Motivation: The metabolic syndrome is characterized by a group of risk factors for cardiovascular disease (CVD) that includes obesity, dyslipidemia, high blood pressure, insulin resistance, glucose intolerance or non-insulin dependant diabetes mellitus, pro-thrombotic state and pro-inflammatory state. The NHANES I11 study showed the prevalence of this syndrome to be 24.0% in men and 23.4% in women in the USA. These figures translate to more than 47 million US residents having the metabolic syndrome. In the THUSA (acronym for Transition and Health in the Urbanization of South Africans) study in South Africa it was found that 12% and 28.4% of men and women, respectively, of the black population of the North West Province had three or more disturbances characterizing this syndrome. Therefore, it is evident that the metabolic syndrome is a health problem not only for developed countries but also for developing countries. As a result, this syndrome has been identified as a target for dietary therapies to reduce the risk of CVD and type 2 diabetes. Epidemiological studies have consistently demonstrated an inverse association between nut consumption and coronary heart disease (CHD) morbidity and mortality in different population groups. Nut consumption may not only offer protection against heart disease, but also increase longevity. Recently, the benefits of nuts consumption were acknowledged by the U.S. Food and Drug Administration when they approved a qualified health claim that eating nuts (1.5 ounces/day ≈ 42.8 g/day) may reduce the risk of CHD. In this regard, the most comprehensively studied mechanism involved the favourable lipid lowering effects of nuts. There is, however, a lack of data in the literature regarding the effect of nuts on the metabolic syndrome. Objective: The main objective of this study was to examine the effects of a high walnut diet and a high unsalted cashew nut diet on markers of the metabolic syndrome in humans. In order to provide a foundational body of evidence for the aforementioned, a secondary objective included conducting a systematic review that investigates the effects of nuts on the lipid profile. Methods: The main project consisted of a controlled feeding trial with a parallel, randomized controlled study design on participants having the metabolic syndrome. Sixty-four subjects having this syndrome (29 men, 35 women) with a mean (±SD) age of 45±10 y and who met with the selection criteria were all fed a 3-week run-in control diet. After this period, participants were grouped according to gender and age and then randomized into three groups, namely, those that received a controlled feeding diet including walnuts (20% energy (E), 60-100g/day; protein:carbohydrate:fat=18:42:40%E). or unsalted cashew nuts (20%E 66- 1 15g/day; protein:carbohydrate:fat=l9:44:37%E) or no nuts (protein:carbohydrate:fat=20:47:33%E) for 8 weeks. The participants' physical activity and weight were maintained for the duration of the study. For the systematic review. human intervention trials that investigated the independent effects of nuts on lipid concentrations were included. Medline and Web of Science databases were searched from the start of the database to August 2004 and supplemented by cross-checking reference lists of relevant publications. These papers received a rating based upon the methodology as it appeared in the publication. No formal statistical analysis was performed due to the large differences in study designs of the dietary intervention trials. The main outcome measures for the systematic review, were percentage differences between treatment and control groups for total blood cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDL-C) and triacyglycerols (TG). Results: Regarding the main objective, we found that both the walnut and unsalted cashew nut intervention diets had no significant effect on the lipid profile, serum fructosamine, insulin, insulin sensitivity, insulin resistance, serum high sensitivity C-reactive protein, blood pressure and serum uric acid concentrations when compared to the control dict. All three groups experienced highly significant increases in serum insulin concentrations when comparing the baseline to end (P<0.05). In turn, insulin resistance increased while insulin sensitivity decreased in all three groups. Plasma glucose concentrations increased significantly in the cashew nut group compared to the control group (P<0.05). By contrast, serum fructosamine was unchanged in the cashew nut group while the control group had significantly increased concentrations of this short-term marker of glycaemic control. The literature search for the systematic review yielded 41 5 publications. After screening, 23 nut studies were included in the review with most of these studies including heart-healthy diets. The majority of the studies were short (4-6 weeks) with only one study lasting 6 months. The number of subjects in most of the studies was sufficient to study the effects on TC and LDL-C but not for HDL-C and TG. The results of three almond (50-100g/day), two peanut (35-68g/day), one pecan nut (72g/day) and four walnut (40-84g/day) studies showed convincing evidence for a lipid lowering effect of TC between 2-1 6% and LDL-C between 2- 19%, when compared to their control diets. Currently, there are indications from inadequately designed intervention studies that hazelnuts (lg/day/kg body weight) and pistachios (20%E) may have a lipid lowering effect. At this stage the evidence for macadamia nuts is less convincing. Furthermore, it is apparent that the components in nuts further reduce TC and LDL-C concentrations beyond the effects predicted by equations based solely on dietary fatty acid profiles. Conclusions: In the controlled feeding trial, subjects displayed no improvement in the markers of the metabolic syndrome after following a walnut or unsalted cashew nut diet compared to a control diet while maintaining body weight (8 weeks). Finally, we suspect that the dramatic increase in insulin resistance may have masked the protective effects of the walnut and cashew nut diets in our subjects with the metabolic syndrome Further research is warranted before a consensus can be reached. From the systematic review it was concluded that the consumption of ≈50-100g (≈1.5-3.5 servings) of nuts five or more times/week as part of a heart-healthy diet with total fat content (high in mono- and /or polyunsaturated fatty acids) of ≈ 35% of energy may significantly decrease TC and LDL-C in normo- and hyperlipidemic individuals. Recommendations: A similar nut controlled feeding trial with some form of calorie restriction, should be done on participants having the metabolic syndrome. Future research should use randomized controlled studies with larger sample sizes and longer duration to investigate the effects of nuts on HDL-C and TG concentrations. Also, studies should investigate the effects on the lipid profile of mixed nuts and those individual nuts not yet considered. In addition, the unique nutrient and non-nutrient composition of nuts requires further research in order to elucidate the possible mechanisms responsible for the LDL-C lowering effect / Thesis (Ph.D. (Nutrition))--North-West University, Potchefstroom Campus, 2005.

