise on Nampt concentrations were evaluated. Correlation analyses to other hormonal- and lab parameters and anthropometric measurements were performed. RESULTS: Nampt showed a diurnal rhythm with increased levels at daytime and a peak in the early afternoon. This diurnal rhythm was significant for all groups but obese males. The Nampt amplitude, measured both relatively and absolutely, was significantly higher in females than in males. Meals did not influence Nampt serum levels, whereas physical exercise and an OGTT did significantly influence Nampt serum levels. CONCLUSION: In conclusion, we found gender specific differences in Nampt amplitude and coefficient variation with both being higher in females. The circadian rhythm of Nampt was independent of gender in healthy lean individuals, whereas it was disturbed in men with obesity.

Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

Health related quality of life associated with extreme obesity in adolescents - results from the baseline evaluation of the YES-study.

BACKGROUND: Obesity can significantly reduce health-related quality of life (HRQoL) and may lead to numerous health problems even in youths. This study aimed to investigate whether HRQoL varies among youths with obesity depending on grade of obesity and other factors. METHODS: For the Youths with Extreme obesity Study (YES) (2012-2014), a prospective multicenter cohort study, a baseline sample of 431 obese and extremely obese adolescents and young adults (age 14 to 24 years, BMI ≥30 kg/m2) was recruited at four German university medical centers and one job center. Obesity grade groups (OGG) were defined according to BMI (OGG I: 30-34.9 kg/m2, OGG II: 35-39.9 kg/m2, OGG III (extreme obesity): ≥40 kg/m2). HRQoL was measured with the Euroqol-5D-3 L (EQ-5D-3 L), DISABKIDS chronic generic (DCGM-31) and the KINDLR obesity module. Differences between OGGs were assessed with logistic and linear regression models, adjusting for age, sex, and study center in the base model. In a second regression analysis, we included other characteristics to identify possible determinants of HRQoL. RESULTS: Three hundred fifty-two adolescents (mean age: 16.6 (±2.4), mean BMI: 39.1 (±7.5) kg/ m2) with available HRQoL data were analysed. HRQoL of youths in all OGGs was markedly lower than reference values of non-obese adolescents. Adjusting for age and sex, HRQoL of youths in OGG III significantly impaired compared to OGG I. Youths in OGG III were 2.15 times more likely to report problems with mobility in the EQ-5D-3 L than youths in OGG I. A mean difference of 9.7 and 6.6 points between OGG III and I were found for DCGM-31 and KINDL respectively and 5.1 points between OGG II and I for DCGM-31. Including further variables into the regression models, showed that HRQoL measured by DCGM-31 was significantly different between OGGs. Otherwise, female sex and having more than 4 h of daily screen time were also associated with lower HRQoL measured by DCGM-31 and KINDL. CONCLUSION: HRQoL of adolescents with obesity is reduced, but HRQoL of adolescents with extreme obesity is particularly affected. Larger and longitudinal studies are necessary to understand the relation of extreme obesity and HRQoL, and the impact of other lifestyle or socioeconomic factors. TRIAL REGISTRATION: Clinicaltrials.gov NCT01625325; German Clinical Trials Register (DRKS) DRKS00004172.

Associations of Speaking-Voice Parameters With Personality and Behavior in School-Aged Children.

