Four studies investigating the assessment of glycaemic control in cystic fibrosis are presented within this thesis. The first was a validation study of continual glucose monitoring (CGM) in cystic fibrosis (CF). 50 stable adults with CF underwent home CGM for 3 days, during which time they attended the CF centre for OGTT. Gold standard fasting (0 hour) plasma glucose and 2 hour plasma glucose values during OGTT were compared with concurrent CGM sensor glucose values using a 'limits of agreement' analysis. CGM was found to be valid in adults with CF, with its accuracy being consistent with that published in non-CF populations. The next investigation compared OGTT with CGM with several objectives: to determine whether OGTT is a relevant and adequate measure of glycaemia in CF, find out whether CGM could offer a superior alternative to OGTT and explore whether OGTT and CGM results are associated with prior change in lung function and weight in adults with CF. Data from the first study was used to show that the OGTT can only identify abnormal glycaemic control in CF at a late stage, and that CGM is a more relevant reflection of everyday glycaemia in CF. No correlation was found between prior change in lung function and nutritional status in CF and glycaemia measured by OGTT or CGM. The subsequent study investigated whether CGM could identify early abnormal glycaemic control in CF. This involved ten non-CF healthy controls undergoing the same study protocol as the 50 stable adults with CF, to determine 'normal' glycaemic control parameters. Of 25 CF patients with normal glucose tolerance by OGTT, 19 (76%) had significantly higher mean and/or variability of CGM levels than healthy controls. This lead to changes in their management, including 2 subjects being commenced on insulin therapy. The final investigation was a questionnaire study, asking the 50 CF patients to provide information on their experience of undergoing CGM. 58% of patients responded, with replies indicating that they found CGM broadly acceptable, interfering little in their lives and that their experiences were generally positive. This insight into patients' experiences of CGM can be used to guide future clinical and research roles for this tool. These studies have provided novel data regarding the assessment of glycaemic in CF. Information captured by CGM has greater relevance to CF patients' daily lives than OGTT. CGM can identify early problems with glycaemic control leading to changes in management that may not be detected by conventional measures. CGM offers potential in further clinical application and research to improve the lives and outcomes for adults with CF.

OBJECTIVE: The key objective of the present investigation was to compare associations between sagittal abdominal diameter (SAD), waist circumference, and BMI to the oral glucose tolerance test (OGTT), along with fasting glucose, HbA1c, and HOMA-IR, in a nationally representative sample of U.S. adults. The study also analyzed the effect of multiple covariates on the anthropometric and glucose metabolism associations. METHODS: A cross-sectional design, including 3,582 subjects, was used. SAD was assessed using an abdominal caliper. All other data were collected following strict NHANES protocol. The OGTT was the primary variable used to index glucose metabolism. Fasting glucose, HbA1c, and HOMA-IR were also evaluated. RESULTS: Mean ± SE values were as follows: SAD: 22.3 ± 0.1 cm; waist circumference: 98.0 ± 0.4 cm; BMI: 28.6 ± 0.2 kg/m2; OGTT: 113.9 ± 1.0 mg/dL; fasting glucose: 99.6 ± 0.3 mg/dL; HbA1c: 5.4 ± 0.01%; HOMA-IR: 3.2 ± 0.1. SAD consistently emerged as the best predictor of all the indices of glucose metabolism, before and after adjusting for the covariates, and with the sample stratified by gender, race, or age. SAD was not a better predictor of OGTT among normal weight adults and non-Hispanic black adults. CONCLUSION: Obesity, especially abdominal obesity, is strongly related to glucose metabolism and type 2 diabetes. In the present study, SAD was the best anthropometric predictor of glucose metabolism, notwithstanding the high correlations among SAD, waist circumference, and BMI. Due to the ease of taking a SAD measurement, we recommend that healthcare providers consider the use of this simple and inexpensive method to more precisely predict diabetes risk, especially among overweight and obese adults.

INTRODUCTION/OBJECTIVES: Current screening guidelines for pre-diabetes and type 2 diabetes mellitus note that there are discrepancies in diagnosing the disease using the fasting plasma glucose test, oral glucose tolerance test, and HbA1c in high-risk populations. The objective of this study is to compare the effectiveness of screening methods for type 2 diabetes mellitus (T2DM) and pre-diabetes by race/ethnicity and gender. METHODS: Secondary analyses of the National Health and Nutrition Examination Survey (NHANES, 2005-2008) were performed using SPSS 19.0. Screening outcomes were assessed and compared for a sample of n=10,566, NHW, NHB, MA, and Multiracial/other men and women. Analyses included cross tabulations, ANOVA and partial correlations to establish disease prevalence, effectiveness of screenings, and statistical significance. RESULTS: It was found that the HbA1c test is comparable in precision, and is correlated with the FPG for racial and ethnic minorities. The specificities for detecting pre-diabetes using the HbA1c were higher (64-66%) for these groups than by using the standard, FPG screening method (42-49%). There were no strong, significant differences for screening effectiveness for men versus women. DISCUSSION: This study revealed that the HbA1c test might be an effective method for screening for pre-diabetes in racial and ethnic minorities instead of the FPG test alone. Screening in high-risk populations will help delay the onset of T2DM, with increased prevention during the pre-clinical phase.

