Einfluss genetischer Varianten auf den Fett- und Zuckerstoffwechsel bei Kindern

Ziel dieser Arbeit war es Kandidatengene, die mit der Entwicklung von Adipositas assoziiert sind, auf eine veränderte Kopienzahl zu untersuchen. Zwar fanden wir in den von uns ausgewählten Genen keine Veränderungen der Kopienzahl, es gelang uns jedoch der Nachweis eines Nukleotid-Polymorphismus in SIM1 (rs3734354). Für diesen konnten wir erstmals eine Assoziation mit Parametern der Adipositas in einer Kinderkohorte zeigen. Weiterführend untersuchten wir die Effekte von Typ-2-Diabetes-assoziierten SNPs auf Glukosehomöostase und Insulinmetabolismus. Wir fanden eine Assoziation von rs2877716 (ADCY5) mit einer verminderten Insulinsekretion und von rs17271305 (VPS13C) mit einem erhöhten Nüchternglukosespiegel. Zusammenfassend unterstreichen die Effekte von SNPs wie VPS13C und ADCY5 die Komplexität der bisher unvollständig verstandenen Interaktionen von Alter, Genotyp und Phänotyp auf die Entwicklung des Typ-2-Diabetes. Für die Entwicklung der Adipositas scheinen Veränderungen der Kopienzahl in den untersuchten Genen bei übergewichtigen Kindern eine untergeordnete Rolle zu spielen. Weiterführende Arbeiten sind zur Erklärung der Heritabilität beider Krankheitsbilder und der komplexen Interaktionen von Phänotyp und Genotyp notwendig.:1 Bibliographische Beschreibung 2 Einführung 2.1 Bedeutung und Interaktion von Diabetes und Adipositas 2.2 Überblick Genetik Adipositas und Typ-2-Diabetes: Epidemiologie, Monogen vs. Polygen und Methodik 2.3 Der Leptin-Melanocortin Kreislauf 2.4 Überblick über Gene des Leptin-Melanocortin Kreislaufs (Leptin, POMC, MCR, SIM1) 2.5 Von Adipositas zu Diabetes 2.6 Charakteristik der Typ-2-Diabetes Kandidatengene (GIPR, ADCY5, GCKR, VPS13C) 2.7 Ziele der Arbeit 3 Publikation 1 'Copy number variations in “classical” obesity candidate genes are not frequently associated with severe early-onset obesity in children' 4 Publikation 2 'Effects of Genetic Variants in ADCY5, GIPR, GCKR and VPS13C on Early Impairment of Glucose and Insulin Metabolism in Children' 5 Zusammenfassung der Arbeit 6 Literaturverzeichnis 7 Anlagen 7.1 Supplementary Methods, Publikation 1 7.2 Supplementary Methods, Publikation 2 7.3 Erklärung über die eigenständige Abfassung der Arbeit 7.4 Erklärung über den wissenschaftlichen Beitrag des Promovenden an der ausgewählten Publikation 7.5 Lebenslauf 7.6 Publikationsverzeichnis 7.7 Danksagun

Effects of Genetic Variants in ADCY5, GIPR, GCKR and VPS13C on Early Impairment of Glucose and Insulin Metabolism in Children

OBJECTIVE: Recent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and insulin levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C) in early impairment of glucose and insulin metabolism in children. RESEARCH DESIGN AND METHODS: We genotyped four variants (rs2877716; rs1260326; rs10423928; rs17271305) in 638 Caucasian children with detailed metabolic testing including an oGTT and assessed associations with measures of glucose and insulin metabolism (including fasting blood glucose, insulin levels and insulin sensitivity/secretion indices) by linear regression analyses adjusted for age, sex, BMI-SDS and pubertal stage. RESULTS: The major allele (C) of rs2877716 (ADCY5) was nominally associated with decreased fasting plasma insulin (P = 0.008), peak insulin (P = 0.009) and increased QUICKI (P = 0.016) and Matsuda insulin sensitivity index (P = 0.013). rs17271305 (VPS13C) was nominally associated with 2 h blood glucose (P = 0.009), but not with any of the insulin or insulin sensitivity parameters. We found no association of the GIPR and GCKR variants with parameters of glucose and insulin metabolism. None of the variants correlated with anthropometric traits such as height, WHR or BMI-SDS, which excluded potential underlying associations with obesity. CONCLUSIONS: Our data on obese children indicate effects of genetic variation within ADCY5 in early impairment of insulin metabolism and VPS13C in early impairment of blood glucose homeostasis

The Strelau Temperament Inventory-Revised (STI-R): Theoretical considerations and scale development

he development of a revised Strelau Temperament Inventory (STI-R) is reported. It is assumed that the STI-R provides a measure of the basic central nervous system (CNS) properties (strength of excitation, strength of inhibition, and mobility of the CNS) as understood by Pavlov. On the basis of a series of studies, the development of the final forms of the revised STI has undergone several steps. The following forms have been elaborated: (1) a 252-item pilot form of the STI-R; (2) a 166-item STI-R with ‘yes’ and ‘no’ answer format; (3) a short form (84 items) of the STI-R (STI-RS) with ‘yes’ and ‘no’ answer format; (4) a 166-item STI-R with a 4-point Likert scale; and (5) an 84-item STI-RS with a 4-point rating scale. The psychometric characteristics of the consecutive versions of the revised STI improved from step to step, and in general these characteristics are judged as being satisfactory. Especially recommended by the authors are versions (4) and (5), which have, among other things, the highest reliability scores. They are regarded as the final forms of the STI-R and STI-RS

Enhanced biodegradation of hexachlorocyclohexane (HCH) in contaminated soils via inoculation with Sphingobium indicum B90A.

Soil pollution with hexachlorocyclohexane (HCH) has caused serious environmental problems. Here we describe the targeted degradation of all HCH isomers by applying the aerobic bacterium Sphingobium indicum B90A. In particular, we examined possibilities for large-scale cultivation of strain B90A, tested immobilization, storage and inoculation procedures, and determined the survival and HCH-degradation activity of inoculated cells in soil. Optimal growth of strain B90A was achieved in glucose-containing mineral medium and up to 65% culturability could be maintained after 60 days storage at 30 degrees C by mixing cells with sterile dry corncob powder. B90A biomass produced in water supplemented with sugarcane molasses and immobilized on corncob powder retained 15-20% culturability after 30 days storage at 30 degrees C, whereas full culturability was maintained when cells were stored frozen at -20 degrees C. On the contrary, cells stored on corncob degraded gamma-HCH faster than those that had been stored frozen, with between 15 and 85% of gamma-HCH disappearance in microcosms within 20 h at 30 degrees C. Soil microcosm tests at 25 degrees C confirmed complete mineralization of [(14)C]-gamma-HCH by corncob-immobilized strain B90A. Experiments conducted in small pits and at an HCH-contaminated agricultural site resulted in between 85 and 95% HCH degradation by strain B90A applied via corncob, depending on the type of HCH isomer and even at residual HCH concentrations. Up to 20% of the inoculated B90A cells survived under field conditions after 8 days and could be traced among other soil microorganisms by a combination of natural antibiotic resistance properties, unique pigmentation and PCR amplification of the linA genes. Neither the addition of corncob nor of corncob immobilized B90A did measurably change the microbial community structure as determined by T-RFLP analysis. Overall, these results indicate that on-site aerobic bioremediation of HCH exploiting the biodegradation activity of S. indicum B90A cells stored on corncob powder is a promising technology