Résumé : La résistance à l’insuline est un facteur de risque important pour le développement du diabète de type 2. Un désordre au niveau du métabolisme postprandial, qui se manifeste par une diminution relative du stockage des acides gras (AG) dans les tissus adipeux, mène à un débordement plasmatique des AG et à leur canalisation dans les tissus maigres tels que le cœur, le foie et les muscles squelettiques sous forme de dépôts ectopiques. Ce phénomène, connu sous le nom de lipotoxicité, se développe dans un contexte de balance énergétique positive chronique favorisée par la consommation alimentaire excessive ainsi que la sédentarité et peut varier entre les hommes et les femmes. Plusieurs études démontrent que le changement des habitudes de vie peut corriger ces désordres métaboliques. Notre laboratoire a développé une méthode unique pour étudier le métabolisme des AG de façon non invasive à l’aide d’un traceur radioactif, l’acide 14(R,S)-fluoro-6-thia-heptadécanoïque ([indice supérieur 18]F-FTHA), un analogue des acides gras à longue chaines utilisé en tomographie par émission de positrons. Nos études antérieures ont démontré que chez les sujets intolérants au glucose (IG+) on observe des niveaux de captage des AG dans le myocarde plus élevés associés à une fraction d’éjection du ventricule gauche ainsi qu’un volume d'éjection systolique diminués. À la suite d’une intervention d’un an axée sur les habitudes de vie des sujets IG+, on note une diminution du captage des AG dans le myocarde ainsi qu’une amélioration des paramètres de la fonction cardiaque. Cependant, chez des sujets IG+ ayant suivi une restriction calorique d’une semaine sans modifications de leur niveau d’activité physique, nous avons observé une augmentation du captage des AG dans le myocarde en parallèle avec une diminution de la fraction d’éjection du ventricule gauche. La restriction calorique, l’activité physique et la perte de poids influencent le métabolisme des substrats énergétiques et la fonction cardiaque chez les IG+, mais le sexe biologique est aussi un facteur important qui agit sur ces derniers. Le captage élevé des AG par le cœur chez les hommes est expliqué par des niveaux de chylomicrons plus élevés alors que chez les femmes il est associé à l’obésité. Bien que nos études ne nous ont pas permis de faire un lien entre les habitudes de vie des sujets IG+ et les anomalies métaboliques observées en période postprandiale chez ces sujets ni d’identifier quels changements dans leurs habitudes de vie ont contribué aux améliorations métaboliques dans le myocarde, elles nous ont amenées à redéfinir nos outils méthodologiques pour mieux étudier les habitudes de vie et de prendre en considération les différences entre les hommes et les femmes dans nos études futures. / Abstract : Insulin resistance is a major risk factor for the development of type 2 diabetes. Abnormalities in postprandial metabolism, which are characterized by a relative decrease in fatty acid storage capacity in adipose tissue leading to fatty acid spillover into the systemic circulation, give rise to ectopic fat deposition in non adipose tissues such as the heart, the liver and skeletal muscles. This phenomenon, commonly referred to as lipotoxicity, arises within the context of a chronic positive energy balance which is the direct result of excessive food consumption together with decreased energy expenditure and may be different in men and women. Many studies have shown, however, that metabolic abnormalities are reversible with changes in lifestyle habits. Our laboratory has developed a unique non-invasive method to study dietary fatty acid (DFA) metabolism using a radioactive tracer, 14(R,S)-[[superscript 18]F]-fluoro-6-thia-heptadecanoic acid ([superscript 18]F-FTHA), a long-chain fatty acid analogue, in combination with positron emission tomography. Our previous work demonstrated that patients with impaired glucose tolerance (IGT+) display an increase in myocardial DFA partitioning associated with a decreased left ventricular ejection fraction and stroke volume. Following a one-year lifestyle intervention regimen in IGT+ subjects, a reduction in myocardial DFA uptake as well as an improvement in cardiac function parameters was observed. However, IGT+ subjects who participated in a short-term caloric restriction while maintaining their usual level of physical activity, experienced an increase in myocardial DFA partitioning in parralel with a decreased left ventricular ejection fraction. Caloric restriction, physical activity and weight loss all have an impact on energy substrate metabolism and cardiac function in IGT+ patients, but gender is a major determinant as well. Increased myocardial DFA uptake in men is driven largely by elevated circulating chylomicron-TG levels whereas in women it appears to be associated with obesity. Although it was not possible for us to establish a link between IGT+ patients’ lifestyle habits and the postprandial metabolic abnormalities that they display nor to identify which lifestyle changes contributed to the metabolic improvements in the heart observed after the intervention, our studies helped redefine our methodological tools for assessing lifestyle parameters and underlined the importance of considering gender differences in our future studies.