OBJECTIVES: Previous studies suggest a link between voice disorders and personality traits. However, nearly nothing is known about the relationship between personality and voice parameters in healthy children. The present study investigated associations between children's personality and the intensity and frequency of their speaking voice. STUDY DESIGN: This is a cross-sectional analysis. METHODS: The study participants included 871 German children aged from 7 to 14 who had not yet experienced voice change in puberty. Within the framework of the LIFE Child study, all participants were asked to perform a speaking-voice task at four different intensity levels (quietest, conversational, presentation, and shouting voice). Associations of fundamental frequency and voice intensity with children's personality and behavioral strengths and difficulties (assessed using parent-reported questionnaires) were estimated using multiple linear regression analyses. RESULTS: With respect to children's personality, the analyses revealed significant positive associations between speaking-voice intensity and extraversion (eg, for the conversational voice, ß = 0.16, P < 0.001) as well as significant negative associations between voice intensity and emotional stability (eg, for the shouting voice, ß = -0.15, P = 0.004) and conscientiousness (for the shouting voice, ß = -0.10, P = 0.033). Regarding behavioral strengths and difficulties, we observed significant positive associations between voice intensity and peer-relationship problems (eg, for the conversational voice, ß = 0.14, P = 0.001) and prosocial behavior (for the conversational voice, ß = 0.11, P = 0.015). In contrast, no significant association was found between speaking fundamental frequency and personality or behavioral difficulties/strengths. CONCLUSIONS: In children, associations exist between a child's speaking-voice intensity and his or her personality, especially extraversion and emotional stability, and behavioral characteristics.

Children and adolescents with obesity have reduced serum bone turnover markers and 25-hydroxyvitamin D but increased parathyroid hormone concentrations - Results derived from new pediatric reference ranges.

BACKGROUND: We aimed to establish age- and gender-specific reference ranges for concentrations of the bone markers osteocalcin (OC), procollagen type 1 N-propeptides (PINP) and carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX-I) as well as for the calciotropic hormones 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in healthy infants, children and adolescents. In addition, the effect of age, gender, puberty and body mass index (BMI) on bone markers was investigated. METHODS: 2416 healthy subjects (5714 blood withdrawals), aged 3 months to 17 years, were included to estimate the age- and gender-dependence of reference ranges. Subsequently, measured values of the biomarkers were transformed to standard deviation scores (SDS) and their associations with age, gender and puberty were analyzed. Bone marker-SDS values of the reference cohort were compared with an obese cohort (n = 317 and 489 blood withdrawals) to analyze the effect of BMI. RESULTS: OC, PINP and CTX-I showed a distinct age- and gender-dependence with peak levels at 10 to 11 years (girls, Tanner 3) and 13 years (boys, Tanner 3-4). Children with obesity had significantly lower SDS levels for OC (-0.44), PINP (-0.27), CTX-I (-0.33), 25(OH)D (-0.43) and higher SDS levels for PTH (+0.44) than the reference cohort. CONCLUSIONS: OC, PINP and CTX-I vary with age, gender and pubertal stage. The body weight status has to be considered in the interpretation of pediatric OC, PINP, CTX-I, 25(OH)D and PTH levels. Consequences of childhood obesity on bone health should be carefully investigated in long-term studies.

Dental health, halitosis and mouth breathing in 10-to-15 year old children: A potential connection.

AIM: The relationship between mouth breathing and dental caries, gingival inflammation, and halitosis in children is contentious with studies reporting positive and negative associations; this study aimed at investigating the effect of mouth breathing on dental, gingival health status, and halitosis. MATERIALS AND METHODS: An observational cross-sectional study was carried out involving 785 randomly selected children and adolescents between the ages of 10 and 15 in the city of Leipzig, Germany (LIFE Child cohort). Caries levels and gingival health status for the upper-right and the lower-left central incisors were assessed by evaluating ICDAS scores and CPI scores, respectively. A standardised questionnaire was used to assess self-reported mouth-breathing habit and halitosis. RESULTS: This study showed a statistically significant association between halitosis and mouth breathing (OR=3.0; 95% CI: 1.5-6.2), and a significant increase in mouth breathing habit in males compared to females (59.7% vs. 40.3%; p<0.05). There were no statistically significant differences in ICDAS scores, orthodontic treatment, CPI scores, or socioeconomic status between the mouth and nasal-breathing groups. CONCLUSION: Mouth breathing habit has no effect on the prevalence of caries or gingivitis based on examining the upper-right central incisor (11) and the lower-left central incisor. However, mouth breathers showed a significant increase in halitosis compared to nasal-breathing individuals.

