Non-alcoholic fatty liver disease (NAFLD) is a liver disorder linked to obesity that is rapidly increasing in incidence worldwide. It is a disorder that ranges in severity; from a benign condition of hepatic steatosis to a potentially deadly one resulting in cirrhosis and hepatocellular carcinoma. It is currently known that NAFLD is strongly associated with various aspects of metabolic syndrome: insulin resistance, elevated triglyceride levels, obesity, and type two diabetes mellitus. The multifactorial pathogenesis of NAFLD is still uncertain and closer attention is needed on the effect of one’s diet on NAFLD. In this study, we directly compare a westernized diet containing high levels of fat and fructose to a diet high in fat and containing cholate using mouse models in order to determine the role of each dietary factor in the incidence and severity of the different stages of NAFLD. We will evaluate the severity of hepatic steatosis and hepatocellular damage via hematoxylin and eosin (H&E) stained liver tissue and the severity of hepatic fibrosis via trichrome-stained liver tissue. Our hypothesis is that mice on the fructose-based diet are expected to have higher levels of hepatic steatosis and hepatocellular damage relative to mice on the cholate-based diet while mice on the cholate-based diet are expected to have higher levels of hepatic fibrosis relative to the fructose-based diet. The results of this study will aid in elucidating and strengthening the connection between one’s diet and the prevalence and severity of NAFLD.

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The glpX gene of Escherichia coli encodes fructose 1,6-bisphosphatase II (FBPase II), an enzyme that would appear to be redundant with FBPase I, encoded by fbp. However, glpX mutants have no apparent phenotype, while fbp mutants are unable to grow on gluconeogenic substrates as sole carbon sources, suggesting that GlpX function is insufficient for growth of fbp mutants under these conditions. To gain insight into the physiological functions of the FBPases, regulation of glpX expression was investigated. It was found that glpX is transcribed as part of a complex glpFKX operon containing promoters upstream of glpF, glpK and glpX (PglpF, PglpK, PglpX, respectively). Transcription start sites of PglpX were found at -24 and -41 relative to the ATG translation initiation site using primer extension analysis. Unlike PglpF, these newly found promoters were not subject to regulation by GlpR or cAMP-CRP. Cra (Catabolite Repressor/Activator) positively regulated expression from PglpK and PglpX by increasing transcription approximately 2 fold. Western analysis using GlpX polyclonal antibodies revealed that GlpX levels were higher in cultures grown on glycerol compared with levels in maltose- or glucose-grown cultures (glycerol>maltose>glucose). Various strains and growth conditions were used to show that GlpX levels are regulated by GlpR, suggesting that PglpF can give rise to expression of glpX. GlpX protein was present in a strain containing a polar insertion in glpK, indicating that PglpX can also give rise to expression of glpX. Strains deficient in FBPase I or CsrA (carbon starvation regulator) did not reveal any difference in GlpX levels with respect to the wild type. All of these data indicate that glpX expression is achieved by its own promoter as well as the operon promoter, PglpF. Finally, the results show that the delta-fbp phenotype is not due to the absence of GlpX. / Ph. D.

Cakes were prepared with high fructose corn syrup (HFCS) at 0, 50, and 75% replacement for sucrose by weight of sugar and pregelatinized cross-bonded waxy corn starch added at 0, 0.5, and 1% by weight of flour. The water was adjusted to allow for the moisture content (literature value) of the syrup. Cakes were tested freshly baked, after 3 days of room temperature storage, and after 14 and 45 days of frozen storage (-16°C). The pH, specific gravity, and sugar composition by HPLC were determined for the cake batters. Baked cakes were evaluated for moisture content, volume, and crust and crumb color. Photographs were taken to record the overall appearance. Sensory evaluation of crust and crumb color, moistness, tenderness, flavor, and overall acceptability were completed on all variations after each storage time. The HFCS level and storage time were significant variables. The addition of starch had no effect on the quality of the cakes. Acceptable cakes were made at all levels of HFCS replacement for sucrose. Crust and crumb color were significantly (P < 0.0001) darker and volume was significantly (P < 0.0001) lower for cakes containing HFCS, however, there was little difference in cakes made with the two levels of HFCS (SO and 75%). Storage did lower the overall quality of the cakes, but not significantly in all cases. Moisture content of the cakes stored for 14 days was equal to that of freshly baked cakes. Crust and crumb color continued to darken slightly with storage. A satisfactory cake suitable for frozen storage may be prepared using HFCS. / M.S.