Adipose tissue represents an important endocrine organ that secretes a multitude of adipokines known to mediate inflammation, lipid metabolism, and insulin sensitivity in peripheral tissues such as skeletal muscle. Specifically, adiponectin stimulates skeletal muscle fatty acid oxidation and is associated with improvements in insulin response. Long-chain n-3 polyunsaturated fatty acids (PUFA) are well known for their anti-inflammatory and insulin-sensitizing properties, and their dietary consumption is associated with a more favourable circulating adipokine profile, including increased adiponectin. However, whether n-3 PUFA can directly stimulate adiponectin secretion from human adipocytes, as well as the underlying mechanisms involved, is unknown. In contrast to n-3 PUFA, diets high in saturated fatty acids (SFA) are thought to decrease adiponectin and increase pro-inflammatory adipokines, as well as blunt skeletal muscle response to both adiponectin and insulin, possibly via activation of inflammatory pathways. The role of n-3 PUFA in mediating the communication between adipose tissue and skeletal muscle, as well as preventing SFA-induced impairments in skeletal muscle function, has yet to be examined. In this thesis, it was found that long-chain n-3 PUFA increase adiponectin secretion from human adipocytes via a peroxisome proliferator-activated receptor gamma-dependent mechanism. The effects of n-3 PUFA on adiponectin secretion were additive when combined with the thiazolidinedione, rosiglitazone. Secondly, incorporation of n-3 PUFA into a high SFA diet prevented impairments in adiponectin response and both prevented and restored impairments in insulin response in rodent skeletal muscle. Interestingly, these findings were paralleled by prevention of SFA-induced increases in toll-like receptor 4 expression by n-3 PUFA, suggesting inflammatory changes may be involved. Finally, dietary n-3 PUFA and SFA modulated the secretion of adipose tissue-derived factors from visceral rodent adipose tissue and subsequent exposure of isolated skeletal muscle to such factors induced acute changes in inflammatory gene expression without affecting insulin sensitivity. Together, the findings in this thesis suggest that n-3 PUFA modulate adipokine secretion from adipose tissue and that adipose-derived factors mediate skeletal muscle inflammation and response to adiponectin and insulin. Ultimately, this work highlights the importance of considering n-3 PUFA as a therapeutic strategy in the prevention and treatment of obesity and related pathologies.

Stress induced hyperglycaemia is prevalent in critical care. Since the landmark paper published by Van den Berghe et al. (2001) a great deal of attention has been paid to intensive insulin therapy in an ICU setting to combat the adverse effects of elevated glucose levels and poor glycaemic control. Glycaemic control protocols have been extensively developed, tested and validated within an ICU setting. However, little research has been conducted on the effects of a glycaemic control protocol in a less acute ward setting. There are many additional challenges presented in a ward setting, such as the variation in meals and levels of activity between patients, from day to day and throughout the day. A simple compartment model is used to describe the nature of insulin and glucose metabolism in patients of the Cardiothoracic Ward (CTW). A stochastic model of the fitted insulin sensitivity parameter is generated for this cohort and validated against cohorts of similar characteristics. The stochastic model is then used to run simulations of predictive control on 7 CTW patients, which shows significantly tighter glucose control than what is obtained with regular clinical procedures. However, the rate of severe hypoglycaemia is an unacceptably high 4.2%. The greatest challenge in maintaining tight glycaemic control in such patients is the consumption of meals at irregular times and of inconsistent quantities. Insulin sensitivity was compared to extensive hourly clinical data of 36 ICU patients. From this data a sepsis score of value 0-4 was generated as gold standard marker of sepsis. Comparing the sepsis score to insulin sensitivity found that insulin sensitivity provides a negative predictive diagnostic for sepsis. High insulin sensitivity of greater than Si = 8 x 10⁻⁵ L mU⁻¹ min⁻¹ rules out sepsis for the majority of patient hours and may be determined non-invasively in real-time from glycaemic control protocol data. Low insulin sensitivity is not an effective diagnostic, as it can equally mark the presence of sepsis or other conditions.