Incompatibilities in paediatric intensive care - pitfalls in drug information.

Drug incompatibilities can lead to loss of effectiveness of drugs or to increased risk for undesirable effects that can even be life-threatening. Especially children are at high risk. Databases are an important source of information in routine care to avoid incompatibilities. However, they were supposedly developed considering drugs for use in adults. Thus, we analysed to what extent databases are appropriate for the identification of incompatibilities in intravenous (i.v.) drug therapy in paediatric intensive care. We analysed the information provided by two databases (Database A and B) on all pairs of two drugs prescribed to be administered via the same i.v. access line in a university paediatric intensive care unit during the study period of 50 days. A total of 50 different i.v. drugs was prescribed in 318 different combinations (drug pairs). We found information on (in)compatibilities in 23.0 % (73/318) in Database A and in 31.1 % (99/318) in Database B. Only in 11.0 % (35/318) of the drug pairs, both databases provided information. Considering those drug pairs, in 17.1 % (6/35) Database B indicated compatibility whereas Database A indicated incompatibility. Compatibility information delivered by databases on drugs used in paediatric intensive care is incomplete, heterogeneous, and partly contradictory. Thus, an increased awareness on the strengths and limitations of different databases is necessary to avoid patient harm.

How do parents perceive adverse drug events of their children's anticonvulsant medication?

BACKGROUND: The main source of knowledge on adverse drug events (ADE) are physicians' reports in controlled clinical trials. In contrast, little is known about the parents' perception of ADE of anticonvulsants their children receive. METHODS: After approval by the local ethics committee, we performed a survey in a neuropediatric outpatient clinic of a university hospital. Based on a structured questionnaire, we interviewed parents of children with current anticonvulsant treatment regarding (i) their fears about potential ADE, (ii) experienced ADE according to parents, and (iii) implications of ADE on the child's life. RESULTS: Parents of 150 patients took part in the interview. (i) 95 (63.3%) parents expressed fears concerning ADE, mostly liver injury/liver failure (33 [22%]). (ii) 129 (86%) parents reported experienced ADE, mostly sedation (65 [43.3%]) and abnormal behavior (54 [36%]). (iii) Parents reported substantial implications of ADE on the child's daily life for 84 (56%) children, and 63 (42%) parents expressed a negative impact on the child's development. CONCLUSION: We recognized a great discrepancy between those ADE that were feared and those that were experienced. Parents feared life-threatening ADE and experienced less severe ADE that nevertheless have a negative impact on the child's daily life.

The BDNF Val66Met polymorphism is associated with lower BMI, lower postprandial glucose levels and elevated carbohydrate intake in children and adolescents.

BACKGROUND: The amino acid-changing exonic variant rs6265 (Val66Met polymorphism) in the brain-derived neurotrophic factor (BDNF) has been linked to obesity in several genotype-phenotype association studies. OBJECTIVE: To identify metabolic factors by which this effect might be conveyed, we aimed to investigate its correlation with (i) obesity, (ii) metabolic parameters, (iii) serum levels of BDNF and (iv) measures of energy intake in children and adolescents. METHODS: We genotyped the variant in 2131 subjects (age 6-18 years) and checked for an association with obesity. Secondly, we correlated the genotype with parameters of glucose and lipid metabolism (fasting/postprandial glucose and insulin levels, HbA1c, homeostasis model assessment, Matsuda, high-density lipoprotein, low-density lipoprotein, total cholesterol and triglycerides) in a smaller subset of 845 subjects. We determined BDNF serum levels in 177 individuals by enzyme-linked immunosorbent assay and assessed the association with genotype and metabolic parameters. Finally, we investigated the association between genotype and macronutrient intake from self-reported food diaries (n = 146). RESULTS: The minor Met allele was associated with lower BMI standard deviation score (p = 0.002). Post-pubertal Met allele carriers showed lower postprandial glucose levels and a lower HbA1c (ß = 0.15, p = 0.046 and ß = 0.27, p = 0.012, respectively). Neither the genotype nor any of the metabolic parameters correlated with BDNF serum levels. We observed an increased total calorie intake (ß = -0.21, p = 0.007) with increased carbohydrate and protein intake (ß = -0.22, p = 0.005 and ß = -0.14, p = 0.028, respectively) in Met allele carriers. CONCLUSIONS: We confirmed the association of the minor Met allele with lower BMI in children and provide new data that it is associated with lower postprandial glucose in post-pubertal subjects. Moreover, Met allele carriers reported to consume more carbohydrates and proteins.