Résumé : Le diabète gestationnel (DG), qui peut entraîner des conséquences importantes pour la mère et l’enfant, résulte d’un défaut de compensation de la sécrétion d’insuline par rapport à la résistance à l’insuline. Comme la grossesse représente en elle-même un modèle d’augmentation physiologique de la résistance à l’insuline, il est intéressant d’étudier et de caractériser les facteurs qui sont impliqués dans la résistance à l’insuline et, ultimement, dans le DG, chez la femme enceinte. Le Tumor necrosis factor alpha (TNFα) est soupçonné d’être un de ces facteurs, suite aux études effectuées chez les animaux et les populations humaines non enceintes, mais les résultats obtenus en grossesse sont encore controversés. Nous avons émis l’hypothèse que les niveaux circulants de TNFα sont associés au DG et à la résistance à l’insuline dans une large cohorte de femmes enceintes. Nous avons aussi investigué les variations des niveaux de TNFα en réponse à l’hyperglycémie provoquée par voie orale (HGPO) chez des femmes enceintes. Nous avons montré que de hauts niveaux de TNFα étaient liés à une résistance à l’insuline augmentée au 2e trimestre de la grossesse et ce, indépendamment de l’âge, de l’adiposité, de l’âge gestationnel, des triglycérides et des niveaux circulants d’adiponectine dans notre cohorte. De plus, les niveaux de TNFα varient différemment au cours de l’HGPO selon le statut de résistance à l’insuline. En effet, les niveaux de TNFα augmentent à 1h puis diminuent à 2h chez les femmes les plus sensibles à l’insuline, alors qu’ils diminuent tout au long du test chez les femmes les plus résistantes à l’insuline, mais restent en tout temps supérieurs aux niveaux mesurés chez les femmes les plus sensibles à l’insuline. Toutefois, les niveaux de TNFα n’étaient pas différents entre les femmes avec DG et celles normoglycémiques. De façon intéressante, la variation du TNFα pendant l’HGPO chez les femmes DG est similaire à celle chez les femmes avec haute résistance à l’insuline. Ces résultats suggèrent donc que le TNFα est indépendamment associé à la résistance à l’insuline en grossesse et que les voies inflammatoires peuvent contribuer aux dysfonctions glycémiques retrouvées en DG. // Abstract : Gestational diabetes mellitus (GDM), which can exert important impacts on mothers and offspring, results from an imbalance between insulin secretion capacity and insulin resistance. Pregnancy is a state of physiologically increased insulin resistance, providing a unique model to study and characterize biological factors linked to insulin resistance in humans and, ultimately, GDM, in pregnant women. Based on animal studies and analyses in non-pregnant populations, tumor necrosis factor alpha (TNFα) is suspected of being involved in insulin resistance, but results obtained from pregnant populations are still controversial. Our hypothesis was that circulating TNFα would be associated with GDM and insulin resistance in a large cohort of pregnant women. We also investigated dynamic variations of TNFα levels over the course of an oral glucose tolerance test (OGTT) in pregnant women. We showed that higher TNFα levels were associated with higher insulin resistance at 2nd trimester of pregnancy, independent of age, adiposity, gestational age, triglycerides and adiponectin levels in our cohort. Furthermore, TNFα levels varied differently over the course of the OGTT according to insulin resistance status: they rose at 1h and then decreased at 2h in insulin sensitive women, whereas they consistently decreased in insulin resistant women over the course of the test (even though they remained statistically higher than insulin sensitive women’s levels at each time point throughout the OGTT). However, TNFα levels were not different between GDM and non-GDM women. Interestingly, variation of TNFα levels over the course of the OGTT in GDM women followed the same pattern as the variation observed in OGTT in women classified with high insulin resistance. Those results suggest that circulating TNFα is independently associated with insulin resistance in pregnancy and that inflammatory pathways might contribute to glycemic dysregulation observed in GDM.

