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.

Digestible carbohydrate is commonly encountered by chinook salmon {Oncorhynchus tshawytscha) in practical culture diets, although little is known regarding its utilization. This study was undertaken to examine (1) the effects of a high carbohydrate diet and (2) glucose tolerance in chinook salmon of selected British Columbia strains. Yearling chinook salmon of three strains were fed to satiation either a high or a low carbohydrate diet for 63 days. The diets were isonitrogenous, and contained respectively 30 % gelatinized wheat starch or an equicaloric amount of herring oil. There was an overall reduction in growth of chinook fed the high-carbohydrate diet over the 63-day feeding period. Although specific growth rates declined initially in the high carbohydrate-fed groups, they were comparable to those of control groups in the final third of the trial, indicating an adaptation response. Chinook fed the high carbohydrate diet had increased carcass protein and ash, and decreased carcass fat levels relative to controls. Feed intake was generally lower in these groups, and differences in feeding response were observed between diets and strains. Although feed and energy efficiencies were reduced in chinook fed the high carbohydrate diet, protein utilization was comparable on the two diets, indicating a protein-sparing effect of the carbohydrate. Consumption of the high carbohydrate diet led to significant elevations in hepatosomatic indices (HSI) and liver glycogen (LG) concentrations. In Quesnel chinook, LG levels exceeding 10 % did not appear to have any detrimental effects on feeding, growth or health. LG concentrations and HSI fell to basal levels in all groups 21 days after feed withdrawal. Some strain differences were evident. For example, Big Qualicum chinook fed the high carbohydrate diet exhibited the lowest liver glycogen accumulation, highest rate of carcass fat deposition, and best energy efficiency ratios relative to control groups, suggesting a difference in carbohydrate metabolism in this strain. On the other hand, Quesnel chinook exhibited the highest relative growth on the high carbohydrate diet. Mortality, although unaffected by diet in the Quesnel and Robertson Creek chinook, appeared to be higher in high carbohydrate-fed Big Qualicum chinook. In the second part of the study, chinook salmon subjected to an oral glucose tolerance test displayed pronounced and persistent hyperglycaemia, indicative of poor glucose tolerance. Strain differences were evident in the magnitude of response. Acclimation to a high carbohydrate diet prior to testing resulted in a significantly reduced elevation of blood glucose, indicating an adaptation response. While plasma glucose concentrations approached 500 mg/dl in some trials, plasma insulin concentrations exhibited a two-fold rise, with indistinct peaks. Plasma glucose and plasma insulin concentrations were poorly correlated, indicating that glucose is a poor insulin secretagogue in chinook salmon. / Land and Food Systems, Faculty of / Graduate

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.

Insulin resistance and obesity are major public health concerns. The impact of diet and genetics on insulin resistance and obesity is well accepted. Additionally, the gut microbiota has been shown to influence obesity and metabolic disorders. However, much remains to be understood about the role of gut microbiota in the development of insulin resistance and obesity. We utilized a mouse model lacking PAS kinase, a protein involved in cellular metabolism, in order to better understand the relationship between diet, genetics and the gut microbiota. Previous research has shown that mice lacking PAS kinase were protected from the effects of a high fat diet, gaining less weight and showing a better response to insulin. Surprisingly, when PAS-kinase deficient mice were placed on a western-style, high fat, high sugar (HFHS) diet, they became obese and had an impaired response to insulin, much like wild type mice on the same diet. Mutant mice did, however, show more resistance to the effects of the unhealthy diet in one aspect-they maintained normal levels of claudin-1 in the colon, suggesting that they were less likely to develop excessive gut permeability (leaky gut). While significant differences in gut microbial composition were seen in response to the HFHS diet, with shifts in the ratio of Firmicutes/Bacteroidetes and increases in the levels of Actinobacteria, none of the differences correlated with genotype. Unexpectedly, however, within the mice on the HFHS diet and regardless of genotype, the composition of the gut microbiota diverged into two clusters. The mice in one cluster showed more resistance to obesity and their glucose response was like that of wild type mice on a healthy normal chow diet (NCD), while mice in the other cluster showed more weight gain and impaired glucose response. No similar gut microbiota divergence occurred in mice on the NCD, suggesting that the HFHS diet made mice vulnerable to (but did not cause) the development of a harmful gut microbiota, whereas the healthy NCD protected against spontaneous harmful shifts in the composition of the gut microbiota.