Factors associated with the emotional health of children: high family income as a protective factor.

Anxiety and depressive symptoms have adverse effects on children's development. The present study investigates the associations of socioeconomic factors as well as maternal emotional health with children's emotional health status. The data were collected between 2011 and 2015 in the LIFE Child study, a population-based cohort study in Leipzig, Germany. The emotional health status of 1093 children (2.5-11.9 years old) was investigated using the subscale 'emotional problems' of the Strengths and Difficulties Questionnaire. Associations of maternal emotional health, family status, and socioeconomic status (SES) with the emotional health status of children were estimated via regression analyses. 21.13% of the participating children were assigned to the 'risk' group for emotional problems. The results furthermore revealed that children of mothers reporting more depressive symptoms, children living in single-parent families, and children of families with lower SES scored higher in the emotional problems scale. When considering the different indicators of SES (parental education, occupational status, and monthly net income) separately, only income showed significant associations with children's emotional health status. The prevalence of emotional problems in children in Leipzig, a city in East Germany, appears to be higher than the previously reported German average. Maternal depressive symptoms, single-parent families, lower SES, and especially lower income can be seen as risk factors for children's emotional health.

[Prevalence of Gastroschisis, Omphalocele, Spina Bifida and Orofacial Clefts of Neonates from January 2000 to December 2010 in Leipzig, Saxony, Saxony-Anhalt and Germany]. / Prävalenz von Gastroschisis, Omphalozele, Spina bifida und orofazialen Spaltbildungen bei Neugeborenen im Zeitraum Januar 2000­Dezember 2010 in Leipzig, Sachsen, Sachsen-Anhalt und Deutschland.

BACKGROUND: Malformations are the most common cause of death in infancy. Numerous studies indicate an increased prevalence of malformations in neonates in recent years in some countries around the world. This study analyzed local and national trends of the prevalences of gastroschisis, omphalocele, spina bifida and orofacial clefts during 2000 till 2010 in Leipzig, Saxony, Saxony-Anhalt and Germany. METHODS: The prevalence of neonatal malformations was studied retrospectively from January 2000 till December 2010 using 4 sources from Leipzig, Saxony, Saxony-Anhalt and Germany. RESULTS: Between 2000 and 2010, the prevalence in Germany and in Saxony, respectively was 1.97/2.12 (gastroschisis), 1.63/1.48 (omphalocele), 5.80/8.11 (orofacial clefts) and 2.92/2.50 (spina bifida) of 10 000 live births. In Saxony, a small increase in prevalence was detected (OR/year: 1.01-1.09). In Germany, the prevalence of malformations also increased significantly (OR/year: 1.01-1.04) with the exception of the prevalence of spina bifida which seemed to decline (OR/year 0.986 (0.97-1.0), p-adjust=0.04). CONCLUSION: Whether or not there has been an actual increase in the prevalence of neonatal malformations in Germany over the years or the apparent increase is just due to bias, coding errors, multiple reporting and/or false registration and codification remains unclear. Importantly, in Germany, since prevalence of malformations is monitored prospectively only in Saxony-Anhalt and Rhineland-Palatinate, only in these states is it possible to recognize recent changes. For early identification of changes in prevalence and timely implementation of preventive measures, a nationwide register or additional regional registers are deemed necessary.