Very premature infants often experience high blood sugar levels as a result of incomplete metabolic development, illness, and stress. High blood sugar levels have been associated with a range of worsened outcomes and increased mortality, but debate exists as to whether high blood sugar levels are a cause of, or marker for, these worsened outcomes. Insulin can be used to lower blood sugar levels, but there is no standard protocol for its use in neonates, and the few clinical studies of insulin use in neonatal intensive care are relatively small and/or have resulted in high incidence of dangerously low blood sugar levels. Hence, there is a need for a safe and effective protocol for controlling blood sugar levels to a normal range in order that potential clinical benefits can be successfully studied in this clinical cohort. This thesis adapted a glucose-insulin model successfully used in adult intensive care for the unique physiology and situation of the very premature infant. The model aims to reflect known physiology. As such, sources and disposal of glucose and insulin within the body are examined using both published data and unique data sets from a study here in New Zealand. In addition, the absorption of glucose from milk feeds is examined. This glucose-insulin physiological model is then used alongside statistical forecasting to develop a protocol for selecting an appropriate insulin dose based on targeting of likely outcomes to a specified target normal range. The protocol is tested in silico using virtual trials, and then clinically implemented, with results showing improved performance over current clinical practice and other published studies. In particular, ~77% of blood glucose is observed within the specified target range across the cohort, and there has been no incidence of dangerously low blood glucose levels. This protocol is thus safe and effective, accounting for inter- and intra- patient variability, and thus enabling patient-specific care.

Motivation: The metabolic syndrome is characterized by a group of risk factors for cardiovascular disease (CVD) that includes obesity, dyslipidemia, high blood pressure, insulin resistance, glucose intolerance or non-insulin dependant diabetes mellitus, pro-thrombotic state and pro-inflammatory state. The NHANES I11 study showed the prevalence of this syndrome to be 24.0% in men and 23.4% in women in the USA. These figures translate to more than 47 million US residents having the metabolic syndrome. In the THUSA (acronym for Transition and Health in the Urbanization of South Africans) study in South Africa it was found that 12% and 28.4% of men and women, respectively, of the black population of the North West Province had three or more disturbances characterizing this syndrome. Therefore, it is evident that the metabolic syndrome is a health problem not only for developed countries but also for developing countries. As a result, this syndrome has been identified as a target for dietary therapies to reduce the risk of CVD and type 2 diabetes. Epidemiological studies have consistently demonstrated an inverse association between nut consumption and coronary heart disease (CHD) morbidity and mortality in different population groups. Nut consumption may not only offer protection against heart disease, but also increase longevity. Recently, the benefits of nuts consumption were acknowledged by the U.S. Food and Drug Administration when they approved a qualified health claim that eating nuts (1.5 ounces/day ≈ 42.8 g/day) may reduce the risk of CHD. In this regard, the most comprehensively studied mechanism involved the favourable lipid lowering effects of nuts. There is, however, a lack of data in the literature regarding the effect of nuts on the metabolic syndrome. Objective: The main objective of this study was to examine the effects of a high walnut diet and a high unsalted cashew nut diet on markers of the metabolic syndrome in humans. In order to provide a foundational body of evidence for the aforementioned, a secondary objective included conducting a systematic review that investigates the effects of nuts on the lipid profile. Methods: The main project consisted of a controlled feeding trial with a parallel, randomized controlled study design on participants having the metabolic syndrome. Sixty-four subjects having this syndrome (29 men, 35 women) with a mean (±SD) age of 45±10 y and who met with the selection criteria were all fed a 3-week run-in control diet. After this period, participants were grouped according to gender and age and then randomized into three groups, namely, those that received a controlled feeding diet including walnuts (20% energy (E), 60-100g/day; protein:carbohydrate:fat=18:42:40%E). or unsalted cashew nuts (20%E 66- 1 15g/day; protein:carbohydrate:fat=l9:44:37%E) or no nuts (protein:carbohydrate:fat=20:47:33%E) for 8 weeks. The participants' physical activity and weight were maintained for the duration of the study. For the systematic review. human intervention trials that investigated the independent effects of nuts on lipid concentrations were included. Medline and Web of Science databases were searched from the start of the database to August 2004 and supplemented by cross-checking reference lists of relevant publications. These papers received a rating based upon the methodology as it appeared in the publication. No formal statistical analysis was performed due to the large differences in study designs of the dietary intervention trials. The main outcome measures for the systematic review, were percentage differences between treatment and control groups for total blood cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDL-C) and triacyglycerols (TG). Results: Regarding