Das Metabolische Syndrom (MetSyn) ist gekennzeichnet durch eine Kombination verschiedener kardiovaskulärer Risikofaktoren: Glukoseintoleranz, Adipositas, Dyslipidämie sowie arterielle Hypertonie. Es gilt beim Menschen als eine der Hauptursachen für Herzkreislauferkrankungen und befindet sich weltweit auf enormem Vormarsch. Die Weichen für die Erkrankung werden zum Teil schon vor der Geburt durch eine veränderte Umwelt in utero gestellt. So können Stress oder eine Glukokortikoidbehandlung während der Schwangerschaft zu einem veränderten Phänotyp des Embryos/Fetus führen - mit Konsequenzen für das gesamte spätere Leben. Dieses Phänomen wird als pränatale Programmierung bezeichnet. Neben diesen epigenetischen Effekten spielen u. a. auch geschlechtsabhängige Faktoren eine Rolle für das Risiko, am MetSyn zu erkranken. Die vorliegende Arbeit befasst sich mit den Auswirkungen einer Glukokortikoidbehandlung in der frühen Trächtigkeit sowie dem Einfluss des Geschlechts auf kardiovaskuläre Risikofaktoren im Erwachsenenalter. Als Modelltier für die Studie wurde der Weißbüschelaffe eingesetzt. In einem 2002 stattgefundenen Vorversuch im Deutschen Primatenzentrum in Göttingen wurde tragenden Tieren (F0) eine Woche lang täglich oral Dexamethason verabreicht. Dieses synthetische Glukokortikoid kann die Plazentaschranke passieren. Die drei folgenden in Leipzig gehaltenen Generationen DexF1/2/3W (weibliche Tiere, n = 4/6/2) und DexF2/3M (männliche Tiere, n = 2/4) gingen in die Untersuchung ein. Tiere, die keine Nachkommen der F0-Generation darstellten, bildeten jeweils eine weibliche (ControlW, n = 11) und eine männliche (ControlM, n = 15) Kontrollgruppe und wurden ebenfalls herangezogen, um die Auswirkungen des Geschlechts auf die untersuchten Parameter zu ermitteln. Es wurde ein oraler Glukosetoleranztest (OGTT) durchgeführt (inklusive der Erfassung der Insulinwerte), der Quantitative Insulin Sensitivity Check Index (QUICKI – Maß für die Insulinsensitivität) berechnet sowie Lipidstoffwechselparameter bestimmt. Außerdem fanden wöchentlich Erfassungen des Körpergewichts statt. In mehreren Sitzungen pro Tier wurde der Blutdruck gemessen. Die statistische Auswertung erfolgte mittels Mann-Whitney-U-Test für unabhängige Stichproben. Unterschiede mit einer Irrtumswahrscheinlichkeit p ≤ 0,05 wurden als signifikant angesehen. Im OGTT wies DexF1W im Vergleich zu ControlW 120 Minuten nach oraler Glukoseapplikation eine signifikant niedrigere Insulinkonzentration auf. Da nach 30 und 120 Minuten auch die Glukosekonzentration signifikant erniedrigt war, ist jedoch nicht von einer klinischen Relevanz auszugehen. Weitere Auswirkungen der Dexamethasonapplikation auf die F1- bis F3-Generation konnten nicht beobachtet werden. Beim Vergleich der weiblichen und männlichen Nachkommen unbehandelter Weißbüschelaffen fiel auf, dass weibliche Tiere signifikant höhere Insulinkonzentrationen und damit eine signifikant größere Insulin-AUC (Fläche unter der Kurve) im OGTT zeigten. Ihr QUICKI war signifikant niedriger. Hyperinsulinämie und niedriger QUICKI stellen Symptome einer gestörten Glukoseregulation dar. Die weiblichen Tiere zeigten außerdem eine signifikante Erhöhung hinsichtlich Körpergewicht, VLDL-Triglycerid- und folglich Plasmatriglyceridkonzentrationen. Ihre HDL-Cholesterolwerte waren signifikant niedriger. Diese Kombination einer Hypertriglyceridämie mit niedrigem HDL-Cholesterol wird als atherogene Dyslipidämie bezeichnet. Eine gestörte Glukosehomöostase, eine Adipositas sowie eine atherogene Dyslipidämie stellen kardiovaskuläre Risikofaktoren und wichtige Komponenten des MetSyn dar. Zusammenfassend lässt sich sagen, dass beim Weißbüschelaffen eine Glukokortikoidbehandlung während der frühen Trächtigkeit nicht zum MetSyn der F1- bis F3-Generationen im Erwachsenenalter führte. Hingegen ergab die Untersuchung auf ein geschlechtsabhängiges Erkrankungsrisiko eine eindeutige Prädisposition bei den weiblichen Tieren. Die zu Grunde liegenden Mechanismen dieses Phänomens bleiben Gegenstand weiterer Untersuchungen. / The metabolic syndrome (MetSyn) consists of a cluster of metabolic disorders, characterized by glucose intolerance, obesity, dyslipidemia and hypertension. In humans, it is a major cause for cardiovascular disease. Its worldwide prevalence is increasing. The way for the disease can be paved even before birth. An adverse intrauterine environment due to prenatal stress or an iatrogenic overexposure of the fetus to glucocorticoids can lead to an altered phenotype with consequences for later life. This phenomenon is