[Endocrine disruptors : Evidence from epidemiological studies necessitates a critical review of model systems]. / Endokrine Modulatoren : Hinweise aus epidemiologischen Studien bedürfen einer kritischen Überprüfung in Modellsystemen.

Endocrine disruptive chemicals (EDCs) cause adverse health effects through interaction with endocrine systems. They are classified by chemical structure, effects on specific endocrine systems, bioaccumulation, persistence in the environment, or clinically observable effects. For research of the complex mechanisms of action in the human body, only in vitro model systems have so far been available, that have insufficient high-throughput capacity, which makes risk evaluation more difficult. In addition, in industrial nations, living people are often exposed to mixtures of substances, with various effects. The clinical importance of epigenetic changes caused by the action of EDCs during vulnerable phases of development is currently unclear. Epidemiological studies are criticized because reproducibility is not always guaranteed. Nevertheless, they remain the method of choice for the development and analysis of suitable model systems. Positive associations, in spite of sometimes conflicting results, are key in the selection of factors that can then be analysed in model systems in an unbiased way. This article depicts the mainly positive epidemiological findings for EDC-caused effects in the fields of growth and metabolism, neurocognitive development and sexual development and reproduction. As a result, there is a need for closer linkage between epidemiological studies and mechanistic research into model systems, especially focusing on the interaction of different EDCs and the consequences of prenatal and early life exposure.

Adipocyte C1QTNF5 expression is BMI-dependently related to early adipose tissue dysfunction and systemic CTRP5 serum levels in obese children.

BACKGROUND/OBJECTIVES: The recently identified adipocytokine C1QTNF5 (encodes for CTRP5) has been demonstrated to inhibit pro-metabolic insulin signaling in adipocytes. We hypothesized that adipocyte C1QTNF5 expression in subcutaneous (sc) adipose tissue (AT) would correlate with the degree of obesity, systemic CTRP5 serum levels, and early AT and metabolic dysfunction in children. SUBJECTS/METHODS: Sc AT samples were obtained from 33 healthy Caucasian lean children aged 10.06±4.84 years and 42 overweight and obese children aged 13.34±3.12 years. C1QTNF5 expression in sc AT as well as in investigated cell lines was assessed by quantitative real-time PCR. Systemic CTRP5 levels were assessed by ELISA. RESULTS: C1QTNF5 expression in sc adipocytes increased with body mass index (BMI) standard deviation score (SDS; R=0.48, P<0.001), body fat percentage (R=0.4, P=0.004), adipocyte number (R=0.69, P<0.001) and systemic CTRP5 serum levels (R=0.28, P=0.025) whereas expression in the stromal vascular fraction (SVF) was inversely correlated with BMI SDS (R=-0.24, P=0.04). Multiple regression analysis confirmed that BMI SDS was the strongest independent predictor for C1QTNF5 expression in sc adipocytes. SVF C1QTNF5 levels strongly correlated with SVF CD31 expression (R=0.54, P<0.001) indicating expression by endothelial cells. Primary human endothelial cells demonstrated stronger expression compared with human Simpson-Golahbi-Behmel syndrome pre-adipocytes and adipocytes. Adipocyte C1QTNF5 expression levels were BMI-dependently related to fasting insulin (R=0.3, P=0.03) and leptin serum levels (R=0.5, P<0.001). Sc AT samples containing crown-like structures (CLS) demonstrated increased adipocyte C1QTNF5 expression compared to CLS-negative samples (P=0.03). Functionally, tumor necrosis factor (TNF)α caused a fourfold induction of C1QTNF5 in human adipocytes (P<0.001) and a 50% reduction in primary human endothelial cells (P<0.001). CONCLUSIONS: In children adipocyte C1QTNF5 expression is already strongly related to the degree of obesity and is associated with obesity-related AT alterations, systemic CTRP5 serum levels as well as circulating markers of metabolic disease and is positively regulated by TNFα in vitro.