the main objective, we found that both the walnut and unsalted cashew nut intervention diets had no significant effect on the lipid profile, serum fructosamine, insulin, insulin sensitivity, insulin resistance, serum high sensitivity C-reactive protein, blood pressure and serum uric acid concentrations when compared to the control dict. All three groups experienced highly significant increases in serum insulin concentrations when comparing the baseline to end (P<0.05). In turn, insulin resistance increased while insulin sensitivity decreased in all three groups. Plasma glucose concentrations increased significantly in the cashew nut group compared to the control group (P<0.05). By contrast, serum fructosamine was unchanged in the cashew nut group while the control group had significantly increased concentrations of this short-term marker of glycaemic control. The literature search for the systematic review yielded 41 5 publications. After screening, 23 nut studies were included in the review with most of these studies including heart-healthy diets. The majority of the studies were short (4-6 weeks) with only one study lasting 6 months. The number of subjects in most of the studies was sufficient to study the effects on TC and LDL-C but not for HDL-C and TG. The results of three almond (50-100g/day), two peanut (35-68g/day), one pecan nut (72g/day) and four walnut (40-84g/day) studies showed convincing evidence for a lipid lowering effect of TC between 2-1 6% and LDL-C between 2- 19%, when compared to their control diets. Currently, there are indications from inadequately designed intervention studies that hazelnuts (lg/day/kg body weight) and pistachios (20%E) may have a lipid lowering effect. At this stage the evidence for macadamia nuts is less convincing. Furthermore, it is apparent that the components in nuts further reduce TC and LDL-C concentrations beyond the effects predicted by equations based solely on dietary fatty acid profiles. Conclusions: In the controlled feeding trial, subjects displayed no improvement in the markers of the metabolic syndrome after following a walnut or unsalted cashew nut diet compared to a control diet while maintaining body weight (8 weeks). Finally, we suspect that the dramatic increase in insulin resistance may have masked the protective effects of the walnut and cashew nut diets in our subjects with the metabolic syndrome Further research is warranted before a consensus can be reached. From the systematic review it was concluded that the consumption of ≈50-100g (≈1.5-3.5 servings) of nuts five or more times/week as part of a heart-healthy diet with total fat content (high in mono- and /or polyunsaturated fatty acids) of ≈ 35% of energy may significantly decrease TC and LDL-C in normo- and hyperlipidemic individuals. Recommendations: A similar nut controlled feeding trial with some form of calorie restriction, should be done on participants having the metabolic syndrome. Future research should use randomized controlled studies with larger sample sizes and longer duration to investigate the effects of nuts on HDL-C and TG concentrations. Also, studies should investigate the effects on the lipid profile of mixed nuts and those individual nuts not yet considered. In addition, the unique nutrient and non-nutrient composition of nuts requires further research in order to elucidate the possible mechanisms responsible for the LDL-C lowering effect / Thesis (Ph.D. (Nutrition))--North-West University, Potchefstroom Campus, 2005.

At the beginning of this project it was known that functional electrical stimulation (FES) rowing was technically feasible, but no studies on health benefits had been conducted and it was unclear what levels of fitness could be reliably attained by spinal cord injured (SCI) users. This thesis shows that training with the first-generation of the FES-rowing system (RowStim II), seven paraplegics achieved high V02peak values (21.0 - 27.9 ml-kg-1-min-1) and a significant (10%) increase in V02peak. This was also found to significantly improve insulin sensitivity and leptin levels but it had no significant effect on lipid profiles or body composition, possibly caused by technological limitations of the RowStim 11. However, training volumes were positively correlated with improvements in lipid profile and body composition. This motivated further technical development of the RowStim to enable paraplegics to train harder and longer. The development included a more stable seat configuration with redesigned trunk retaining straps, a rigid low friction carriage/brake system, improved leg stabiliser, improved stimulation control and a gravity-assisted return phase. This RowStim III has enabled paraplegics to participate in the British (2004, 2005 and 2006) and World Indoor Rowing Championships (2006). The rowers have achieved higher exercise intensities (26.8 -31.0 ml. kg- I .min-1) and increased exercise volumes (1,150 kcal-week-1) with the RowStim III. Such levels of physical activity, which are difficult to achieve for paraplegics using traditional exercises, are correlated with significant health benefits in the able-bodied. Preliminary results suggest that perfusion of the quadriceps muscle during FES-rowing might limit the exercise time in novice rowers. Other preliminary data from pressure mapping indicate that there is a dynamic pattern during FES-rowing, which might reduce the risk for pressure sores during FES-rowing. This thesis shows that FES-rowing is now a rapidly developing exercise modality, which has been shown to enable safe and well-tolerated exercise for individuals with SCI. It can offer unprecedented levels of cardiovascular fitness, competitive challenges and potentially important health benefits.

