Medicine (Austin & Northern Health) - Theses
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ItemNo Preview AvailableHealth consequences for mother and baby of substantial pre-conception weight loss in women with obesity( 2019)Obesity in women of child-bearing age is common. There is little evidence that modest weight loss using lifestyle modification alters pregnancy outcomes. Bariatric surgery results in substantial weight loss, which reduces the risk of adverse outcomes for the mother but may increase risks for the baby. In order to reduce obesity-related adverse pregnancy outcomes for both mother and baby, alternative approaches to the management of obesity in women planning pregnancy are needed. OBJECTIVE: This study aims to explore the health consequences of substantial pre-conception weight loss, compared with modest pre-conception weight loss, in women with obesity. OUTCOMES: Primary outcome: To determine if non-surgical substantial pre-conception weight loss (10-15% body weight) in women with obesity (BMI 30-55kg/m2) causes a 10% reduction in fasting glucose at 26-28 weeks’ gestation compared with modest pre-conception weight loss (≤ 3% body weight). Secondary outcome: To determine if non-surgical substantial (10-15% body weight) compared with modest pre-conception weight loss (≤ 3% body weight) in women with obesity (BMI 30-55kg/m2) results in a reduction in the rate of (1) a composite of gestational diabetes, gestational hypertension/pre-eclampsia, delivery <37 weeks’ gestation, primary Caesarean section, shoulder dystocia/birth injury, large-for-gestational-age offspring, intra-uterine-growth-restriction, neonatal hypoglycaemia, neonatal hyperbilirubinemia and neonatal SCN/ICU admission, (2) gestational diabetes (3) large-for-gestational-age neonates (4) intra-uterine-growth-restriction (5) gestational hypertension/preeclampsia, (6) delivery >37 weeks’ gestation, (7) primary Caesarean section, (8) neonatal hypoglycaemia, (9) neonatal SCN/ICU admission, (10) maternal and neonatal length-of-stay, (11) a decrease in time-to-conception, (12) an increase in live birth rate (13) no difference in gestational weight gain. METHODS: This is a two-arm, parallel group, randomised controlled trial. 164 women with obesity (BMI 30–55 kg/m2), aged 18-28 years old and planning pregnancy were recruited via a social media platform. They were randomised to a 12-week intervention: modest weight loss (MWL ≤ 3% body weight) using a hypocaloric diet or substantial weight loss (SWL 10–15% body weight) using a modified very low energy diet (VLED). Completers of the intervention (Phase 1) were observed for 48-weeks (Phase 2: weight maintenance and Phase 3a: pre-pregnancy). Pregnancies were observed and pregnancy outcome data collected (Phase 3b). RESULTS: This thesis presents an interim analysis of results. In Phase 1, weight loss in MWL and SWL at Week 12 was 3.1% (3.2 0.6 kg) and 11.9% (13.0 0.5 kg) respectively (p<0.01). Cox proportional model demonstrated SWL had a significantly shorter time-to-conception than MWL (p=0.03). There was no difference in the change in fasting maternal glucose between baseline (pre-pregnancy) and 26-28 weeks’ gestation in those achieving modest (MWL -0.41 ± 0.14 (-7.6%)) and substantial (SWL -0.57 ± 0.11 (-10.6%)) pre-conception weight loss (p=0.40). A composite of pre-specified obesity-related adverse pregnancy outcomes was significantly reduced in SWL (34/21 events) compared with MWL (18/28 events) (p=<0.01). CONCLUSION: In women with obesity, non-surgical substantial pre-conception weight loss does not change fasting glucose at 26-28 weeks’ gestation compared with modest pre-conception weight loss. However, it does result a significant reduction in a composite of obesity-related pregnancy outcomes.