An estimated 20.5% of adolescents ages 12 – 19 years were obese (≥95th percentile of BMI-for-age) in 2011 – 2014. Consumption of added sugars (AS) has been linked with adverse effects on weight and cardiovascular disease risk factors. Approximately 16% of adolescents’ calories come from AS, of which sugar-sweetened beverages (SSB) are a major contributor. However, the relationship between AS/SSB intake and obesity is controversial, partly due to limitations in self-reported dietary data. Objective dietary intake biomarkers may circumvent this problem. The δ13C biomarker for AS intake is based upon the fact that C4 plants– major source for sugar production in the United States – have elevated δ¹³C values compared to C3 plants, which includes most fruits and vegetables. The δ¹³C value of blood, which is influenced by diet, has been established as a valid, reliable, and sensitive biomarker, but when compared to selfreported AS intake. This investigation evaluated the sensitivity and reliability of the δ13C biomarker, assessed with fingerstick blood samples, in adolescents using a controlled feeding, crossover design. Fingerstick δ¹³C values significantly changed by -0.05‰ and +0.03‰ after subjects completed the 5% and 25% AS diets, respectively (F(1, 30) = 18.828, p < 0.001). High reliability was found between two consecutive fingerstick δ¹³C values on the low (ICC = 0.996) and high (ICC = 0.997) AS diets. Thus, fingerstick δ¹³C may be a sensitive and reliable indicator of AS intake in adolescents. Future investigations should develop an equation to estimate AS intake based on fingerstick δ¹³C / Master of Science / Approximately one-fifth of adolescents 12 – 19 years old were obese in 2011 – 2014. A diet high in added sugars (AS), which are sugars that do not naturally occur in a food product, is associated with increased weight and higher risk for cardiovascular, or heart, disease. About 16% of adolescents’ calories come from AS, and a major source of AS intake is sugary beverages. Because people tend to inaccurately report what they eat and drink, researchers are interested in biomarkers to objectively estimate dietary intake. The δ¹³C biomarker measures carbon isotope ratios. Since most of the sugar produced in the United States comes from corn, sugarcane, and sorghum – which have a higher δ ¹³C content compared to most fruits and vegetables – δ ¹³C could indicate AS intake. Studies have reported that the δ ¹³C value of whole blood, which is influenced by diet, is valid, reliable, and sensitive, but when compared to self-reported AS intake. This investigation evaluated the sensitivity and reliability of whole blood δ ¹³C, sample using fingersticks, in adolescents consuming controlled diets so that AS intake was known. Fingerstick δ ¹³C values significantly changed after subjects completed the low and high AS diets (<i>F</i>(1, 30) = 18.828, <i>p</i> < 0.001). High reliability was found between two consecutive fingerstick δ ¹³C values on the low (ICC = 0.996) and high (ICC = 0.997) AS diets. Thus, fingerstick δ ¹³C may be a sensitive, reliable indicator of AS intake in adolescents. Future studies should develop an equation to estimate AS intake based on fingerstick δ ¹³C.

Le premier objectif de nos travaux était d'évaluer l'impact de différents facteurs d'ordre alimentaire sur la modulation de la glycémie, de l'insuline et de la réponse hormonale contre-régulatrice à l'effort chez le diabétique de type 2. Plus précisément, nous avons entrepris deux études qui nous ont permis d'étudier trois facteurs précis soit le statut nutritionnel, le contenu en macronutriment du repas pré-exercice et l'impact de la nature du sucre consommé (sucrose, fructose et aspartame) sur la modulation de la glycémie à l'effort. Ainsi, ces études ont réitéré l'aspect sécuritaire de pratiquer un exercice de type aérobie dans un état nutritionnel de jeûne chez un individu diabétique de type 2. Toutefois, les effets bénéfiques anticipés de la substitution du sucrose par de l'aspartame n'ont pas été observés dans notre deuxième étude, laissant croire en la possibilité que le goût sucré de l'aspartame ait stimulé inopinément la phase céphalique de la sécrétion d'insuline via un réflexe sensoriel en lien avec le goût sucré. Les mécanismes associés à cette stimulation sensorielle semblent avoir altéré à la fois la modulation de la glycémie, de l'insuline et de la contre-régulation hormonale à l'effort. De plus, nous avons documenté dans le cadre de cette étude des symptômes cliniques sévères d'hypoglycémie à cinq reprises lorsqu'un exercice était précédé d'un repas sucré avec du sucrose et/ou de l'aspartame. En rétrospective, ces cas d'hypoglycémies sont probablement dus à une contre-régulation hormonale altérée du métabolisme glucidique chez ces patients et l'aspartame pourrait être mise partiellement en cause. Notre troisième étude avait comme objectif d'évaluer l'impact d'un facteur pharmacologique, soit la prise d'un bêtabloquant, sur la modulation de la glycémie, de l'insuline et la réponse hormonale contrerégulatrice à l'effort chez le diabétique de type 2, tant à jeun qu'en situation postprandiale. Cette évaluation a permis de faire ressortir qu'un traitement à court terme à l'aide d'un bêtabloquant n'induit pas une augmentation de la glycémie et de l'insuline, ni une baisse plus importante du glucose et de l'insuline à l'effort comparativement à des situations expérimentales similaires sans bêtabloquant. Dans l'ensemble, ces résultats suggèrent que le statut nutritionnel a un impact plus important sur la modulation du glucose que le bêtabloquant en soi. / Type 2 diabetes is a growing epidemic which is closely associated with obesity; sedentary lifestyle and consumption of energy-dense foods of poor nutritional value. A variety of therapies may help to reduce the incidence of type 2 diabetes and its associated metabolic abnormalities, such as diet and physical activity, in order to achieve a better glycemic control, reduce the need for hypoglycemic agents and achieve/maintain a healthy body weight. The objective of this thesis was to evaluate the influence of meals with different macronutrient compositions and dietary status on plasma glucose, insulin and counter-regulatory hormonal responses in type 2 diabetes. This has been performed by varying the ratio of protein, fat and carbohydrate within a meal, using different types of carbohydrate (sucrose, fructose and aspartame) and by fluxuating the glycemic index. In addition, the impact of an acute p-blocker treatment on glucose and insulin response during exercise (performed in different dietary states) in patients with type 2 diabetes has also been evaluated in this thesis.