METRNL decreases during adipogenesis and inhibits adipocyte differentiation leading to adipocyte hypertrophy in humans.

BACKGROUND: Meteorin-like (METRNL) is a recently described circulating protein shown to be highly expressed in white adipose tissue and to beneficially affect energy metabolism in mice. OBJECTIVE: We systematically evaluated the role of METRNL for human adipogenesis and its association with obesity, browning and hyperinsulinemia in children. In addition, we assessed the functional relevance of METRNL for human adipogenesis. RESULTS: METRNL expression decreased during human adipocyte differentiation in vitro. Coherently, METRNL expression was lower in isolated adipocytes compared with stromal vascular fraction (SVF) cells in human samples. Withdrawal of the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone from adipogenic media partially preserved the METRNL downregulation during adipogenesis. METRNL expression was higher in adipocytes of obese compared with lean children and correlated with adipocyte size, whereas in SVF METRNL expression correlated with proliferation capacity. Concordantly, overexpression of METRNL inhibited human adipocyte differentiation as shown by decreased lipogenesis and lower expression of PPARγ and markers of adipogenesis, whereas experimental downregulation promoted adipogenesis. Proliferation, in contrast, was advanced by METRNL overexpression. These interactions with adipose tissue dynamics may contribute to the clinically observed body mass index-independent association of METRNL expression with hyperinsulinemia and adipose tissue inflammation in human samples. METRNL was not associated with UCP1 expression or induction of browning in white adipocytes. CONCLUSIONS: Taken together, the downregulation of METRNL during adipogenesis and functional induction of increased proliferation in SVF cells with concomitant inhibition of adipocyte differentiation may result in hypertrophic AT accumulation. This may also explain our observations of increased METRNL expression in adipocytes but not SVF cells in obese children compared with lean children and the subsequent hyperinsulinemia.

Nicotinamide phosphoribosyltransferase production in human spermatozoa is influenced by maturation stage.

High amounts of nicotinamide phosphoribosyltransferase (NAMPT) were found in human seminal plasma. This enzyme influences energy metabolism and apoptosis and is essential for the regulation of cellular nicotinamide adenine dinucleotide (NAD)+ levels in somatic cells. NAD+ is required as a co-substrate for dehydrogenases, which are potentially important for spermatogenesis. The functional significance of intra- and extracellular NAMPT in human reproduction, however, has not been defined yet. The objectives of the study were therefore to determine NAMPT protein expression in human spermatozoa and testes, the secretion of NAMPT by spermatozoa depending on their maturation stage and the impact of NAMPT enzymatic function on sperm viability, motility, fertilisation capacity and induction of apoptosis. Firstly, we detected NAMPT protein in different cell types of human testes. NAMPT protein was also detected in spermatozoa, with significantly higher amounts in immature than in mature ejaculated spermatozoa. Additionally, NAD+ levels were significantly higher in immature than in mature spermatozoa. Secondly, NAMPT was released into the supernatant of human spermatozoa, with significantly higher NAMPT levels in supernatant of immature spermatozoa compared with mature cells. Finally, the specific inhibition of the enzyme by FK866 did not influence motility, capacitation or apoptosis signalling. In summary, NAMPT is produced in human spermatozoa in a maturation-dependent manner.

Prepubertal onset of obesity negatively impacts on testicular steroidogenesis in rats.

Obesity is a global health problem and impacts negatively on levels of testosterone and quality of sperm production. At present little is known about mechanisms that attenuate testicular function in obese males. Our study characterized testicular steroidogenesis and explored levels of relevant paracrine and hormonal factors in rats with short- and long-term obesity. We have found that obesity state increased serum levels of estradiol and leptin in both groups of obese rats and inhibited the expression of StAR and Cyp11a1 associated with low levels of intratesticular testosterone in rats with long-term obesity. Further, long-term obesity reduced the number of Leydig cells, increased the testicular levels of the proinflammatory adipocytokine TNFα and the number of testicular macrophages. All together, our data indicate that long-term obesity may cause chronic inflammation in the testis and negatively impacts on Leydig cell steroidogenesis.