called prenatal programming. In addition gender specific factors play a leading role for the risk of developing MetSyn. The aim of the present study was to investigate the influence of a glucocorticoid application in early pregnancy and gender on cardiovascular risk factors in adulthood. The common marmoset was used as model species. In a preliminary experiment (2002) at the german primate centre (Göttingen) animals (F0) were orally treated with dexamethasone for one week during early pregnancy. Dexamethasone is a synthetic glucocorticoid that can pass the placental barrier. The following three generation offspring, reared in Leipzig, DexF1/2/3W (female animal, n = 4/6/2) and DexF2/3M (male animal, n = 2/4) were regarded. Animals that were no descendants of the F0 generation built a female (ControlW, n = 11) and a male (ControlM, n = 15) control group and were also regarded for gender-specific risk for MetSyn. An oral glucose tolerance test (OGTT) was carried out (including measurements of insulin concentration), the Quantitative Insulin Sensitivity Check Index (QUICKI – measure of insulin sensitivity) was calculated and parameters of lipid metabolism were investigated. Furthermore, all animals were weighed weekly and blood pressure was monitored at a series of meetings. Statistical analysis was performed by Mann-Whitney-U-Test for independent samples. The level of significance was defined at p ≤ 0.05. DexF1W in comparison to ControlW had a significantly lower insulin concentration 120 minutes after glucose application in the OGTT and a significantly lower glucose concentration 30 and 120 minutes after reaching the sugar solution. These findings did not seem to be clinically relevant. Apart from that, no consequences could be determined in the F1-3 generation offspring after dexamethasone treatment in pregnancy. Regarding gender comparison of untreated common marmosets, female animals had significantly higher insulin concentrations in OGTT and therefore a significantly greater insulin AUC (area under the curve). QUICKI was significantly lower. Hyperinsulinemia and a low QUICKI are symptoms of an impaired glucose regulation. Furthermore, the female animals showed an increase in body weight, VLDL triglycerides and therefore total triglycerides. HDL cholesterol was significantly lower. Hypertriglyceridemia in combination with low HDL cholesterol is called atherogenic dyslipidemia. A disturbed glucose homeostasis, obesity and an atherogenic dyslipidemia are cardiovascular risk factors and important components of MetSyn. In summary, dexamethasone applied in early pregnancy did not lead to metabolic syndrome in the F1-F3 generation offspring of common marmoset in adulthood. However, the female gender was associated with a higher risk of developing the disease. The underlying mechanisms require further investigation.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-09-04T19:38:44Z No. of bitstreams: 1 MariaGloriaTavares.pdf: 1578457 bytes, checksum: d6ddc32a3c245b3f67f5abd4e4158ad0 (MD5) / Made available in DSpace on 2017-09-04T19:38:44Z (GMT). No. of bitstreams: 1 MariaGloriaTavares.pdf: 1578457 bytes, checksum: d6ddc32a3c245b3f67f5abd4e4158ad0 (MD5) Previous issue date: 2017-07-07 / Gestational Diabetes Mellitus (GDM) is classified as glucose intolerance, whose onset or detection occurs during pregnancy. One of the ways to identify GDM is 75g oral glucose tolerance test. According to the International Diabetes and Pregnancy Association Study Group(IADPSG), GDM is diagnosed when at least 1 of the three curve points are greater than or equal to 92, 180 and 153 mg / dl at time 0 , 1 and 2 hours respectively. A characteristic of this criterion is the diagnosis based on a single altered value. However, the mechanisms involved in impaired fasting glucose (IFG) are different from those found in impaired glucose tolerance (IGT) after oral glucose tolerance test (OGTT). So, differences in pregnancy outcomes are possible according to OGTT behavior. This work had as general objective to categorize pregnant women diagnosed with GDM, using the IADPSG criteria, according to the type of glycemic alteration found in the OGTT results, and to correlate with fetal weight birth. In order to do so, the cases of DMG treated at the University Hospital of the Federal University of Maranhão, from December 2013 to December 2015, were divided into 3 groups, according to the alterations found in the glycemic curve of the OGTT (Group 1: IFG isolated, Group 2: IGT only, Group 3: IFG and IGT). A total of 89 patients were