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ItemEffect of testosterone therapy combined with a very low caloric diet in obese men: a randomised controlled trial( 2017)Context: Whilst testosterone treatment is indicated for men with classical hypogonadism, there is no consensus as to whether treatment should be given to men with functional hypogonadism due to paucity of high-quality randomised controlled trials (RCT) of long duration. Obesity is commonly associated with low testosterone with approximately one third of adult men in developed countries classified as obese and one third of these men have low testosterone levels. Weight loss through diet and exercise can lead to modest increases in testosterone levels and improve quality of life but whether the addition of testosterone treatment has additional benefits on body composition and constitutional symptoms is unknown. Objective and methods: In this 56-week RCT of 100 obese men with low total testosterone levels subjected to a rigorous weight loss program, we investigated the effect of intramuscular testosterone undecanoate treatment on fat mass, lean mass, body weight, metabolic parameters, constitutional symptoms, adipokines, gut-derived hormonal mediators of appetite, bone mineral density and bone remodelling markers. A pre-specified blinded follow-up study was conducted for a duration of at least one year following the end of the RCT to determine whether any changes in the RCT were maintained following treatment withdrawal. Results: Testosterone treatment led to reductions in total fat mass (mean adjusted difference, MAD, -2.9kg, [ 95% CI -5.7, -0.20], P=0.04) and visceral fat (-2,678mm2 [-5,180, -176], P=0.04) over and above that achieved with dieting. Diet-induced loss of muscle mass was mitigated (MAD 3.4kg [1.3, 5.5], P=0.002) following testosterone treatment. Testosterone treatment improved Aging Males Symptoms (AMS) score (MAD -0.34, [-0.65, -0.02], P=0.04) and international index of erectile function version 5 (IIEF-5) scores (MAD -0.32 [-0.59, -0.05], P=0.025). Testosterone treatment led to a reduction in circulating leptin levels, MAD -3.6ng/ml [-5.3, -1.9], P<0.001. The changes in gut-derived hormonal mediators of appetite following weight loss in men receiving placebo was not modified by the addition of testosterone treatment. There was a reduction in c-telopeptide, MAD -66ng/L [-113, -19], P=0.018 and in procollagen type 1 N propeptide, MAD -5.6ug/L [-10.1, -1.1], P=0.03, but no change in bone mineral density between testosterone and placebo-treated men. The changes in fat mass and lean mass following testosterone treatment in the RCT were not preserved in the follow-up observation period. Twelve months after RCT completion, total testosterone levels were no different in previously testosterone and placebo-treated (P=0.71) men. Conclusions: In this rigorously conducted RCT comprehensively examining testosterone treatment in obese men, the use of testosterone treatment in obese men promoted favourable changes in body composition and improved constitutional symptoms over and above those achieved with diet alone. As the benefits of testosterone treatment are not maintained following treatment withdrawal, further studies are required to establish the long-term risk/benefit profile in this large group of men who may be considered for testosterone treatment.
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ItemInvestigating the relative contribution of obesity and glucose in the development of β-cell dysfunction( 2016)Insulin resistance and impaired insulin secretion are hallmark features that contribute to the development of hyperglycaemia in type 2 diabetes (T2D) and other complications such as kidney failure, stroke and cardiovascular disease. Obesity is considered to be one of the main drivers in expediting hyperglycaemia by inducing insulin resistance in the liver, muscle and fat. These defects place additional stress on the β-cell to increase insulin output to compensate for the prevailing glucose and over time, can result in declined β-cell function and T2D. Pre-clinical and clinical studies investigating interventions that reduce obesity in pre-diabetes have shown that the incidence of T2D can be attenuated by preserving β-cell function through enhanced insulin sensitivity. However, as obesity clearly induces hyperglycaemia, it has become inherently difficult to dissociate the relative contribution of each in the progression of impaired glucose tolerance (IGT) to T2D. Accordingly, the scope of this thesis was to use dietary and pharmacological interventions to determine the contribution of obesity and glucose in the development of metabolic defects associated with T2D, namely glucose intolerance, insulin resistance and β-cell dysfunction. The overall hypothesis was that both obesity and excess glucose contribute to these defects. In order to address the overall aim of this thesis, it was necessary to firstly characterise a pre-clinical model that does not rely on the presence of obesity to drive hyperglycaemia and subsequently, insulin resistance and β-cell dysfunction. We therefore utilised the phosphoenolpyruvate carboxykinase (PEPCK) transgenic rat, which is characterised by a 2-3 fold induction of PEPCK in the liver and kidney that leads to the impaired suppression of endogenous glucose production. Through the use of in vivo and in vitro experimental techniques, we show that the PEPCK transgenic rat develops defective glucose-stimulated insulin secretion in parallel with the worsening of glucose tolerance at 14 weeks of age, and that this is primarily due to the significant reduction in β-cell Glut2 gene expression and the inability of the constituents that make up the K+ATP channel, Sur1 and Kir6.2, to