Das Equine Metabolische Syndrom (EMS) beschreibt einen Cluster von metabolischen Störungen, die durch Adipositas, Insulinresistenz und Hufrehe im Zusammenhang stehen. Ziel dieser Arbeit war es, den Einfluss einer achtwöchigen oralen Supplementierung von Chrom, Metformin beziehungsweise von einer Kombination aus Chrom und Metformin auf die Insulinsensitivität und die Glukosetoleranz bei adipösen Pferden und Ponys zu untersuchen. Für diese Studie standen 24 Pferde und Ponys (14,4 ± 3,87 Jahre, 14 Stuten und 10 Wallache) mit Adipositas, Insulinresistenz und Hufrehe zur Verfügung. Während der achtwöchigen Versuchsphase bekamen die Tiere eine Heuration (1,5 kg Heu/100 kg Körpermasse (KM)) und zweimal täglich das ihnen zugewiesene Supplement (Chrom: 25 µg/kg KM, Metformin: 15 mg/kg KM, Chrom+Metformin: 25 µg/kg KM Chrom + 15 mg/kg KM Metformin in jeweils 25 g Grünmehl/100 kg KM) verabreicht. Eine vierte Gruppe erhielt als Placebo 25 g Grünmehl/100 kg KM ohne Supplement. Vor Versuchsbeginn und nach Versuchsende durchliefen die Pferde und Ponys, an zwei aufeinanderfolgenden Tagen, nach jeweils einer zwölfstündigen Fastenperiode einen kombinierten Glukose-Insulin-Toleranztest (KGIT) zur Bestimmung der Insulinsensitivität und einen oralen Glukose-Toleranz-Test (OGTT) zur Bestimmung der Glukoseabsorption und -toleranz. Im Verlauf des Versuchszeitraums konnte bei den Pferden ein durchschnittlicher Gewichtsverlust von 2,77 ± 2,99 % verzeichnet werden (Behandlung p > 0,05). Beim OGTT zeigte sich keine signifikante Veränderung der Glukose- und Insulinreaktionen zwischen Versuchsbeginn und Versuchsende. Die Seruminsulinmaximalwerte der mit Metformin und der mit Chrom+Metformin supplementierten Gruppen waren nach der Versuchszeit numerisch gesunken (Metformin Versuchsbeginn: 452 ± 642 µU/ml, Versuchsende: 202 ± 121 µU/ml; Chrom+Metformin Versuchsbeginn: 388 ± 347 µU/ml, Versuchsende: 342 ± 164 µU/ml, Behandlung p > 0,05). Im KGIT zeigten sich bei den Glukosewerten keine signifikanten Unterschiede zwischen den einzelnen Behandlungsgruppen und zwischen den Werten vor Versuchsbeginn und nach Versuchsende. Die Seruminsulinkonzentrationen lagen im KGIT vor Versuchsbeginn bei allen Probanden zum Zeitpunkt Minute 45 über 100 µU/ml. Somit gelten alle Versuchsteilnehmer per definitionem als insulinresistent. Nach den acht Wochen Supplementierung befanden sich beim KGIT zum Zeitpunkt Minute 45, mit Ausnahme eines Probanden aus der Chrom+Metformin-Gruppe, alle Seruminsulinwerte weiterhin >100 µU/ml. Somit sind die übrigen 23 Pferde und Ponys weiterhin als insulinresistent einzustufen. Weder Chrom, noch Metformin oder die Kombination von Chrom+Metformin konnte in den hier im Versuch angewandten Dosierungen die Insulinsensitivität und Glukosetoleranz der erkrankten Pferde und Ponys verbessern.

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.