studied, the majority belonging to groups 3 (54%). This same group had the highest glycemic averages at diagnosis and during follow-up, being the group with the highest occurrence of newborns large for gestational age (LGA), with 39.6%. Then group 1 with an occurrence of 27.3% of newborns LGAs. It was concluded that, as pregnant women with DMG with altered fasting glycemia in the OGTT, especially those with associated glucose intolerance, presented a higher risk for newborns large for gestational age. / Diabetes Mellitus Gestacional (DMG) é classicamente definido como intolerância à glicose de gravidade variável, cujo início ou detecção ocorre durante a gravidez. Uma das formas de rastreá-la é através da curva glicêmica após sobrecarga oral de glicose, com 75g de dextrosol. Segundo o critério do International Association of Diabetes and Pregnancy Study Group (IADPSG), considera-se diagnóstico de DMG quando pelo menos um dos três pontos da curva encontra-se maior ou igual a 92, 180 e 153 mg/dl, nos tempos 0, 1, 2 horas respectivamente. Uma característica deste critério, é o diagnóstico baseado em apenas um único valor alterado, seja ele em jejum ou após a sobrecarga. No entanto, os mecanismos que levam à alteração da glicemia jejum (GJA) são diferentes daqueles encontrados na intolerância à glicose (ITG) após sobrecarga de glicose. Sendo assim, acredita-se poder haver diferenças, em relação aos desfechos fetais, a depender do perfil encontrado na curva glicêmica das gestantes com diagnóstico de DMG. Este trabalho teve como objetivo geral categorizar as gestantes diagnosticadas com DMG pelo teste de tolerância oral à glicose (TTOG), utilizando o critério do IADPSG, de acordo com o tipo de alteração glicêmica encontrada na curva de sobrecarga, e correlacionar com o peso fetal ao nascimento. Para isso, foram revisados os casos de DMG atendidos no Hospital Universitário da Universidade Federal do Maranhão (HUUFMA), no período de dezembro de 2013 a dezembro de 2015, estes foram divididos em 3 grupos, de acordo com as alterações encontradas na curva glicêmica do TOTG (Grupo 1: GJA isoladamente; Grupo 2: ITG isoladamente, Grupo 3: GJA e ITG). Foram estudadas 89 pacientes, a maioria pertencente ao grupo 3 (54%). Este mesmo grupo apresentou as médias glicêmicas mais elevadas ao diagnóstico e durante o seguimento, sendo o grupo com maior ocorrência de recém-nascidos grandes para idade gestacional (GIG), com 39,6%. Em seguida o grupo 1 com uma ocorrência de 27,3% de recém nascidos GIGs. Concluiu-se que as gestantes com DMG com alteração na glicemia de jejum no TTOG, principalmente aquelas com intolerância à glicose associada, apresentaram maior risco para recém-nascidos grandes para idade gestacional.

Submitted by MARIANA PINTO SIRIMARCO null (mpsirimarco@yahoo.com.br) on 2016-04-08T03:04:00Z No. of bitstreams: 1 VERSÃO FINAL 2 08-04.pdf: 1774461 bytes, checksum: 13e24ee503bed7a9ca8d50a2f58cd2aa (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-04-08T16:39:33Z (GMT) No. of bitstreams: 1 sirimarco_mp_me_bot.pdf: 1774461 bytes, checksum: 13e24ee503bed7a9ca8d50a2f58cd2aa (MD5) / Made available in DSpace on 2016-04-08T16:39:33Z (GMT). No. of bitstreams: 1 sirimarco_mp_me_bot.pdf: 1774461 bytes, checksum: 13e24ee503bed7a9ca8d50a2f58cd2aa (MD5) Previous issue date: 2016-02-29 / JUSTIFICATIVA – desde agosto de 2011 o Serviço Especializado de Diabetes e Gravidez da Faculdade de Medicina de Botucatu/Unesp (SEDG-FMB/Unesp) adotou o novo protocolo diagnóstico para o DMG recomendado pela ADA/IADPSG. Entretanto, o Perfil Glicêmico (PG) continuou associado ao TOTG 75g, para diagnosticar a Hiperglicemia Gestacional Leve (HGL), reconhecida e tratada em nosso Serviço como se fosse DMG. A controvérsia sobre o custo-benefício do novo protocolo da ADA/IADPSG e a dúvida sobre a necessidade de manutenção do PG no protocolo do Serviço justificam o presente estudo. OBJETIVOS – avaliar o impacto do novo protocolo da ADA/IADPSG na prevalência de HGL e de DMG, na ocorrência de resultados perinatais adversos (RPNA) e na associação TOTG 75g e PG para diagnóstico de HGL no SEDG-FMB/Unesp. MÉTODO – estudo de corte transversal, incluindo gestantes, e seus recém-nascidos (RN), submetidas aos protocolos diagnósticos e que realizaram pré-natal e parto no Serviço, antes (janeiro de 2008 a 14 de agosto de 2011) e após (15 de agosto de 2011 a dezembro de 2014) à mudança do protocolo, definindo uma amostra por conveniência. Considerando os dois períodos, foram comparadas a prevalência de DMG e de HGL e a ocorrência de