Eine gezielte bewegungstherapeutische Intervention verbessert den Glukosestoffwechsel, reduziert den Grad der Adipositas und belegt einen antiinflammatorischen Effekt. Ungeklärt ist dabei, in welchem Zeitintervall sich die jeweiligen Risikoparameter Adipositas, Glukosestoffwechsel und chronische Entzündungsreaktionen, in einer 12-monatigen Kontroll-Interventionsstudie bei Patienten mit gestörter Glukosetoleranz (IGT) im Vergleich zu einer Rosiglitazontherapie und einer unbehandelten Kontrollgruppe adaptieren. In der vorliegenden Untersuchung wurden 60 Patienten aus einer Population von 500 Probanden mittels 2-Stunden oralem Glukose Toleranztest (2h-oGTT) als Patienten mit gestörter Glukosetoleranz identifiziert und randomisiert den zwei Therapiearmen, Rosiglitazon- und Bewegungstherapie, sowie einer Kontrollgruppe zugeführt. Es werden dabei die Effekte einer 3-mal wöchentlichen Bewegungstherapie auf den Body Mass Index (BMI), Waist Hip Ratio (WHR), Fasting Plasma Insulin (FPI), Fasting Plasma Glukose (FPG), HbA1c, 2h-oGTT, maximale Sauerstoffaufnahme (VO2max) sowie Interleukin 6 (IL6) und C-reaktives Protein (CrP) nach 1, 6 und 12 Monaten untersucht. Die Bewegungstherapie erzielt nach 1 Monat eine signifikante Verbesserung der Adipositas und des Glukosestoffwechsels. Eine Reduzierung der chronischen Entzündungsreaktion via IL6 konnte nach 12 Monaten erreicht werden. Im vergleichbaren Zeitraum zeigt die Kontrollgruppe keine statistischen Änderungen des BMI, des WHR und der inflammatorischen Parameter. Die Insulinsensitivität verminderte sich in der Kontrollgruppe signifikant innerhalb von 12 Monaten. Unter Applikation von täglich 4 mg Rosiglitazon verbessert sich der Glukosestoffwechsel nach 6 Monaten. Änderungen des Grades der Adipositas und der chronischen Entzündungsreaktion konnten nicht erzielt werden. Die Untersuchungen belegen den hohen Stellenwert der Bewegungstherapie in der Behandlung von IGT-Patienten als Standardtherapieoption. Die Bewegungstherapie sollte mindestens 3-mal wöchentlich als kombiniertes Kraft- und Ausdauertraining bei einer Intensität von 70 - 85 % VO2max und 70 - 85 % 1RM erfolgen.:1 Hintergrund und Ziel der Arbeit 2 Studiendesign und Methoden 3 Ergebnisse 3.1 Einfluss der Bewegungstherapie auf den Gewichtsverlust 3.2 Einfluss der Bewegungstherapie auf den Glukosestoffwechsel 3.3 Einfluss der Bewegungstherapie auf chronische Entzündungsreaktionen 3.4 Einfluss des IL6-Polymorphismus IL6-SNP -174G/C 4 Schlussfolgerung 5 Literaturverzeichnis 6 Publikation Long-term exercise training decreases interleukin-6 (IL6) Serum levels in subjects with impaired glucose tolerance: effect of the -174G/C variant in IL6 gene 7 Zusammenfassung 8 Anhang Erklärung über die eigenständige Abfassung der Arbeit Lebenslauf und wissenschaftlicher Werdegang Danksagung