La fibrose kystique (FK) est une des maladies rares la plus fréquente au Canada avec un âge médian de survie de 50.9 ans. Toutefois, l'amélioration de l’espérance de vie est associée à l'émergence de complications secondaires telles que le diabète associé à la FK (DAFK). Présent chez 25 à 40% des adultes, il augmente de 6 fois le risque de morbidité et de mortalité. Plusieurs études sur des populations atteintes de diabète de type 2 ont démontrés les bienfaits de programmes d’exercices combinés (aérobie et résistance) sur l’amélioration du contrôle glycémique. L’objectif de l’étude visait à déterminer si un programme d’exercices combinés permettait d’améliorer les anomalies de la tolérance au glucose et le contrôle glycémique chez les patients atteints de FK. Méthodologie: 18 adultes atteints de FK, sédentaires avec une intolérance au glucose ont été recrutés pour cette étude (8 hommes, 10 femmes, âge: 33 ± 9.4 ans, FEV1 71.5% pred ± 12.5, IMC 23.57 kg/m2 ± 3,4). Les participants ont été assignés au hasard à un groupe contrôle ou exercice. Les tests suivants ont été réalisés avant et après l’intervention : VO2max, HGPO, mesure de l'endurance et de la force musculaire, ainsi qu’un questionnaire sur la qualité de vie. Résultats: 14 participants ont complété le protocole. Les participants du groupe exercice ont amélioré leur valeur de glycémie plasmatique à la 2e heure de l’HGPO (-2.34 +/- 0.87 mmol/L; p <0.01; CI 99.22%), à la 1re heure de l’HGPO (-2.0 mmol/L; p<0.05) et ont présenté une réduction de 17.2% (p<0.05) de l’aire sous la courbe de glucose. Conclusion: Un programme d'exercices combinés améliore le contrôle glycémique chez les patients atteints de FK. Cette approche thérapeutique non-pharmacologique pourrait offrir une intervention ayant le potentiel de retarder l'apparition de DAFK. / Cystic fibrosis (CF) is one of the most common rare diseases in Canada with a median age of survival of 50.9 years. However, the improvement in life expectancy is associated with the emergence of secondary complications such as CF related diabetes (CFRD). Present in 25 to 40 % of adults, CFRD is associated with decreased lung function and weight as well as a 6 times increase in risk of morbidity and mortality. CFRD is primarily caused by insulinopenia, however, insulin resistance contribution remains controversial in CF. Recent studies in type 2 diabetes described an improvement of glycemic control in patients undertaking combined exercise program (aerobic & resistance). In CF, an improvement in insulin sensitivity may result in improved glucose tolerance. There is currently no study demonstrating that exercise improves glucose tolerance in patients with CF. The aim of this study is to determine, in CF patients, if a combined exercise program is beneficial to improve glucose values at the 2nd hour of the OGTT. Method: 18 sedentary adults with CF and with abnormal glucose tolerance were recruited for this study (8 men, 10 women, age: 33 ± 9.4 years, FEV1 71.5% pred ± 12.5, BMI 23.57 kg/m2 ± 3.4). Participants were randomly assigned to a control or exercise group. VO2max, OGTT, muscular endurance and strength, and quality of life were measured pre and post intervention. Results: 14 participants completed the protocol. Participants from exercise group improved their plasmatic glucose at the 2nd hour of OGTT (-2.34 +/- 0.87 mmol/L; p < 0.01; CI 99.22%), at 1st hour of OGTT (-2.0 mmol/L; p<0.05) and presented a reduction of 17.2% (p<0.05) in the total glucose area under the curve. Conclusion: Combined exercise program improves glycemic control in CF patients. This non pharmacological approach could have the potential to delay the onset of CFRD.

Diabetes Mellitus tipo 2 e demência são doenças altamente prevalentes na população idosa. Estudos têm evidenciado que o DM 2 está associado com perda cognitiva e um elevado risco tanto para demência vascular quanto para demência do tipo Alzheimer. Idosos com tolerância à glicose diminuída também apresentam perda cognitiva, sendo que a hiperinsulinemia parece explicar o déficit cognitivo nesses pacientes. Objetivos: Avaliar em pacientes idosos diabéticos e com tolerância à glicose diminuída a presença de alterações cognitivas comparados aos normais e uma possível associação com resistência insulínica, síndrome metabólica, marcadores inflamatórios e adiponectina. E diagnosticar entre os pacientes com alteração cognitiva aqueles com demência através da avaliação neuropsicológica. Pacientes e Métodos: Foram estudados 140 pacientes com idades entre 65 e 86 anos, sendo 107 do sexo feminino e 33 do sexo masculino classificados em 3 grupos conforme TOTG: tolerância à glicose normal (52), tolerância à glicose alterada (42) e DM (46). Os pacientes foram avaliados antropometricamente e realizada dosagem de glicemia, hemoglobina glicada, colesterol total e frações, insulina, adiponectina, TNF-alfa e IL-6. Realizados testes de rastreio cognitivo, através do mini-exame do estado mental, teste do relógio e fluência verbal. Os pacientes com baixo desempenho passaram por avaliação neuropsicológica. Resultados: os grupos foram comparáveis em relação à idade, gênero e escolaridade. Não encontramos diferença estatística entre os grupos em relação à presença de HAS, IMC e cintura abdominal. A prevalência de dislipidemia e síndrome metabólica foi maior nos pacientes com intolerância à glicose e diabetes. Os pacientes com resistência insulínica, definida pelo HOMA-IR, tiveram maiores níveis de IL-6 e TNF-a e menor adiponectinemia. Nos testes de triagem, 42 sujeitos apresentaram desempenho abaixo do esperado para idade e escolaridade e destes 33 apresentaram alteração cognitiva. Não houve diferença estatística entre os pacientes com alteração cognitiva e os normais, em relação à resistência insulínica, adiponectina e marcadores inflamatórios. Pacientes com alteração cognitiva apresentaram significantemente menor funcionalidade, prejuízo na memória imediata e de evocação, no reconhecimento da lista de palavras e na memória lógica de Wescheler. Conclusões: Não observamos nos pacientes idosos diabéticos e com tolerância à glicose diminuída maior presença de alterações cognitivas em comparação aos normais. Pacientes diagnosticados com comprometimento cognitivo leve e demência não apresentaram diferenças dos normais em relação à presença da resistência insulínica, síndrome metabólica e marcadores inflamatórios / Introduction: Type 2 Diabetes (T2D) and dementia are highly prevalent diseases among the elderly population. Studies have been evincing that type 2 diabetes are associated with cognitive impairment and also shows a high risk for vascular dementia and for Alzheimers disease. Studies suggest that elderly people with impaired glucose tolerance (IGT) present cognitive loss, and the hyperinsulinemia seems to explain the cognitive deficit in those patients. Objective: To evaluate the presence of cognitive alterations compared to the normal and a possible association of insulin resistance (IR), metabolic syndrome (MS), inflammatory markers and adiponectin in T2D elderly and IGT; to diagnose dementia among patients with cognitive alteration by neuropsychological examination. Patient and Methods: 140 patients with ages between 65 and 86 years were studied 107 of whom were women and classified in 3 groups according to GTT: Normal glucose tolerance (NGT), IGT and T2D. Anthropometric measurements and analyses of glucose and insulin, A1c, total cholesterol and fractions, adiponectin, TNF-alpha and IL-6, were performed in this patients. Cognitive function was measured by mini-mental state examination, clock drawing and verbal fluency test. The patients with cognitive impairment were submitted to neuropsychological battery. Results: The groups were comparable in relation to age, gender and level of education. We did not find statistical differences among the groups in relation to the presence of HA, BMI, waist and inflammatory markers. The presence of MS and IR was increased in the IGT and T2D groups. Patients with IR had high IL-6 and TNF-a and low adiponectin. In the neuropsychological battery, 42 subjects were below the expected for their age and level of education, and, of these, 33 presented cognitive alteration. There was not statistical significance among patients with cognitive deficit the presence of insulin resistance measured by HOMA-IR, adiponectin and inflammatory markers. Patients with cognitive impairment showed poorer performance in immediate and delayed recall of a word list, recognition test and Weschelers memory logic. Conclusion: T2D and IGT were not associated with impaired cognitive function. No difference in insulin resistance, metabolic syndrome, and inflammatory markers has been seen between normal patients and patients with impairment cognitive

O objetivo do primeiro estudo foi avaliar a produção in vitro de embriões (PIVE) em vacas holandesas não lactantes submetidas a aspiração oocitária (OPU) posteriormente ao protocolo de superestimulação folicular similar ao descrito por Nivet et al. (2012) em comparação à realização da OPU em dia aleatório do ciclo estral. Para tal, vacas holandesas não lactantes e não gestantes foram distribuídas aleatoriamente em delineamento tipo crossover em Controle (n = 35), em que as vacas não foram tratadas com FSH, mas submetidas a uma sessão de aspiração em dia aleatório do ciclo estral; ou p-FSH (n = 35), em que, 36 horas após a OPU para sincronização da onda folicular, as vacas foram tratadas com p-FSH por 3 dias e 44 horas após, submetidas a sessões de OPU. O número total de complexos cumulusoócito (CCO) recuperados e o número de oócitos viáveis foram semelhantes entre os grupos controle e p-FSH. Além disso, não houve aumento na proporção de CCO viáveis (CCO viáveis / CCO total recuperado). Da mesma forma, não se detectaram diferenças no número de embriões / sessão de OPU e taxa de blastocistos. O protocolo de superestimulação folicular não melhorou a PIVE em vacas holandesas não lactantes. O experimento 2 testou a hipótese de que vacas leiteiras de alta produção se tornam cada vez mais resistentes à insulina com o avançar da lactação, e consequentemente, a qualidade do oócito é comprometida. Foram utilizadas vacas holandesas em 50 (51,5 ± 3,7; n = 30), 100 (102,3 ± 9,4; n = 30) e 150 (154,5 ± 18,9; n = 30) dias em lactação (DEL). Durante o teste de tolerância à glicose (TTG), não houve diferença entre grupos para qualquer variável relacionada à glicose circulante. No entanto, medidas de insulina circulante foram diferentes em vacas aos 150 DEL em comparação com 50 ou 100 DEL, tais como: maior insulina basal, pico, &Delta; máx de insulina e AUC 5-60. Porém, não houve diferença entre os grupos para o número ou percentagem de oócitos viáveis. Assim, as vacas desenvolveram resistência à insulina com o aumento do DEL. No entanto, o aumento da resistência à insulina não foi associado com alteração detectável na qualidade dos oócitos aspirados de folículos pequenos e médios. O experimento 3 foi para avaliar se o aumento de insulina circulante durante os períodos de pré e pós desvio folicular aumenta o desenvolvimento inicial e final, do folículo, bem como do corpo lúteo (CL). Além disso, por induzir a ovulação de um folículo maior, o CL resultante de vacas com alta insulina circulante também é maior e mais esteroidogênico, refletindo em maiores concentrações circulantes de progesterona (P4). O delineamento experimental utilizado foi o quadrado latino em arranjo fatorial 2x2, em quatro grupos experimentais: 1) CC = água pré e pós desvio folicular (n = 16); 2) CP = água e propilenoglicol (PPG) pré e pós desvio folicular, respectivamente (n = 16); 3) PC = PPG e água pré e pós desvio folicular, respectivamente (n = 16) e 4) PP = PPG pré e pós desvio folicular (n = 16). O aumento agudo e transitório, durante os períodos de pré e pós desvio não aumentou o desenvolvimento folicular, luteal e concentrações plasmáticas de P4. / The aim of the first study was to evaluate the in vitro embryo production (IVEP) in nonlactating Holstein cows subjected to ovum pick-up (OPU) after ovarian superstimulation with a protocol similar to that described by Nivet et al. (2012) in comparison with OPU at a random day of the estrous cycle. Nonlactating Holstein cows were randomly assigned in a crossover design to: Control (n = 35) in which cows were not treated with p-FSH, but subjected to OPU at a random day of the estrous cycle; or p-FSH (n = 35), in which, 36 hours after OPU to synchronize follicle wave, the cows were treated with p-FSH for 3 days and 44 hours later, subjected to OPU sessions. The total number of cumulus-oocyte complex (COC) recovered and the number of viable oocytes were similar between control and p-FSH groups. In addition, there was no increase in the proportion of viable COC (viable COC / overall COC recovered). Likewise, we detected no differences in the number of embryos / OPU session and blastocyst rate. Follicle superstimulation protocol with p-FSH did not improve IVEP in nonlactating Holstein cows. Experiment 2 tested the hypothesis that high-producing dairy cows become increasingly resistant to insulin with advancing lactation, and consequently oocyte quality is compromised. We used Holstein cows at 50 (51.5 ± 3.7; n = 30), 100 (102.3 ± 9.4; n = 30) and 150 (n = 30 154.5 ± 18.9) days in milk (DIM). During the glucose tolerance test (GTT), there was no difference between groups for any variable related to circulating glucose. However, circulating insulin measurements such as basal insulin, peak insulin, &Delta; max and AUC 5-60 were higher for cows at 150 DIM. Nevertheless, there was no difference between groups for the number or percentage of viable oocytes. Therefore, although cows developed insulin resistance with increasing DIM, this has not been associated with detectable change in the quality of oocytes aspirated from small and medium follicles. The third experiment assessed whether the increase in circulating insulin during periods of pre- and post-follicle deviation increases the initial and final follicle size and corpus luteum (CL) volume. Moreover, by inducing ovulation of greater follicles, resulting in greater CL, cows with high circulating insulin also have higher circulating progesterone (P4). The experimental design was a Latin square in a 2x2 factorial arrangement in four groups: 1) CC = water pre and post follicle deviation (n = 16); 2) CP = water pre and propylene glycol (PPG) post follicle deviation (n = 16); 3) PC = PPG and water pre and post follicle deviation, respectively (n = 16), 4) PP = PPG pre and post follicle deviation (n = 16). Acute and transient circulating insulin increase during periods of pre and post follicle deviation has not affected follicle development, luteal volume or plasma concentrations of P4.

Objetivo: O objetivo desse estudo foi identificar a associação entre fatores clínicos e laboratoriais com o uso de insulina em gestantes com DMG no momento do diagnóstico e analisar os possíveis fatores preditores do uso de insulina. Método: Foram estudadas, de forma retrospectiva, 294 pacientes com diabetes melito gestacional (DMG) diagnosticado por meio do teste de tolerância à glicose oral de 100 gramas (TTGO-100g) entre 24 e 33 semanas completas de gestação, cujo seguimento pré-natal foi realizado ambulatorialmente pelo setor de Endocrinopatias e Gestação da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de 1 de julho de 2002 a 30 de junho de 2008. Os seguintes fatores clínicos e laboratoriais, que pudessem estar associados ao uso de insulina para controle glicêmico, foram analisados: idade materna, obesidade pré-gestacional - índice de massa corpórea (IMC) > 30 Kg/m2, antecedente familiar de diabetes melito (DM), tabagismo, hipertensão arterial, uso de corticosteróides sistêmicos, antecedente obstétrico de DMG e de macrossomia fetal, nuliparidade, multiparidade, antecedente obstétricos de natimortos e neomortos, idade gestacional no momento do diagnóstico, gemelidade, índice de líquido amniótico (ILA) aumentado ILA > 18 cm, polidrâmnio (ILA > 25 cm), número de valores anormais do TTGO-100g, glicemia de jejum anormal no TTGO- 100g glicemia de jejum > 95 mg/dL; média das quatro glicemias aferidas no TTGO-100g; valor da glicemia de jejum, de 1ª, 2ª e 3ª horas do TTGO-100g e hemoglobina glicada (HbA1c). A associação entre cada fator e a necessidade de insulinoterapia foi analisada individualmente (2 de Pearson / teste exato de Fisher e teste t de Student). O modelo de regressão logística para a análise multivariada foi usado para predizer a probabilidade desses fatores em relação ao uso de insulina. Resultados: Das 294 pacientes avaliadas, 39,8% (117/294) necessitaram de insulinoterapia para controle glicêmico. Observou-se correlação positiva entre o uso de insulina e obesidade pré-gestacional, antecedente familiar de DM, hipertensão arterial, antecedente obstétrico de DMG e de macrossomia fetal, número de valores anormais no TTGO-100g, glicemia de jejum > 95 mg/dL no TTGO-100g; média das quatro glicemias aferidas no TTGO-100g; valor da glicemia de jejum, de 1ª, 2ª e 3ª horas do TTGO-100g e HbA1c pela análise univariada (P<0,05). Na análise do modelo de regressão logística foram desenvolvidos dois modelos que incluíam os seguintes fatores preditores do uso de insulina: obesidade pré-gestacional, antecedente familiar de DM, número de valores anormais no TTGO-100g (só modelo 1) e valor da glicemia de jejum do TTGO-100g (só modelo 2). Os dois primeiros modelos foram novamente analisados, incluindo-se a variável HbA1c para verificação de sua contribuição na predição do uso de insulina. Curvas de probabilidade e escores foram construídos com base nas quatro combinações de fatores preditores. Conclusões: É possível estimar a probabilidade do uso de insulinoterapia para controle glicêmico em gestantes com DMG por meio de IMC pré-gestacional, antecedente familiar de DM, número de valores anormais do TTGO-100g, valor da glicemia de jejum no TTGO-100g e da HbA1c. / Objective: To determine the association between clinical and laboratory parameters and insulin requirement in pregnancies complicated by gestational diabetes mellitus (GDM), and to evaluate possible factors predicting the need for insulin therapy. Methods: A total of 294 patients with GDM diagnosed by the 100- g/3-h oral glucose tolerance test (OGTT) between 24 and 33 complete weeks of gestation were retrospectively studied. These patients were under prenatal follow-up at the Obstetric Clinic of the University of Sao Paulo School of Medicine (HCFMUSP) between July 1, 2002 and June 30, 2008. The clinical and laboratory factors which could be associated to the need for insulin therapy were analyzed: maternal age, prepregnancy obesity body mass index (BMI) > 30 Kg/m2, family history of diabetes mellitus (DM), smoking, hypertension, use of systemic corticosteroids, prior GDM, prior fetal macrosomia, nulliparity, multiparity, prior stillbirth, prior neonatal death, gestational age at diagnosis of GDM, multiple pregnancy, elevated amniotic fluid index (AFI) AFI > 18 cm, polyhydramnios (AFI > 25 cm), number of abnormal 100-g/3-h OGTT values, 100-g/3-h OGTT fasting plasma glucose > 95 mg/dL, mean of the four 100-g/3-h OGTT values, 100-g/3-h OGTT fasting/one/two/three plasma glucose values, and glycated hemoglobin (HbA1c). The association between each factor and the need for insulin therapy was then analyzed individually (Pearsons chi-square/Fishers exact or Student t test). The performance of these factors to predict the probability of insulin therapy was estimated using a logistic regression model. Results: Among the 294 patients studied, 39.8% (117/294) required insulin for glycemic control. Univariate analysis showed a positive correlation between insulin therapy and prepregnancy obesity, family history of diabetes, hypertension, prior GDM, prior fetal macrosomia, number of abnormal 100-g/3-h OGTT values, 100-g/3-h OGTT fasting plasma glucose > 95 mg/dL, mean of the four 100-g/3-h OGTT values, 100-g/3-h OGTT fasting/one/two/three plasma glucose values, and HbA1c (P < 0.05). Two logistic regression models were developed and included the following parameters: prepregnancy obesity, family history of diabetes, number of abnormal 100-g/3-h OGTT values (just model 1) and 100-g/3-h OGTT fasting plasma glucose (just model 2). The two first models were analysed another time including the variable HbA1c to verify its contribution on prediction of the need for insulin therapy. Probability curves and scores were constructed based on the four combinations of predictive factors. Conclusions: The probability of insulin therapy can be estimated in pregnant women with GDM based on prepregnancy obesity, family history of diabetes, number of abnormal 100-g/3-h OGTT values, 100-g/3-h OGTT fasting plasma glucose, and HbA1c concentration.

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.

Objetivo: O objetivo desse estudo foi identificar a associação entre fatores clínicos e laboratoriais com o uso de insulina em gestantes com DMG no momento do diagnóstico e analisar os possíveis fatores preditores do uso de insulina. Método: Foram estudadas, de forma retrospectiva, 294 pacientes com diabetes melito gestacional (DMG) diagnosticado por meio do teste de tolerância à glicose oral de 100 gramas (TTGO-100g) entre 24 e 33 semanas completas de gestação, cujo seguimento pré-natal foi realizado ambulatorialmente pelo setor de Endocrinopatias e Gestação da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de 1 de julho de 2002 a 30 de junho de 2008. Os seguintes fatores clínicos e laboratoriais, que pudessem estar associados ao uso de insulina para controle glicêmico, foram analisados: idade materna, obesidade pré-gestacional - índice de massa corpórea (IMC) > 30 Kg/m2, antecedente familiar de diabetes melito (DM), tabagismo, hipertensão arterial, uso de corticosteróides sistêmicos, antecedente obstétrico de DMG e de macrossomia fetal, nuliparidade, multiparidade, antecedente obstétricos de natimortos e neomortos, idade gestacional no momento do diagnóstico, gemelidade, índice de líquido amniótico (ILA) aumentado ILA > 18 cm, polidrâmnio (ILA > 25 cm), número de valores anormais do TTGO-100g, glicemia de jejum anormal no TTGO- 100g glicemia de jejum > 95 mg/dL; média das quatro glicemias aferidas no TTGO-100g; valor da glicemia de jejum, de 1ª, 2ª e 3ª horas do TTGO-100g e hemoglobina glicada (HbA1c). A associação entre cada fator e a necessidade de insulinoterapia foi analisada individualmente (2 de Pearson / teste exato de Fisher e teste t de Student). O modelo de regressão logística para a análise multivariada foi usado para predizer a probabilidade desses fatores em relação ao uso de insulina. Resultados: Das 294 pacientes avaliadas, 39,8% (117/294) necessitaram de insulinoterapia para controle glicêmico. Observou-se correlação positiva entre o uso de insulina e obesidade pré-gestacional, antecedente familiar de DM, hipertensão arterial, antecedente obstétrico de DMG e de macrossomia fetal, número de valores anormais no TTGO-100g, glicemia de jejum > 95 mg/dL no TTGO-100g; média das quatro glicemias aferidas no TTGO-100g; valor da glicemia de jejum, de 1ª, 2ª e 3ª horas do TTGO-100g e HbA1c pela análise univariada (P<0,05). Na análise do modelo de regressão logística foram desenvolvidos dois modelos que incluíam os seguintes fatores preditores do uso de insulina: obesidade pré-gestacional, antecedente familiar de DM, número de valores anormais no TTGO-100g (só modelo 1) e valor da glicemia de jejum do TTGO-100g (só modelo 2). Os dois primeiros modelos foram novamente analisados, incluindo-se a variável HbA1c para verificação de sua contribuição na predição do uso de insulina. Curvas de probabilidade e escores foram construídos com base nas quatro combinações de fatores preditores. Conclusões: É possível estimar a probabilidade do uso de insulinoterapia para controle glicêmico em gestantes com DMG por meio de IMC pré-gestacional, antecedente familiar de DM, número de valores anormais do TTGO-100g, valor da glicemia de jejum no TTGO-100g e da HbA1c. / Objective: To determine the association between clinical and laboratory parameters and insulin requirement in pregnancies complicated by gestational diabetes mellitus (GDM), and to evaluate possible factors predicting the need for insulin therapy. Methods: A total of 294 patients with GDM diagnosed by the 100- g/3-h oral glucose tolerance test (OGTT) between 24 and 33 complete weeks of gestation were retrospectively studied. These patients were under prenatal follow-up at the Obstetric Clinic of the University of Sao Paulo School of Medicine (HCFMUSP) between July 1, 2002 and June 30, 2008. The clinical and laboratory factors which could be associated to the need for insulin therapy were analyzed: maternal age, prepregnancy obesity body mass index (BMI) > 30 Kg/m2, family history of diabetes mellitus (DM), smoking, hypertension, use of systemic corticosteroids, prior GDM, prior fetal macrosomia, nulliparity, multiparity, prior stillbirth, prior neonatal death, gestational age at diagnosis of GDM, multiple pregnancy, elevated amniotic fluid index (AFI) AFI > 18 cm, polyhydramnios (AFI > 25 cm), number of abnormal 100-g/3-h OGTT values, 100-g/3-h OGTT fasting plasma glucose > 95 mg/dL, mean of the four 100-g/3-h OGTT values, 100-g/3-h OGTT fasting/one/two/three plasma glucose values, and glycated hemoglobin (HbA1c). The association between each factor and the need for insulin therapy was then analyzed individually (Pearsons chi-square/Fishers exact or Student t test). The performance of these factors to predict the probability of insulin therapy was estimated using a logistic regression model. Results: Among the 294 patients studied, 39.8% (117/294) required insulin for glycemic control. Univariate analysis showed a positive correlation between insulin therapy and prepregnancy obesity, family history of diabetes, hypertension, prior GDM, prior fetal macrosomia, number of abnormal 100-g/3-h OGTT values, 100-g/3-h OGTT fasting plasma glucose > 95 mg/dL, mean of the four 100-g/3-h OGTT values, 100-g/3-h OGTT fasting/one/two/three plasma glucose values, and HbA1c (P < 0.05). Two logistic regression models were developed and included the following parameters: prepregnancy obesity, family history of diabetes, number of abnormal 100-g/3-h OGTT values (just model 1) and 100-g/3-h OGTT fasting plasma glucose (just model 2). The two first models were analysed another time including the variable HbA1c to verify its contribution on prediction of the need for insulin therapy. Probability curves and scores were constructed based on the four combinations of predictive factors. Conclusions: The probability of insulin therapy can be estimated in pregnant women with GDM based on prepregnancy obesity, family history of diabetes, number of abnormal 100-g/3-h OGTT values, 100-g/3-h OGTT fasting plasma glucose, and HbA1c concentration.

<p>Conclusion of this study: These data suggest that 6 weeks of high-fat feeding induces hypertension but does not produce obesity, dyslipidemia and insulin resistance. However, this model may be useful in studying vascular reactivity in hypertension in the absence of insulin resistance.</p>