RN-GIG, macrossomia, primeira cesárea e tempo de internação dos RN. Na análise estatística foram utilizados análise de Poison e teste t-Student, teste do Qui-quadrado ou Exato de Fischer e cálculo de risco (RR e IC 95%) para os desfechos avaliados. O limite de significância estatística foi de 95% (p < 0,05). RESULTADOS – o NOVO protocolo resultou em aumento no número de mulheres com DMG e deixou de identificar 17,3% do total de gestantes, que mantiveram o diagnóstico de HGL, apesar do TOTG 75g normal. O novo protocolo ADA/IADPSG não influenciou o desfecho perinatal. CONCLUSÕES – esses resultados reforçam a validade da manutenção do PG no protocolo diagnóstico do SEDG-FMB/Unesp. Para concluir sobre o custo-benefício do NOVO protocolo, são necessários grandes estudos, multicêntricos e com tamanho amostral adequado. / BACKGROUND - since August 2011 the Specialized Center of Diabetes and Pregnancy of the Botucatu Medical School / Unesp (SEDG-FMB / Unesp) has adopted a new diagnostic protocol for Gestational Diabetes Mellitus (GDM) recommended by the ADA / IADPSG guidelines. However, the glycemic profile (GP) remained associated with the 75g OGTT to diagnose Mild Gestational Hyperglycemia Lite (MGH), recognized and treated in our department as if it were GDM. The controversy over the cost-effectiveness of the new ADA / IADPSG guideline and doubt about the need for GP maintenance in the service protocol justify this study. OBJECTIVES - To assess the impact of the new ADA / IADPSG guideline in the prevalence of MGH and GDM, in the incidence of adverse perinatal outcomes (APNO) and in the association 75g OGTT and PG for diagnosis of MGH at the SEDG-FMB / Unesp. METHOD - cross-sectional study, including pregnant women and their newborns (NB) that underwent diagnostic protocols and had their prenatal care and delivery at the service before (January 2008 to August 14, 2011) and after (15 August 2011 to December 2014) the protocol modification, defining a convenience sample. Considering the two periods, the prevalence of GDM and MGH and the occurrence of LGA-NB, macrosomia, first cesarean delivery and NB hospital stay were compared. For statistical analysis, Poison analysis and Student's t test, chi-square or Fisher's exact test were used and risk estimate (RR and 95% CI) for the assessed outcomes. The statistical significance threshold was 95% (p <0.05). RESULTS - The new protocol resulted in a increase in the number of women with GDM, but failed to identify 17.3% of pregnant women who maintained the diagnosis of MGH, despite normal 75g OGTT. The new ADA / IADPSG guideline did not influence the perinatal outcome. CONCLUSIONS - These results reinforce the validity of maintaining the GP in the diagnosis protocol at the SEDG-FMB / Unesp. To conclude on the cost-effective of the new protocol, large multicenter studies with adequate sample size are required

Orientador: Iracema de Mattos Paranhos Calderon / Resumo: JUSTIFICATIVA – desde agosto de 2011 o Serviço Especializado de Diabetes e Gravidez da Faculdade de Medicina de Botucatu/Unesp (SEDG-FMB/Unesp) adotou o novo protocolo diagnóstico para o DMG recomendado pela ADA/IADPSG. Entretanto, o Perfil Glicêmico (PG) continuou associado ao TOTG 75g, para diagnosticar a Hiperglicemia Gestacional Leve (HGL), reconhecida e tratada em nosso Serviço como se fosse DMG. A controvérsia sobre o custo-benefício do novo protocolo da ADA/IADPSG e a dúvida sobre a necessidade de manutenção do PG no protocolo do Serviço justificam o presente estudo. OBJETIVOS – avaliar o impacto do novo protocolo da ADA/IADPSG na prevalência de HGL e de DMG, na ocorrência de resultados perinatais adversos (RPNA) e na associação TOTG 75g e PG para diagnóstico de HGL no SEDG-FMB/Unesp. MÉTODO – estudo de corte transversal, incluindo gestantes, e seus recém-nascidos (RN), submetidas aos protocolos diagnósticos e que realizaram pré-natal e parto no Serviço, antes (janeiro de 2008 a 14 de agosto de 2011) e após (15 de agosto de 2011 a dezembro de 2014) à mudança do protocolo, definindo uma amostra por conveniência. Considerando os dois períodos, foram comparadas a prevalência de DMG e de HGL e a ocorrência de RN-GIG, macrossomia, primeira cesárea e tempo de internação dos RN. Na análise estatística foram utilizados análise de Poison e teste t-Student, teste do Qui-quadrado ou Exato de Fischer e cálculo de risco (RR e IC 95%) para os desfechos avaliados. O limite de signifi... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: BACKGROUND - since August 2011 the Specialized Center of Diabetes and Pregnancy of the Botucatu Medical School / Unesp (SEDG-FMB / Unesp) has adopted a new diagnostic protocol for Gestational Diabetes Mellitus (GDM) recommended by the ADA / IADPSG guidelines. However, the glycemic profile (GP) remained associated with the 75g OGTT to diagnose Mild Gestational Hyperglycemia Lite (MGH), recognized and treated in our department as if it were GDM. The controversy over the cost-effectiveness of the new ADA / IADPSG guideline and doubt about the need for GP maintenance in the service protocol justify this study. OBJECTIVES - To assess the impact of the new ADA / IADPSG guideline in the prevalence of MGH and GDM, in the incidence of adverse perinatal outcomes (APNO) and in the association 75g OGTT and PG for diagnosis of MGH at the SEDG-FMB / Unesp. METHOD - cross-sectional study, including pregnant women and their newborns (NB) that underwent diagnostic protocols and had their prenatal care and delivery at the service before (January 2008 to August 14, 2011) and after (15 August 2011 to December 2014) the protocol modification, defining a convenience sample. Considering the two periods, the prevalence of GDM and MGH and the occurrence of LGA-NB, macrosomia, first cesarean delivery and NB hospital stay were compared. For statistical analysis, Poison analysis and Student's t test, chi-square or Fisher's exact test were used and risk estimate (RR and 95% CI) for the assessed outcomes.... (Complete abstract click electronic access below) / Mestre

Das Metabolische Syndrom (MetSyn) ist gekennzeichnet durch eine Kombination verschiedener kardiovaskulärer Risikofaktoren: Glukoseintoleranz, Adipositas, Dyslipidämie sowie arterielle Hypertonie. Es gilt beim Menschen als eine der Hauptursachen für Herzkreislauferkrankungen und befindet sich weltweit auf enormem Vormarsch. Die Weichen für die Erkrankung werden zum Teil schon vor der Geburt durch eine veränderte Umwelt in utero gestellt. So können Stress oder eine Glukokortikoidbehandlung während der Schwangerschaft zu einem veränderten Phänotyp des Embryos/Fetus führen - mit Konsequenzen für das gesamte spätere Leben. Dieses Phänomen wird als pränatale Programmierung bezeichnet. Neben diesen epigenetischen Effekten spielen u. a. auch geschlechtsabhängige Faktoren eine Rolle für das Risiko, am MetSyn zu erkranken. Die vorliegende Arbeit befasst sich mit den Auswirkungen einer Glukokortikoidbehandlung in der frühen Trächtigkeit sowie dem Einfluss des Geschlechts auf kardiovaskuläre Risikofaktoren im Erwachsenenalter. Als Modelltier für die Studie wurde der Weißbüschelaffe eingesetzt. In einem 2002 stattgefundenen Vorversuch im Deutschen Primatenzentrum in Göttingen wurde tragenden Tieren (F0) eine Woche lang täglich oral Dexamethason verabreicht. Dieses synthetische Glukokortikoid kann die Plazentaschranke passieren. Die drei folgenden in Leipzig gehaltenen Generationen DexF1/2/3W (weibliche Tiere, n = 4/6/2) und DexF2/3M (männliche Tiere, n = 2/4) gingen in die Untersuchung ein. Tiere, die keine Nachkommen der F0-Generation darstellten, bildeten jeweils eine weibliche (ControlW, n = 11) und eine männliche (ControlM, n = 15) Kontrollgruppe und wurden ebenfalls herangezogen, um die Auswirkungen des Geschlechts auf die untersuchten Parameter zu ermitteln. Es wurde ein oraler Glukosetoleranztest (OGTT) durchgeführt (inklusive der Erfassung der Insulinwerte), der Quantitative Insulin Sensitivity Check Index (QUICKI – Maß für die Insulinsensitivität) berechnet sowie Lipidstoffwechselparameter bestimmt. Außerdem fanden wöchentlich Erfassungen des Körpergewichts statt. In mehreren Sitzungen pro Tier wurde der Blutdruck gemessen. Die statistische Auswertung erfolgte mittels Mann-Whitney-U-Test für unabhängige Stichproben. Unterschiede mit einer Irrtumswahrscheinlichkeit p ≤ 0,05 wurden als signifikant angesehen. Im OGTT wies DexF1W im Vergleich zu ControlW 120 Minuten nach oraler Glukoseapplikation eine signifikant niedrigere Insulinkonzentration auf. Da nach 30 und 120 Minuten auch die Glukosekonzentration signifikant erniedrigt war, ist jedoch nicht von einer klinischen Relevanz auszugehen. Weitere Auswirkungen der Dexamethasonapplikation auf die F1- bis F3-Generation konnten nicht beobachtet werden. Beim Vergleich der weiblichen und männlichen Nachkommen unbehandelter Weißbüschelaffen fiel auf, dass weibliche Tiere signifikant höhere Insulinkonzentrationen und damit eine signifikant größere Insulin-AUC (Fläche unter der Kurve) im OGTT zeigten. Ihr QUICKI war signifikant niedriger. Hyperinsulinämie und niedriger QUICKI stellen Symptome