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Type II Diabetes Mellitus (T2D) and cardiovascular diseases (CVD) are non-communicable chronic diseases that involves impairments in glucose metabolism and vascular function. Multiple factors may increase the risk for T2D, including but not limited to genetics, obesity and lifestyle, such as physical inactivity and diet. The gut microbiota, the human's largest population of microorganisms, plays an essential role in health and disease. The physiology and function of the gastrointestinal tract can be influenced by the diet. Phosphatidylcholine (PC), a source of choline in the diet, is rich in Western-type diets. Gut microbiota metabolize choline to trimethylamine (TMA) which circulates and is oxidized in the liver to form trimethylamine N-oxide (TMAO). As a result, ingestion of PC or choline could increase levels of TMAO. Preclinical studies indicate a role of TMAO in the development of atherosclerosis. Likewise, multiple observations support a potential role of TMAO in the development of insulin resistance and T2D. Much of the research has been conducted on rodent models, while others are observational human studies. Whether acute and short-term increases in TMAO contribute to impairments in insulin sensitivity in humans remains unknown. To address this, we performed two studies utilizing a double-blind, placebo controlled, crossover design. Eligible participants consumed a 1000mg/day dose of choline bitartrate and placebo (maltodextrin) the night before each testing session (for the acute choline study) or for 4 weeks (for the short-term choline ingestion study). Oral glucose tolerance test, continuous glucose monitoring, flow-mediated dilation, and applanation tonometry was performed the day after the acute choline load and before and after the short-term choline ingestion period. We hypothesized that gut microbiota-generated increase in TMAO will impair insulin sensitivity, glucose tolerance, endothelial function and arterial stiffness in healthy sedentary humans. Following acute choline ingestion, significant increases in plasma TMAO (p = 0.013) and choline (p = 0.003) were evident. There was no statistically significant difference in insulin sensitivity, glucose tolerance or in any of the endothelial function and arterial stiffness measurements. Four weeks of 1000mg choline ingestion per day, significantly increased plasma (p = 0.042) and urine (p = 0.008) TMAO concentrations compared to the placebo. However, no significant differences were observed for any other measurements of insulin sensitivity, glucose tolerance, glycemic variability, endothelial function, and arterial stiffness. More research is needed to elucidate the mechanisms behind the mechanistic observations between elevated TMAO concentrations and T2D and CVD. / Doctor of Philosophy / Type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD) increase the risk of all-cause mortality. Choline is a nutrient that can be found in foods such as red meat, dairy, fish, and eggs. Choline is metabolized from bacteria in our gut and a metabolite called trimethylamine (TMA) is formed. TMA is then oxidized in the liver and trimethylamine-N-oxide (TMAO) is produced. A Western-type diet is rich in red meat, dairy, fish, and eggs and has been shown to increase production of the compound TMAO. Preclinical studies have suggested a causal role of TMAO in atherosclerosis and T2D and elevated plasma TMAO concentrations have been associated with an increased risk for CVD and T2D in observational studies. However, the causal nature of this relationship in humans is unknown. The studies described herein aimed to investigate the effects of increases in TMAO on insulin sensitivity and vascular function in healthy adults. The first study tested the effect of increasing TMAO on insulin sensitivity, glucose tolerance, and vascular function following an acute choline load (1000mg) and placebo (carbohydrate) the night before each testing session. In the second study, we examined the effect of increasing TMAO on insulin sensitivity, glucose tolerance, and vascular function in healthy adults, following a short-term choline load (1000mg/day) and placebo (carbohydrate) for 4 weeks. Acute and short-term choline ingestion significantly increased plasma TMAO concentrations. No significant differences were observed following acute or short-term choline ingestion for any measurement of insulin sensitivity, glucose tolerance 24-hout glycemic variability, vascular function., and arterial stiffness.