Die trockene, offene Erhitzung von Inulin im Bereich zwischen 100 und 220 °C resultiert in einem Abbau der Fructanketten. Dabei entsteht in Abhängigkeit vom pH-Wert ein weites Spektrum an Abbauprodukten, primär Mono- und Disaccharide, vorrangig Fructose und verschiedene Di-D-Fructose Dianhydride (DFDA). Da bisher nur ein DFDA als kommerzieller Standard erhältlich ist, wurden aus einem Inulinkaramell nach Aufreinigung per Flash-Chromatographie und semipräparativer HPLC-RI vier DFDA isoliert und identifiziert. Dabei handelt es sich um α-D-Fruf-1,2´:2,3´-β-D-Fruf (DFA III), α-D-Fruf-1,2´:2,1´-α-D-Fruf (DFA VII), β-D-Fruf-1,2´:2,1´-β-D-Fruf und α-D-Fruf-1,2´:2,1´-β-D-Fruf (DFA I). Eine fünfte Verbindung wurde als α-D-Fruf-1,2´-β-D-Fruf identifiziert, welches vermutlich aus α-D-Fruf-1,2´:2,6´-β-D-Fruf (DFA V) freigesetzt wird. Während unter sauren Bedingungen vor allem Fructose bestimmt wurde, kommt es unter basischen Erhitzungsbedingungen verstärkt zur Bildung löslicher, farbiger Verbindungen. Durch einen basischen Zusatz kann außerdem die antioxidative Wirksamkeit der Inulinkaramelle gesteigert werden, wobei wahrscheinlich besonders die farbigen Verbindungen für die antioxidative Wirkung verantwortlich sind. Die präbiotische Wirkung kann durch die Erhitzung nicht gesteigert werden, wird jedoch bei moderaten Erhitzungsbedinungen (etwa 160 °C) nicht verrringert. Durch eine gezielte Erhitzung kann Inulin so verändert werden, dass sich neue Eigenschaften und damit auch neue Einsatzmöglichkeiten in der Lebensmittelindustrie ergeben.

L'augmentation récente de la prévalence du diabète de type 2 (DT2) et du syndrome métabolique est actuellement au coeur des préoccupations des organismes de santé publique ; ces deux maladies métaboliques favoriseraient le développement des maladies cardio-vasculaires. Ce rapide accroissement peut être relié aux changements de nos modes de vie, notamment la surconsommation en sucres et la sédentarité. L’impact de ces deux paramètres à différents niveaux physiologiques a été évalué grâce à la mise en place d’un modèle murin. Des rats Wistar ont été nourris à l'aide d'une boisson enrichie en fructose (20-25% w/v), induisant le développement progressif d'un syndrome métabolique (résistance à l'insuline, hypertension, dyslipidémie, hyperglycémie à jeun), sans pour autant présenter de DT2 (pas d'intolérance au glucose). Le régime hyper-fructosé entraîne des perturbations du système antioxydant (Superoxide dismutase, Catalase, Glutathion Peroxidase) et l'apparition tardive d'une dysfonction endothéliale de l'aorte thoracique.La pratique d'une activité physique modérée permet de prévenir l'apparition de la résistance à l'insuline et améliore le fonctionnement vasculaire de l'aorte thoracique. Ce dernier effet serait en lien avec un fonctionnement du système antioxydant plus performant. Malgré tout, l'entraînement associé au régime hyper-fructosé engendrerait des effets délétères au niveau hépatique. / The recent increase of type 2 diabetes (T2D) and metabolic syndrome prevalence is a key concern of public health organizations. Both diseases can promote the development of cardiovascular diseases. This steep increase can be linked to lifestyle changes, such as sugar overconsumption and lack of physical activity. The effects of these two parameters can be evaluated at various physiological levels using a murine model. For this purpose, Wistar rats were fed with a fructose-enriched drink (20-25% w/v), which results in the progressive development of a metabolic syndrome (insulin resistance, hypertension, dyslipidemia, fasting hyperglycemia). These rats did not present T2D (no glucose intolerance). The fructose-enriched diet promotes perturbations in the antioxidant system (SOD, CAT, GPx) as well as a late endothelial dysfunction on the thoracic aorta.Moderate physical activity prevents the development of insulin resistance and increases thoracic aorta vascular function. This later may be link to the best performances of the antioxidant system. However, exercise training associated with fructose-enriched diet may be deleterious for hepatic health.