In den vorliegenden Studien wurde der Fragestellung nachgegangen, wie sich unterschiedliche Fütterungsprotokolle während der Aufzuchtperiode auf den peripartalen Energie- und Fettstoffwechsel und die Insulinsensitivität von Färsen auswirken. Besonderes Augenmerk lag dabei auf der Frage, ob der „Revised Quantitative Insulin Sensitivity Check Index“ (RQUICKI) bei Färsen sinnvoll angewendet werden kann, um eine Aussage hinsichtlich der Insulinsensitivität zu treffen. Auch mögliche Auswirkungen auf das Konzeptionsalter, den Kalbeverlauf, die Milchleistung und die postpartale Morbidität wurden untersucht. Aus 46 Kälbern der Rasse Deutsche Holstein wurden drei Fütterungsgruppen gebildet. Gruppe 1 (n = 18) wurde gemäß den Richtlinien der GfE energetisch optimal gefüttert (Kontrollgruppe), Gruppe 2 (n = 14) wurde intensiv und Gruppe 3 (n = 14) restriktiv gefüttert. Im Abstand von zwei Wochen wurden die Tiere jeweils gewogen. Aus den vorliegenden Daten wurde die durchschnittliche tägliche Körpermassezunahme berechnet. Außerdem wurde zehn, sechs, drei und eine Woche vor der Kalbung sowie zwei Wochen nach der Kalbung die Rückenfettdicke (RFD) sonografisch bestimmt. Weiterhin wurden das Alter bei erfolgreicher Konzeption, Kalbeverlauf sowie Daten der Kälber, Milchleistungsprüfungsdaten und Rastzeit erfasst. Vor und nach der Kalbung wurde aus der Vena caudalis mediana Blut entnommen. Aus dem Serum wurden die Konzentrationen der folgenden Parameter bestimmt: Insulin, Insulin-like growth factor 1 (IGF-1), Glukose, freie Fettsäuren (FFS), Bilirubin, Cholesterol, Harnstoff, Betahydroxybutyrat (BHB) sowie Gesamteiweiß. Erkrankungen im postpartalen Zeitraum, wie Endometritis, Mastitis, Stoffwechselstörungen, Erkrankungen des Bewegungsapparates sowie Zyklusstörungen wurden ebenfalls in die Studien miteinbezogen. Zur Bestimmung der Insulinsensitivität wurde das Rechenmodell „Revised Quantitative Insulin Sensitivity Check Index“ (RQUICKI) verwendet. Unter Einbeziehung der Serumkonzentrationen von Glukose, Insulin und FFS lautete die Formel RQUICKI = 1/[log (Glukose) + log (Insulin) + log (FFS)]. Ein niedriger Index-Wert bedeutet eine verminderte Insulinsensitivität. Die intensiv aufgezogenen Tiere der Gruppe 2 zeigten mit 13,3 ± 1,0 Monaten ein signifikant (p = 0,003) früheres Konzeptionsalter im Gegensatz zu den Tieren der beiden anderen Gruppen (Gruppe 1: 16,0 ± 1,5 Monate; Gruppe 3: 17,7 ± 1,4 Monate). Eine Woche ante partum wiesen die Tiere der Gruppe 2 eine signifikant (p = 0,022) höhere RFD auf als die Tiere der beiden anderen Gruppen. Der RQUICKI korrelierte eine Woche ante partum signifikant negativ mit der RFD (r = -0,573; p = 0,003). RQUICKI war bei den Tieren der Gruppe 2 eine Woche ante partum signifikant (p < 0,05) niedriger als bei den Tieren der anderen Gruppen. In allen drei Gruppen konnten am dritten Tag post partum die niedrigsten Index-Werte nachgewiesen werden. Aus den errechneten Index-Werten lässt sich für Färsen für die Zeitpunkte eine Woche ante partum sowie vier Wochen post partum ein Referenzbereich von RQUICKI = 0,40 ± 0,04 ableiten. Um den dritten Laktationstag liegt bei Färsen der Referenzbereich von RQUICKI = 0,34 ± 0,02. Die intensiv aufgezogenen Färsen zeigten insgesamt mit 85,7 % die höchste Anzahl an Komplikationen bei der Kalbung, der Unterschied war statistisch allerdings nicht zu sichern. Die unterschiedliche Fütterung wirkte sich weder auf das Geschlecht der Kälber noch auf deren Geburtsgewicht aus. Signifikante Unterschiede (p < 0,05) ergaben sich bei den Serumkonzentrationen von Insulin, IGF-1, FFS und Cholesterol ante partum sowie den Bilirubin- und FFS-Konzentrationen 28 Tage post partum. Es konnten keine statistisch signifikanten Unterschiede bei den Konzentrationen von Glukose, Harnstoff, BHB und Totalprotein ermittelt werden (p > 0,05). Beim Vergleich der 305-Tage-Milchleistung wiesen die Tiere der Gruppe 2 die niedrigste Milchleistung auf. Eine signifikant (p = 0,039) höhere Inzidenz von postpartalen Zyklusstörungen war bei den Tieren der Gruppe 2 erkennbar. Eine Woche ante partum korrelierte RQUICKI signifikant negativ (r = -0,509, p = 0,008) mit dem Auftreten von Zyklusstörungen post partum. Die Untersuchungen haben gezeigt, dass durch die Fütterungsintensität während der Aufzuchtperiode die Zuchtreife, der peripartale Energie- und Fettstoffwechsel einschließlich der Insulinsensitivität, die Milchleistung sowie die postpartale Fertilität beeinflusst werden. Aus der intensiven Aufzucht resultieren eine frühere Zuchtreife, höhere Rückenfettdicken, eine gesteigerte peripartale Lipolyse einschließlich reduzierter Insulinsensitivität, eine verminderte Milchleistung und eine schlechtere Fertilität. / The aim of these studies was to investigate how different diets during the rearing period influence peripartal energy and fat metabolism as well as insulin sensitivity of heifers. Special attention was paid to the question if the „Revised Quantitative Insulin Sensitivity Check Index“ (RQUICKI) could be used to estimate insulin sensitivity in heifers. Possible influences on age at first breeding, calving, milk yield and postpartal morbidity were analysed as well. Furthermore, the aim of this investigation was to prove, if different diets at rearing influence the peripartal insulin sensitivity of heifers. 46 German Holstein calves were randomly divided in three groups. Group 1 (n = 18) was fed with an optimal diet (control group) based on recommendations of the German Society of Nutrition Physiology, group 2 (n = 14) was fed with a highly-concentrated diet and group 3 (n = 14) got a low-concentrated diet. In intervals of two weeks the heifers were weighed. With the obtained data the averaged daily weight gain was computed. In addition, ten, six, three and one week ante partum as well as two weeks post partum the backfat thickness (BFT) was measured ultrasonographically. Age at first breeding, calving, data of the calves, milk yield and interval to first service post partum were recorded, too. Before and after calving blood samples were taken from the Vena caudalis mediana. The concentrations of the following parameters were measured in blood serum: Insulin, insulin-like growth factor 1 (IGF-1), glucose, free fatty acids (FFA), bilirubin, cholesterol, urea, betahydroxybutyrat (BHB) as well as total protein. Furthermore, postpartal diseases like endometritis, mastitis, metabolic disorders, limb diseases and fertility disorders were included. To determine insulin sensitivity a mathematic model called “Revised Quantitative Insulin Sensitivity Check Index” (RQUICKI) was used. Serum concentrations of glucose, insulin and FFA were included in the formula RQUICKI = 1/[log (glucose) + log (insulin) + log (FFA)]. A low index value represents a decreased insulin sensitivity. Intensive reared heifers of group 2 reached age at first breeding (13.3 ± 1.0 months) significant (p = 0.003) earlier than heifers of the other both groups (group 1: 16.6 ± 1.5 months; group 3: 17.7 ± 1.4 months). One week ante partum heifers of group 2 showed significant (p = 0.022) higher BFT than heifers of the other groups. At the same timepoint, RQUICKI correlated significant negative with the BFT (r = -0.573; p = 0.003). In heifers of group 2, RQUICKI was significant lower (p < 0.05) one week ante partum than in heifers of the other groups. In all groups, the index values were lowest three days post partum. Based on the received index values reference ranges for RQUICKI in heifers can be proposed. One week ante partum as well as four weeks post partum the reference range for RQUICKI can be defined as RQUICKI = 0.40 ± 0.04. Three days after calving the reference range can be defined as RQUICKI = 0.34 ± 0.02. The intensive reared heifers show with an overall of 85.7 % the most difficulties at calving, but this was statistically not different. The different diets didn’t influence neither the sex of the calves nor their birth weight. Ante partum, serum concentrations of Insulin, IGF-1, FFA and cholesterol differed significantly (p < 0.05) as well as serum concentrations of bilirubin and FFA differed on day 28 post partum. No significant differences could be determined in serum concentrations of glucose, urea, BHB and total protein (p > 0.05). Heifers of group 2 showed the lowest 305-day milk yield. The incidence of postpartal ovarian diseases was significantly (p = 0.039) higher in heifers of group 2. A significant negative correlation (r = -0.509, p = 0.008) existed between RQUICKI ante partum and the incidence of postpartal ovarian diseases. In conclusion, different diets during the rearing period influence age at first breeding, peripartal energy and fat metabolism including insulin sensitivity, milk yield as well as postpartal fertility. An intensive rearing results in an earlier age at first breeding, increased BFT, enhanced peripartal lipolysis as well as reduced insulin sensitivity, decreased milk yield and poorer fertility.

The daily patterns of life, for example, food, physical activity and inactivity and sleep as well as physical fitness are associated with the accumulation of excess body fat in children. A positive energy balance between food (energy intake) and metabolism, particularly physical activity (energy output) is the accepted explanation. The reality of daily life for children is excessive calorie consumption, imbalances in macronutrient intake and missed opportunities for activity are being driven by the physical and social environment. Excess body fat tracks into adulthood and is associated with decreased insulin sensitivity, which may lead to increased risk of insulin resistance and chronic disease. Resting metabolic rate and substrate utilisation (measured by respiratory exchange ratio) are implicated in the prediction of weight gain in adults, but these relationships have been rarely explored in children. Both insulin and respiratory exchange provide insights into the pathways of accumulation of body fat. The purpose of this body of work presented here was to explore and explain how lifestyle patterns, substrate metabolism, physical fitness attributes and insulin resistance are related to excess body fat accumulation in children. “Project Energize” is a Waikato District Health Board-initiated through-school nutrition and physical activity intervention, operated in a growing number of primary schools throughout the Waikato. Data was collected from Project Energize control and programme schools between 2004 and 2006. The children that participated in this body of work were aged between 5 and 12 years of age (20% Māori). Fat mass (FM) change in Hamilton and Waikato primary school age children over a two year period is reported in study one (n=618). Study two (n=69) and three (n=169) are cross-sectional sub-studies of low decile schools (<3) that employ two methods of metabolic assessment; indirect calorimetry and glucose homeostasis; to investigate the relationships between food, activity, fitness with body composition and metabolic risk. More than 70% of the increase in body mass index (BMI) and percentage body fat (PBF) could be explained by the same measures two years earlier and more than 10% of the reported food, activity and sleep behaviours were able to be predicted from the responses two years earlier. There were no clear associations found with resting respiratory exchange ratio (RER), but resting metabolic rate (RMR) was best explained (45%) by fat free mass with a further 3% explained by cardiorespiratory fitness. Children with longer legs (as represented by height) travelled further, but FM attenuated final speed. Children with more fat had higher insulin resistance. Physical fitness was not associated with insulin resistance. Overall, a pattern of increased FM was linked to: 1. FM two years previously 2. a lesser speed attained in the 20m Shuttle Run Test and 3. higher insulin resistance. A focus on weight gain rather than change in FM and FFM, fitness and metabolic markers as the outcome of interventions is unlikely to show short or medium term changes. Therefore it is recommended that when instigating school-based nutrition and physical activity programmes, there must also be a focus on the daily patterns of life alongside community, family and culture-based partnerships to support sustainable behavioural change.

Submitted by LEVY MALMONGE (l.malmonge@hotmail.com) on 2016-05-11T13:53:42Z No. of bitstreams: 1 Dissertação Mestrado Levy Malmonge.pdf: 1689039 bytes, checksum: 8283104d3ab314c8cf56c74d68981798 (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-05-13T14:41:52Z (GMT) No. of bitstreams: 1 martinneto_lm_me_bot.pdf: 1689039 bytes, checksum: 8283104d3ab314c8cf56c74d68981798 (MD5) / Made available in DSpace on 2016-05-13T14:41:52Z (GMT). No. of bitstreams: 1 martinneto_lm_me_bot.pdf: 1689039 bytes, checksum: 8283104d3ab314c8cf56c74d68981798 (MD5) Previous issue date: 2016-02-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A insulina é o hormônio produzido pelas células beta das ilhotas pancreáticas, responsável pela captação da glicose pelos tecidos periféricos. A glicose é o principal estimulante para a secreção deste hormônio e é também o substrato energético mais utilizado pelas células para produção de energia ou armazenamento na forma de glicogênio. A insulina atinge os tecidos-alvo e se liga a um receptor de superfície da membrana plasmática, ativando uma cascata de fosforilação envolvendo as proteínas IRS1, PI-3 cinase, AKT e GLUT4. Qualquer defeito nesta sequência resulta em uma menor captação da glicose e uma maior secreção de insulina, estabelecendo um quadro chamado resistência periférica à insulina, frequente em pacientes portadores de malignidades que apresentam também uma síndrome conhecida como caquexia, caracterizada pela perda de peso, de tecido adiposo, atrofia muscular e anorexia. Esse conjunto de fatores é resultado da tentativa do organismo de produzir energia em grande escala para suprir o hospedeiro e seu tumor. Trabalhos anteriores em nosso laboratório já haviam descrito que a secreção de insulina por ilhotas de camundongos portadores de tumor solido de Ehrlich, apóes 14 dias de inoculação, apresentava-se diminuída, enquanto a sensibilidade periférica tanto à insulina quanto à glicose se mostraram aumentadas, portanto, o presente trabalho teve como objetivo avaliar a via de sinalização de insulina em tecido muscular, hepático e