Insulin-Like Peptide 5 Interacts with Sex Hormones and Metabolic Parameters in a Gender and Adiposity Dependent Manner in Humans.

Insulin-like peptide 5 (INSL5) is a gut hormone produced by L-cells in the colorectal epithelium and may play a role in the regulation of metabolic processes. The biological role of INSL5 is poorly investigated and nothing is known about the role of this hormone in obese and lean humans. Two cohorts were analyzed in the study. In the first cohort (n=76) the relationship between serum levels of INSL5 and different metabolic and hormonal parameters in obese and lean men and women were investigated. In the second cohort 14 male subjects underwent bariatric surgery. Circulating levels of INSL5 were then measured before and after interventions.We report for the first time that circulating INSL5 interacts with multiple metabolic and hormonal variables in lean and obese men and women and is affected by bariatric surgery. Serum levels of INSL5 negatively correlated with testosterone and blood lipids but positively with cortisol in obese men. In contrast to males, obese women had a strong negative correlation of plasma levels of INSL5 with C-reactive protein (CRP). We observed that adipose tissue loss after bariatric surgery significantly reduced serum levels of INSL5 in obese men with and without Type 2 Diabetes Mellitus (T2DM) that was associated with the restoration of circulating levels of testosterone. All together, our data demonstrated that INSL5 may interact with some metabolic parameters in obese humans and this process is dependent of gender and obesity state.

Primary prevention of beta-cell autoimmunity and type 1 diabetes - The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives.

OBJECTIVE: Type 1 diabetes can be identified by the presence of beta-cell autoantibodies that often arise in the first few years of life. The purpose of this perspective is to present the case for primary prevention of beta-cell autoimmunity and to provide a study design for its implementation in Europe. METHODS: We examined and summarized recruitment strategies, enrollment rates, and outcomes in published TRIGR, FINDIA and BABYDIET primary prevention trials, and the TEDDY intensive observational study. A proposal for a recruitment and implementation strategy to perform a phase II/III primary prevention randomized controlled trial in infants with genetic risk for developing beta-cell autoimmunity is outlined. RESULTS: Infants with a family history of type 1 diabetes (TRIGR, BABYDIET, TEDDY) and infants younger than age 3 months from the general population (FINDIA, TEDDY) were enrolled into these studies. All studies used HLA genotyping as part of their eligibility criteria. Predicted beta-cell autoimmunity risk in the eligible infants ranged from 3% (FINDIA, TEDDY general population) up to 12% (TRIGR, BABYDIET). Amongst eligible infants, participation was between 38% (TEDDY general population) and 97% (FINDIA). Outcomes, defined as multiple beta-cell autoantibodies, were consistent with predicted risks. We subsequently modeled recruitment into a randomized controlled trial (RCT) that could assess the efficacy of oral insulin treatment as adapted from the Pre-POINT pilot trial. The RCT would recruit infants with and without a first-degree family history of type 1 diabetes and be based on general population genetic risk testing. HLA genotyping and, for the general population, genotyping at additional type 1 diabetes susceptibility SNPs would be used to identify children with around 10% risk of beta-cell autoimmunity. The proposed RCT would have 80% power to detect a 50% reduction in multiple beta-cell autoantibodies by age 4 years at a two-tailed alpha of 0.05, and would randomize around 1160 infants to oral insulin or placebo arms in order to fulfill this. It is estimated that recruitment would require testing of between 400,000 and 500,000 newborns or infants. CONCLUSION: It is timely and feasible to establish a platform for primary prevention trials for type 1 diabetes in Europe. This multi-site European infrastructure would perform RCTs, supply data coordination and biorepository, provide cohorts for mechanistic and observational studies, and increase awareness for autoimmune diabetes.