There is an association between the human microbiome and disease. Gut microbes metabolize dietary sources to release trimethylamine (TMA). TMA is absorbed and then oxidized by flavin monooxygenase 3 (FMO3) to form trimethylamine N-oxide (TMAO). Elevated TMAO is associated with increased risk of cardiovascular disease and type 2 diabetes; however, the causal nature is unclear. There is also limited evidence supporting the efficacy of strategies to reduce accumulation of TMAO. Therefore, the purpose of these studies is to determine the effects of increases in TMAO on cardiometabolic health. In study 1, healthy sedentary and endurance trained males consumed a high fat diet. Blood samples were obtained in a fasted state and every hour during a 4-hour high fat challenge. We hypothesized sedentary individuals would produce higher TMAO concentrations. In study 2, healthy sedentary individuals consumed an acute 1000 mg dose of choline (CHOL) and placebo (PLC). Fasted blood samples were collected, flow-mediated dilation (FMD) and oral glucose tolerance (OGT) were measured. In study 3, healthy sedentary individuals consumed 4-wks of CHOL and PLC. Fasted blood samples were collected, FMD and OGT were measured. We hypothesized acute and 4-wk choline supplementation would impair FMD and OGT. In study 1, neither fasting (1.49± 1.2 µM vs. 2.25 ± 1.4 µM, p>0.05) or postprandial TMAO changed significantly with the HFD in sedentary or endurance trained individuals even with the endurance group consuming more TMA dietary precursors. Study 2 found increased plasma TMAO concentrations after choline supplementation on day 1(PLC; 4.14 ± 2.6 μM vs. CHOL; 23.6 ± 33.8 μM, p=0.018) and day 2 (PLC; 5.13±4.9 μM vs. CHOL; 32.6±37.5 μM, p=0.082) however, there were no differences in OGT or FMD. Study 3 found no differences in FMD or OGT following 4-wks of choline consumption. In summary, there were no differences between sedentary and endurance trained individuals fasting or post-prandial TMAO. There was also no effect on acute or 4-wk supplementation of choline on FMD and OGT. More research is needed to understand effects of elevated TMAO on cardiometabolic health. / Doctor of Philosophy / For years, research has been performed to identify the health effects of eating large amounts of red meat on cardiovascular disease (CVD). Consuming red meat, fish, poultry and eggs increases a substance created during digestion and metabolism, called trimethylamine N-oxide (TMAO). Elevated TMAO has been associated with increased risk of CVD and type 2 diabetes but the direct causes are unknown. The purpose of these studies is to determine the effects of increases in TMAO on health in humans. Study 1 included healthy, sedentary and endurance trained males who consumed a high fat diet. Blood samples were collected to measure TMAO before and after a high fat meal. Study 2 included healthy, sedentary males and females who consumed 2 days of 1000 mg of choline, which is commonly found in red meat fish and eggs, and a placebo (carbohydrate) after subjects completed a series of tests to evaluate health. Study three included healthy, sedentary males and females who consumed 4-weeks of 1000 mg of choline per day and a placebo (carbohydrate). Following supplementation subjects underwent a series of tests to assess health. Overall, there were no differences found between sedentary and endurance trained individuals. Acute and 4-week supplementation of choline did not affect measures of blood sugar or blood vessel function.

Prediabetes is a condition affecting 35% of US adults and about 50% of US adults age 65+. Foods rich in polyphenols, including flavanols and other flavonoids, have been studied for their putative beneficial effects on many different health conditions including type 2 diabetes mellitus and prediabetes. Studies have shown that some flavanols increase glucagon-like peptide 1 (GLP- 1) levels. GLP-1 is a feeding hormone that increases insulin secretion after carbohydrate consumption and increased GLP-1 levels may be responsible for some of the beneficial effects on glycemic control after flavanol consumption. The present study explored the effects of grape powder consumption on metrics of glycemic health in normoglycemic and prediabetic C57BL/6J mice; additionally, the mechanism of action of grape powder was investigated. Grape powder significantly reduced (p<0.01) blood glucose levels following oral glucose gavage after GLP-1 receptor antagonism by exendin-3 (9-39) compared to sugar-matched control; indicating that it was able to attenuate the hyperglycemic effects of GLP-1 receptor antagonism. Grape powder was employed in acute (1.6 g grape powder/kg bodyweight) and long-term high fat diet (grape powder incorporated into treatment diets at 5% w/w) feeding studies in normoglycemic and prediabetic (diet-induced obesity) mice; grape powder did not improve glycemic control in these studies versus sugar-matched control. The mechanisms by which grape powder ameliorates the deleterious effects of GLP-1 receptor antagonism warrants further study. / Master of Science in Life Sciences