adiposo de camundongos caquéticos portadores do tumor sólido de Ehrlich 14 dias após inoculação. Foram analisadas as expressões gênicas por RT-qPCR e expressão protéica por Western Blotting das proteínas da via de sinalização da insulina, como IR, IRS1, PI3-K e AKT. Em uma análise geral do quadro sistêmico dos camundongos, estes apresentaram alterações metabólicas condizentes com o quadro de caquexia já estabelecido, como perda de peso, esplenomegalia, diminuição de colesterol, de glicogênios hepático e muscular e aumento de triglicerídeos plasmáticos. No tecido hepático, proteínas-chave na regulação da via - IR e AKT – apresentaram niveis proteicos aumentadas, enquanto no tecido muscular a proteína IRS1 em sua forma inativa, juntamente com AKT, estavam diminuídas. O tecido adiposo apresentou aumento na expressão gênica de algumas proteínas, mas não apresentou alteração na expressão proteica das mesmas. Portanto, o mesmo organismo apresenta orgãos com maior sensibilidade à insulina, como o tecido hepático e outros com resistencia à insulina, como o tecido muscular, mostrando uma resposta tecido-especifica à ação da insulina. / Insulin is the hormone produced by the β cells of the pancreatic islets, responsible for the absorption of glucose by peripheral tissues. Glucose is the major stimulant for the secretion of this hormone and is also the main substrate used by the cells for energy production or storage as glycogen. After the stimulus, insulin arrives at the target tissues and binds to its receptor at the surface of the cell membrane, activating a cascade of proteins phosphorylation such as IRS1, PI-3 kinase, AKT and GLUT4. Any defect in this sequence results in a lower glucose uptake and increased insulin secretion, resulting in a situation called insulin resistance, often seen in patients with malignancies and intimately linked with a syndrome called cachexia characterized by loss of weight and fat mass, muscle wasting and anorexia. These factors are the result of an attempt of the body to produce energy on a large scale to supply the host and his tumor because tumor cells absorb nutrients faster than normal cells. This study aimed to investigate the insulin signaling pathway in muscle, liver and fat tissue of solid Ehrlich carcinoma-bearing mice after 14 days of inoculation. At this time, previous studies of our laboratory had already described that the secretion of insulin showed significant decrease, while the peripheral sensitivity, for both insulin and glucose was increased. From this, we analyzed the gene expression by RT-PCR and protein expression by Western Blotting of the insulin signaling pathway proteins such as IR, IRS1, PI3-K and AKT. In a general analysis, the animals showed metabolic abnormalities consistent with cachexia already established, such as weight loss, splenomegaly, decreased cholesterol, liver and muscle glycogen and increased plasma triglycerides. In liver, IR and AKT, key proteins in the pathway regulation, were increased, while in muscle IRS1 protein in its inactive form, along with AKT were decreased. The fat tissue showed no alterations in protein expression, but showed a increased expression of genes for some proteins of the pathway. These data allow us to conclude that the sensitivity shown in ipITT it is a tissue-specific response, that is, while there is greater sensitivity to insulin in the liver, muscle appears to be resistant to the hormone.

The main aim of this thesis was to increase our understanding of the metabolic responses associated with short-term high-fat overfeeding. To this end, four separate studies are described in this thesis; each of which involved the provision of a high-fat, high-energy diet to young, healthy, lean individuals. The first of these experimental chapters (Chapter 2) determined the effects of a 7-day, high-fat (65%), high-energy (+50%) diet on postprandial metabolic and endocrine responses to a mixed meal challenge. This chapter demonstrates that 7-days of overfeeding impaired glycaemic control in our subject cohort but did not influence the response of selected gut hormones (acylated ghrelin, GLP-1 and GIP). In a mechanistic follow up study utilising stable isotope tracer methodology we then demonstrate that overfeeding-induced impairments in glycaemic control are attributable to subtle alterations in plasma glucose flux, rather than the overt tissue-specific adaptations (e.g. increased EGP, or reduced glucose disposal) that have previously been reported (Chapter 3). In an attempt to delineate the time-course of diet-induced impairments in glycaemic control, we then investigated the effects of 1-day of overfeeding (+80% energy with 73% of total energy coming as fat) (Chapter 4). Results demonstrate that a single day of overfeeding elicits responses which are comparable to 7-days of high-fat overfeeding; highlighting the rapidity with which excessive high-fat food intake can negatively influence glucose metabolism. In chapter 5 we utilised stable isotope tracer and muscle biopsy techniques to demonstrate that 7-days of high-fat overfeeding impairs glycaemic control but does not influence the fed-state mixed muscle protein fractional synthesis rate (FSR). In conclusion, the findings of this thesis demonstrate that while short-term high-fat overfeeding negatively influences whole-body glucose metabolism, skeletal muscle protein metabolism appears to be relatively unaffected in young, lean, healthy humans.