function properly. This defect in insulin secretion progressively worsens by 20 weeks due to the combination of β-cell dysregulation and reduced β-cell mass. We next investigated the potential of the selective glucose-lowering SGLT2 inhibitor, dapagliflozin, in preventing the progression of insulin resistance and β-cell dysfunction in the PEPCK transgenic rat. We show that in older animals with established insulin resistance and β-cell dysfunction, dapagliflozin treatment for 6 weeks resulted in lower body weight gain despite the compensatory increase in food intake due to energy loss from the urine, reduced plasma glucose and insulin levels, and improvements in glucose tolerance which was associated with enhanced insulin sensitivity and glucose uptake in muscle and fat. In addition, dapagliflozin treatment in PEPCK transgenic rats significantly improved GLUT4 protein content in fat while adipocyte number was increased and the size reduced. A subset of PEPCK transgenic rats were also calorie-restricted in order to prevent further weight gain so that they could be used to account for any potential weight-induced insulin-sensitising benefits seen with dapagliflozin treatment. The prevention of weight gain in these PEPCK transgenic rats greatly enhanced peripheral insulin sensitivity to levels comparable with dapagliflozin treatment. Interestingly, dapagliflozin treatment did not preserve β-cell mass or improve the insulin secretory response to glucose. These data suggest that dapagliflozin elicits its effects on the β-cell in an indirect manner by increasing insulin sensitivity and providing an islet β-cell sparring effect. To dissociate the relative contribution of obesity and glucose per se in IGT and β-cell dysfunction, obesity and glucose excess were prevented by commencing calorie-restriction and dapagliflozin treatment prior to any metabolic defects in 5 week-old PEPCK transgenic rats. Our findings show that preventing either obesity or glucose improves glucose tolerance but does not directly increase the insulin secretory capacity when assessed by a hyperglycaemic clamp or static incubation of isolated islets. These results support the hypothesis that both obesity and glucose per se contribute to the development of glucose intolerance, insulin resistance and β-cell dysfunction in the PEPCK transgenic rat and that enhancing insulin sensitivity with either intervention could effectively prevent the decline in β-cell function with age.
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ItemThe importance of gastrointestinal hormones in the development of obesity-related hypertension( 2015)In recent years, obesity has reached pandemic proportions and leading risk factor for the development of cardiovascular diseases. Obese individuals have been shown to have 3.5 times greater risk of developing hypertension than individuals with normal body weight. According to the Framingham Study, up to 75% newly-diagnosed cases of hypertension may be attributable to obesity. While sympathoactivation had been established as one of the main contributors to obesity-related hypertension, recent evidence suggests that attenuated sympathoinhibitory mechanisms may be just as important. Disruption to the delicate balance of sympathoinhibitory and sympathoexcitatory mechanisms may cause a disturbance to vasoconstrictor and vasodilator mechanisms, thus impacting cardiovascular homeostasis. The hormone leptin has received considerable attention in the aetiology of obesity-related hypertension. This peptide is primarily derived from adipose tissue and acts centrally to reduce appetite and increase energy expenditure. However obesity is associated with leptin resistance as many obese individuals have abnormally elevated circulating levels of leptin (hyperleptinaemia). This phenomenon is known as selective leptin resistance, in which the beneficial metabolic effects of leptin on energy expenditure are abolished but the sympathoexcitatory effects are sustained. This prolonged sympathoactivation is thought to contribute to the development of hypertension in obesity. Leptin is not only found in adipose tissue but also the stomach. This gastric-derived leptin is involved in the short-term regulation of food intake and satiety signalling, unlike adipose leptin that is involved on long-term regulatory mechanisms via transcriptional changes occurring in forebrain regions. The gut peptide, cholecystokinin (CCK), is involved in regulating satiety and many other digestive processes. Studies have shown that feeding and CCK administration induce the release of gastric leptin. Our laboratory was the first to demonstrate that the gut peptides, CCK and leptin, play a role in cardiovascular control via a centrally-mediated tri-synaptic reflex. CCK and gastric leptin have an interactive relationship in cardiovascular regulation, and the effects of gastric leptin are due to CCK release within the gut. CCK elicits a centrally-mediated bimodal sympathetic reflex dependent on the activation of CCK1 receptors located on subdiaphragmatic vagal afferents. Our laboratory has found that CCK inhibits a subpopulation of presympathetic vasomotor neurons in the rostral ventrolateral medulla (RVLM) that are critical to blood pressure regulation. Furthermore, this subset of neurons is proposed to modulate sympathetic vasomotor outflow specifically to the gastrointestinal and renal vascular beds, inhibition of which results in withdrawal of sympathetic vasomotor tone to promote vasodilation. The gastrointestinal and renal circulations receive up to 50% of total blood volume postprandially. Since the satiety effects of gastric leptin and CCK are affected in obesity, we hypothesised that disruption to the sympathoinhibitory and vasodilator effects of gut