einer gestörten Glukoseregulation dar. Die weiblichen Tiere zeigten außerdem eine signifikante Erhöhung hinsichtlich Körpergewicht, VLDL-Triglycerid- und folglich Plasmatriglyceridkonzentrationen. Ihre HDL-Cholesterolwerte waren signifikant niedriger. Diese Kombination einer Hypertriglyceridämie mit niedrigem HDL-Cholesterol wird als atherogene Dyslipidämie bezeichnet. Eine gestörte Glukosehomöostase, eine Adipositas sowie eine atherogene Dyslipidämie stellen kardiovaskuläre Risikofaktoren und wichtige Komponenten des MetSyn dar. Zusammenfassend lässt sich sagen, dass beim Weißbüschelaffen eine Glukokortikoidbehandlung während der frühen Trächtigkeit nicht zum MetSyn der F1- bis F3-Generationen im Erwachsenenalter führte. Hingegen ergab die Untersuchung auf ein geschlechtsabhängiges Erkrankungsrisiko eine eindeutige Prädisposition bei den weiblichen Tieren. Die zu Grunde liegenden Mechanismen dieses Phänomens bleiben Gegenstand weiterer Untersuchungen. / The metabolic syndrome (MetSyn) consists of a cluster of metabolic disorders, characterized by glucose intolerance, obesity, dyslipidemia and hypertension. In humans, it is a major cause for cardiovascular disease. Its worldwide prevalence is increasing. The way for the disease can be paved even before birth. An adverse intrauterine environment due to prenatal stress or an iatrogenic overexposure of the fetus to glucocorticoids can lead to an altered phenotype with consequences for later life. This phenomenon is called prenatal programming. In addition gender specific factors play a leading role for the risk of developing MetSyn. The aim of the present study was to investigate the influence of a glucocorticoid application in early pregnancy and gender on cardiovascular risk factors in adulthood. The common marmoset was used as model species. In a preliminary experiment (2002) at the german primate centre (Göttingen) animals (F0) were orally treated with dexamethasone for one week during early pregnancy. Dexamethasone is a synthetic glucocorticoid that can pass the placental barrier. The following three generation offspring, reared in Leipzig, DexF1/2/3W (female animal, n = 4/6/2) and DexF2/3M (male animal, n = 2/4) were regarded. Animals that were no descendants of the F0 generation built a female (ControlW, n = 11) and a male (ControlM, n = 15) control group and were also regarded for gender-specific risk for MetSyn. An oral glucose tolerance test (OGTT) was carried out (including measurements of insulin concentration), the Quantitative Insulin Sensitivity Check Index (QUICKI – measure of insulin sensitivity) was calculated and parameters of lipid metabolism were investigated. Furthermore, all animals were weighed weekly and blood pressure was monitored at a series of meetings. Statistical analysis was performed by Mann-Whitney-U-Test for independent samples. The level of significance was defined at p ≤ 0.05. DexF1W in comparison to ControlW had a significantly lower insulin concentration 120 minutes after glucose application in the OGTT and a significantly lower glucose concentration 30 and 120 minutes after reaching the sugar solution. These findings did not seem to be clinically relevant. Apart from that, no consequences could be determined in the F1-3 generation offspring after dexamethasone treatment in pregnancy. Regarding gender comparison of untreated common marmosets, female animals had significantly higher insulin concentrations in OGTT and therefore a significantly greater insulin AUC (area under the curve). QUICKI was significantly lower. Hyperinsulinemia and a low QUICKI are symptoms of an impaired glucose regulation. Furthermore, the female animals showed an increase in body weight, VLDL triglycerides and therefore total triglycerides. HDL cholesterol was significantly lower. Hypertriglyceridemia in combination with low HDL cholesterol is called atherogenic dyslipidemia. A disturbed glucose homeostasis, obesity and an atherogenic dyslipidemia are cardiovascular risk factors and important components of MetSyn. In summary, dexamethasone applied in early pregnancy did not lead to metabolic syndrome in the F1-F3 generation offspring of common marmoset in adulthood. However, the female gender was associated with a higher risk of developing the disease. The underlying mechanisms require further investigation.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19892号 / 医博第4141号 / 新制||医||1016(附属図書館) / 32969 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川村 孝, 教授 横出 正之, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM