Thesis (Ph.D.)--University of Melbourne, Dept. , 200. / Typescript. Includes bibliographical references.

Thesis (Ph. D.)--Oregon State University, 2006. / Printout. Includes bibliographical references (leaves 110-121). Also available on the World Wide Web.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Oct. 30, 2007). Includes bibliographical references (p. 47-62).

Estudos sugerem que a suplementação de creatina pode atenuar a resistência à insulina, embora sejam escassas evidências que atestem a segurança desse suplemento. Diante disso, esse estudo teve como objetivo investigar a eficácia e segurança da suplementação de creatina em diabéticos do tipo 2. Foi conduzido um estudo clínico, randomizado, duplo-cego, controlado por placebo. Ao longo de três meses, os pacientes foram submetidos a treinamento físico e suplementação de creatina (CR) ou placebo (PL). No período basal e após a intervenção, os indivíduos realizaram avaliações de controle glicêmico, perfil lipídico, capacidade física, composição corporal e efeitos adversos. Além disso, os voluntários foram submetidos à biópsias musculares, para análises da expressão proteica e translocação de GLUT-4, e espectrometria de fósforo para determinação dos conteúdos intramusculares de fosforilcreatina. Após a intervenção, as concentrações intramusculares de fosforilcreatina foram maiores no grupo CR (diferença estimada entre as médias: 23,6 mmol/Kg músculo úmido; p = 0,03). Esse grupo também apresentou menores concentrações de hemoglobina glicada quando comparado ao grupo PL (diferença estimada entre as médias: -1,1%; p = 0,004). Os testes de tolerância oral à refeição demonstraram menores valores de glicemia de jejum e pós-prandial (momentos 30 e 60 minutos) no grupo CR versus PL. A expressão proteica de GLUT-4 não foi diferente entre os grupos, porém o aumento na translocação dessa proteína foi significantemente superior no grupo CR (p = 0,03). Não houve diferenças significantes entre os grupos para a insulinemia, perfil lipídico, concentrações séricas de peptídeo C, composição corporal, condicionamento aeróbio, força e função musculares. A suplementação de creatina não provocou deterioração nas funções renal e hepática. Os demais efeitos adversos relatados também não foram diferentes entres os grupos. Desta forma, concluímos que a suplementação de creatina aliada ao treinamento físico é uma estratégia terapêutica segura e efetiva em melhorar o controle glicêmico em diabéticos do tipo 2. Número de registro no domínio Clinicaltrials.com: NCT00992043 / Some studies have suggested that creatine supplementation may attenuate insulin resistance, but whether this supplement is safe remains uncertain. In light of this, the aim of this trial was to investigate the efficacy and safety of creatine supplementation combined with exercise training in patients with type II diabetes. A randomized, double-blind, placebo-controlled, clinical trial was conducted. The patients were submitted to exercise training and received either creatine (CR) or placebo (PL) for 12 weeks. At baseline and after the intervention, glycemic control, lipid profile, physical capacity, body composition, and adverse effects were assessed. Moreover, muscular biopsies were performed to determine the muscle GLUT-4 content and the GLUT-4 translocation, and muscle phosphorylcreatine was assessed by using magnetic resonance spectroscopy. After the intervention, muscle phosphorylcreatine content was higher in the CR group (estimated difference of means: 23.6 mmol/Kg wet muscle; p = 0.03). The CR group also presented decreased glycosylated hemoglobin when compared to the PL group (estimated difference of means: -1.1%; p = 0.004). The oral meal tolerance tests revealed reduced fasting and postprandial glycemia (30 and 60 minutes) in the CR versus the PL group. The muscle GLUT-4 content was similar between groups, but the increase in GLUT-4 translocation was significantly superior in the CR group when compared to the PL group (p = 0.03). In addition, No significant differences between groups were observed for insulinemia, lipid profile, serum peptide C concentration, body composition, aerobic conditioning, strength, and muscle function. Cr supplementation provokes no deleterious effects on kidney and liver functions. The reported adverse effects were similar between groups. Thus, we concluded that creatine supplementation is safe and capable of improving glycemic control in type 2 diabetic patients. ClinicalTrials.gov registration number: NCT00992043

Made available in DSpace on 2014-06-11T19:30:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-12-20Bitstream added on 2014-06-13T20:21:06Z : No. of bitstreams: 1 ramos_app_dr_arafcf.pdf: 851100 bytes, checksum: 7ccabebac97be5df71fc05a6ae2c90ff (MD5) / Universidade Estadual Paulista (UNESP) / O excesso de peso, classificado como sobrepeso ou obesidade, tem aumentado em grande proporção em todo o mundo e está associado à elevação da morbidade e da mortalidade, pois é considerado um importante fator de risco para as Doenças Cardiovasculares (DCV). A epidemia do excesso de peso tem afetado indistintamente todos os grupos etários e classes sociais e está associado ao aumento da prevalência de síndrome metabólica e de Diabetes mellitus tipo 2 (DM 2), inclusive em crianças e adolescentes. O objetivo geral desse trabalho foi avaliar os parâmetros metabólicos e os indicadores de RI associados à síndrome metabólica em adolescentes do sexo feminino. Foram incluídas no estudo 50 adolescentes do sexo feminino com excesso de peso (sobrepeso ou obesidade) e 189 adolescentes com peso corporal normal. Os parâmetros determinados foram insulinemia de jejum, glicemia de jejum, glicemia pós-sobrecarga (TOTG), leptinemia, perfil lipídico, peptídeo C, ácido úrico, proteína C ultra-sensível (PCR-us), pressão arterial e circunferência abdominal e os índices de RI determinados foram QUICKI e HOMA. De acordo com os critérios mais utilizados para a caracterização da síndrome metabólica, pelo menos 28% das adolescentes com excesso de peso apresentavam síndrome metabólica. Entretanto, as adolescentes não classificadas com a síndrome metabólica também apresentaram alterações importantes como obesidade abdominal, hiperleptinemia, hiperuricemia e níveis de PCR-us aumentados. Em conclusão, as adolescentes do sexo feminino com excesso de peso apresentaram alterações importantes de fatores de risco cardiovascular especialmente hiperinsulinemia, hiperleptinemia e obesidade abdominal. / The excess of weight, meant as overweight or obesity, has grown greatly in the whole world and it is associated with the increase of morbidity and mortality. It has been considered an important risk factor for the cardiovascular diseases (CVD). The epidemic of obesity has indistinctly affected all ages and social categories and it is associated to the expansion of the metabolic syndrome and diabetes mellitus type 2, including children and adolescents. The main objective of this work was to analyze the metabolic parameters and the indicators of the IR associated to the metabolic syndrome in female adolescents. A total of 50 adolescents were included in this study with overweight or obesity and 189 adolescents with normal corporal weight. The determining parameters were: fasting insulin, fasting glucose, glucose tolerance test, leptin, lipidic profile, C-peptide, uric acid, ultra-sensitive C-reactive protein (CRP-us), blood pressure, abdominal circumference, and the IR indexes QUICKI and HOMA. According to the most used criteria for the characterization of the metabolic syndrome, at least 28% of the adolescents who presented overweight also presented the metabolic syndrome. However, the adolescents who were not classified as having the metabolic syndrome also showed important alterations such as abdominal obesity, high leptin and high PCR-us. In conclusion, the overweight female adolescents presented important risk factors for cardiovascular diseases especially abdominal obesity hyperinsulinemia and hyperleptinemia.

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Introdução: Irisina é uma adipocina / miocina, descrita pela primeira vez em 2012 e parece estar envolvida na termogênese do tecido adiposo e na homeostase metabólica. A síndrome dos ovários policísticos (PCOS) é reconhecida como um distúrbio endocrinológico prevalente em mulheres com idade reprodutiva, e está frequentemente associado à obesidade abdominal, resistência à insulina, dislipidemia e hipertensão arterial. Objetivos: Determinar os níveis circulantes de irisina numa amostra de mulheres com PCOS e controles ovulatórias não hirsutas e verificar se os níveis séricos de irisina estão associados com variáveis hormonais, metabólicas e de composição corporal nestas participantes. Métodos: Neste estudo caso-controle foram incluídas 49 mulheres com PCOS e 33 mulheres controles ovulatórias não-hirsutas com idade e índice de massa corporal (IMC) semelhantes. Variáveis demográficas, antropométricas, hormonais e metabólicas foram obtidas através de dados da história médica, exame físico e dosagens bioquímicas e hormonais convencionais. A composição corporal foi avaliada por absorciometria de raios-X de dupla energia (DXA). Os níveis séricos de irisina foram mensurados por um kit ELISA humano. Resultados: A pressão arterial sistólica, HOMA, testosterona total e índice de androgênios livres (IAL) foram significativamente maiores e a SHBG foi menor nas PCOS. Após a estratificação por IMC, massa gorda e razão massa gorda / massa magra foram menores em mulheres com peso normal do que em mulheres com sobrepeso / obesidade. O grupo PCOS com peso normal apresentou menos massa magra total do que o grupo PCOS com sobrepeso / obesidade e subgrupos controles. A proporção de massa magra apendicular / IMC foi significativamente maior nas controles de peso normal que em controles com sobrepeso / obesidade, mas os subgrupos de PCOS foram semelhantes entre si e com as controles de peso normal e obesas. Os níveis séricos de irisina foram significativamente maiores nas pacientes 8 PCOS com sobrepeso / obesidade em comparação com as controles de peso normal. A irisina circulante correlacionou-se positivamente com o HOMA. Observou-se também correlação positiva da irisina com massa magra total e razão massa gorda /massa magra em mulheres com PCOS, mesmo após ajuste para IAL. Conclusão: Os dados do presente estudo sugerem uma associação de irisina com variáveis de composição corporal. / Introduction: Irisin is an adipokine / myokine, first described in 2012 and appears to be involved in adipose tissue thermogenesis and metabolic homeostasis. The polycystic ovary syndrome (PCOS) is recognized as a frequent endocrine disorder in women of reproductive age, and is often associated with abdominal obesity, insulin resistance, dyslipidemia, and hypertension. Objectives: To determine the circulating levels of irisin in women with PCOS and non-hirsute ovulatory control women, and to evaluate whether serum irisin levels are associated with hormone, metabolic and body composition variables in these participants. Methods: In this case-control study, 49 women with PCOS and 33 nonhirsute ovulatory controls women with similar age and body mass index (BMI) were enrolled. Demographic, anthropometric, hormone and metabolic variables were assessed by medical history, physical examination and conventional biochemical and hormon determinations. Body composition was assessed by double-energy X-ray absorptiometry (DXA). Serum irisin levels were measured by a human ELISA kit. Results: Systolic blood pressure, HOMA, total testosterone and FAI were higher and SHBG was lower in PCOS. After stratification by BMI, fat mass and fat mass / lean mass ratio were lower in women of normal weight in overweight / obese women. The PCOS group at normal weight had less total lean mass than the overweight / obese PCOS group and control subgroups. The lean appendicular mass / BMI ratio was significantly higher in normal weight controls than in overweight / obese controls, but PCOS subgroups were similar between them and with normal and obese weight controls. Serum irisin levels were significantly higher in overweight / obese PCOS patients than in normal weight controls. Circulating irisin was positively correlated with HOMA. A positive correlation was also observed between irisin 10 and total lean mass and fat mass / lean mass ratio in women with PCOS, even when adjusted for FAI. Conclusion: Our data suggest an association of irisin and body composition variables.

La résistance à l’insuline (RI) est un processus biologique fondamental impliqué dans la plupart des maladies complexes avec un important impact dans la mortalité des populations humaines et qui reconnaît une composante génétique en interaction avec les facteurs nutritionnels. Les aminoacides ramifiés (BCAA) sont des composantes essentielles de notre diète et ont été reconnus comme de nouveaux acteurs dans la pathogénie de l’obésité et du diabète sucré soit comme des bio-marqueurs soit comme des régulateurs au niveau périphérique ou dans le système nerveux central. Ce travail a été proposé dans le cadre du projet Européen MEDIGENE (FP7-279171) visant le syndrome métabolique dans les populations Méditerranéennes. Dans ce contexte, nous avons utilisé une approche génétique combinant les SNP (single nucleotide polymorphism) et la cartographie dense des haplotypes. Nous avons mis en évidence de nouveaux gènes dans les phases tardives du catabolisme des BCAA, bien que le signal d’association ait été en relation complexe avec les taux plasmatiques de BCAA et la mesure in vivo de la RI. Dans une approche similaire, nous avons identifié sur le chromosome 4p14 un nouveau locus en relation avec la RI et le système de récompense cérébral impliquant le fibroblast growth factor (FGF) 21. Ces données ont soulevé l’intérêt pour une estimation rapide et efficace de l’apport en BCAA dans la diète nous emmenant à développer une nouvelle base de données du contenu des aliments en BCAA. Cette base est intégrée dans un nouveau logiciel pour le recueil des enquêtes alimentaires (rappels de 24h) et qui pourra être utilisée par des praticiens d’une manière sécurisée dans les pays de la Méditerranée, ouvrant ainsi de nouvelles perspectives en nutrigénomique. / Insulin resistance (IR) is a fundamental biological process involved in majority of complex disorders with high impact on mortality of human populations and with a strong genetic component in interaction with nutritional factors. Branched chain amino acids (BCAA) are essential components of human diet and recognized as new actors in pathogenesis of obesity and diabetes mellitus either as biomarkers or regulators at the peripheral systemic and nervous system. This work was proposed in the frame of the European project MEDIGENE (FP7-279171) studying the metabolic syndrome in several Mediterranean populations. In this context, we have used a genetic approach combining SNP (single nucleotide polymorphism) and fine scale haplotype mapping. We identified new genes in the later steps of BCAA catabolism responsible for IR, albeit displaying a complex signal in relation with BCAA plasma levels and in vivo IR measured by minimal model. With a similar approach, we identified equally a new locus of Chromosome 4p14 for IR in cooperation with the cerebral rewarding system involving fibroblast growth factor (FGF) 21 regulation. These data roused particular interest in estimating BCAA intake leading to the development of a novel database of BCAA content in food. This database is embedded in a new computer program for collecting dietary records (24HDR) and can be used securely by practitioners around Mediterranean countries and opening new perspectives in the nutrigenomic field.

Human muscle metabolism, the biochemical reactions which lead storage and usage of energy, is complex, but important in understanding human health and disease. Optimal muscle metabolism can help maintain a healthy organism by adequately storing and utilizing energy for subsequent use in contraction and recovery and adaption from contraction and exercise. Dysregulated muscle metabolism can lead to insulin resistance and obesity among other health problems. Flux balance analysis (FBA) and constraint-based modeling have successfully elucidated important aspects of metabolism in single-celled organisms. However, limited work has been done with multicellular organisms. The foci of this dissertation are (1) to show how novel applications of this technique can aid in the investigation of human nutrition and (2) to elucidate metabolic phenotypes associated with the insulin resistance (IR) characteristics of Type 2 Diabetes (T2D). First, for human nutrition a novel steady-state constraint-based model of skeletal muscle tissue was constructed to investigate the effect of amino acid supplementation on protein synthesis. Several in silico supplementation strategies implemented showed that amino acid supplementation could increase muscle contractile protein synthesis, which is consistent with published data on protein synthesis in a post-resistance exercise state. These results suggest that increasing bioavailability of methionine, arginine, and the branched-chain amino acids can increase the flux of contractile protein synthesis. Thus, this dissertation introduces the prospect of using systems biology as a framework to investigate how supplementation and nutrition can affect human metabolism and physiology. Second, given the complexity of metabolism, the cause(s) of the altered muscle metabolism in IR remain(s) unknown. Attempting to elucidate this complexity, the constraint-based modeling framework was expanded upon to develop the first in silico analysis of muscle metabolism under varying nutrient conditions and during transitions from fasted to fed states. Systematic perturbations of the metabolic network identified reactions which mimic IR phenotypes: reduced ATP/creatine phosphate synthesis, reduced TCA cycle flux, and reduced metabolic flexibility. Reduced flux through a single reaction is not sufficient to recapitulate the IR phenotypes, but knockdowns in pyruvate dehydrogenase in combination with either reduced lipid uptake or lipid/amino acid oxidative metabolism do so. These combinations also decrease complete lipid oxidation and glycogen storage. Thus, the computational model also provides a novel tool to identify candidate enzymes contributing to dysregulated metabolism in IR.

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