hormones may impact on cardiovascular homeostasis, thus contributing to hypertension in obesity. Specifically, this thesis has focussed on the cardiovascular role of gastrointestinal hormones in the aetiology of obesity-related hypertension. In order to address this hypothesis, we first established a diet induced obesity (DIO) model using polygenic out-bred male Sprague-Dawley rats fed a moderately high-fat diet (MHFD; 32% kcal from fat). After a 13-15 week feeding period, MHFD fed animals were segregated according to weight gain, with the upper tertile weight-gainers being assigned to the obesity-prone (OP) group and the lower tertile to the obesity-resistant (OR) group. Control animals were fed a low-fat diet (LFD; 9% kcal from fat). Initial weights of the animals were not significantly different between the groups. OP animals typically developed elevated resting arterial pressure (AP), increased weight gain, adiposity index and plasma leptin levels when compared with OR or control animals. However the plasma lipids, insulin and glucose were not significantly different between OP, OR or control animals, indicating that this model is independent of the metabolic syndrome. Using this DIO model, we examined the effects of CCK (2 µg/kg) and leptin (15 µg/kg) administered close to the coeliac artery and within the gastrointestinal circulation (termed "close arterial") on splanchnic sympathetic nerve discharge (SND), in artificially ventilated, isoflurane-anaesthetised animals. To determine whether any effects were attributable to obesity or the high-fat diet, animals were analysed according to weight gain (OP versus OR) or diet (all MHFD animals (including middle tertile) versus LFD animals). When analysed according to weight gain, the splanchnic sympathoinhibitory responses to CCK and leptin were significant attenuated or reversed respectively, in both the OP and OR animals when compared with control animals (P < 0.05). The splanchnic SND responses to these peptides were not significantly different between OP or OR animals (P > 0.05). Collectively, MHFD animals had significantly lower levels of CCK when compared to the LFD animals (P < 0.05) and this corresponded with attenuated or reversed splanchnic SND responses to CCK (P < 0.05) and leptin (P < 0.001), respectively. Since plasma CCK was only lower in MHFD animals, this suggested that diet alters the release of this peptide. The sympathoinhibitory effects of gastric leptin have been proposed to be due to CCK release. Therefore, in light of the attenuated sympathoinhibitory effects of CCK in MHFD rats, it is not surprising that the modest effects of close arterial leptin were reversed, possibly due to the unmasking of sympathoexcitatory mechanisms. These findings demonstrated that a high-fat diet is associated with blunted/reversed splanchnic sympathoinhibitory responses to CCK and gastric leptin, possibly impacting on sympathetic vasomotor mechanisms involved in circulatory control. Renal sympathetic nerve activity (SNA) has been implicated in the development of hypertension in obesity. Furthermore, hypertension has been associated with increased vascular resistance and impaired vasodilator mechanisms. To test whether renal SND and regional vasodilator responses to CCK were affected in obesity we recorded renal SNA and examined vasodilator responses in renal and superior mesenteric arteries using Doppler flowmetry techniques. We found that CCK (0.1 - 8 µg/kg) inhibited renal SND and increased renal vascular conductance (VC) in control and OR animals, however these responses were significantly attenuated in OP rats (P < 0.05 for all). While there was a tendency for the OP rats to have reduced mesenteric VC, this did not reach statistical significance. Resting AP was directly correlated with weight gain and was inversely correlated with CCK-induced vasodilatation in both the renal and mesenteric arteries (P < 0.05 for all). Animals with higher resting AP tended to have vasoconstrictor rather than vasodilator responses. These results suggest that in obese rats, disruption of CCK-induced sympathoinhibitory signals evoked by CCK reduces vasodilation in the splanchnic or renal regions. Our laboratory has proposed that the cardiovascular effects of gastric leptin are dependent on the release of CCK. We have shown that rats on a MHFD have lower circulating levels of CCK, suggesting that in these animals the release of this peptide is compromised. Since the splanchnic sympathoinhibitory effects of gastric leptin are abolished/reversed in MHFD animals, we therefore sought to investigate whether the renal sympathoinhibitory and regional vasodilator effects of gastric leptin are also altered. Close arterial leptin (15 µg/kg) inhibited renal SND in control animals, however this response was abolished in OP and OR rats (P < 0.01 for both). Renal VC was increased in control animals in response to leptin, but this response was significantly blunted only in the OP rats (P < 0.05). However the vasodilator response in the superior mesenteric artery was not significantly different between OP, OR or control rats (P > 0.05 for all). In agreement with our previous findings, renal sympathoinhibitory responses of gastric leptin were affected by diet. However the vasodilator response of this peptide in the renal vascular bed was only affected in OP animals, suggesting these responses are altered as a result of obesity. While we established that the typical sympathoinhibitory and vasodilatory effects of CCK and gastric leptin are attenuated or reversed in obese hypertensive animals, we did not identify the mechanisms for these changes. In the following study we sought to investigate whether these changes are due to aberrant central or peripheral mechanisms. The renal and splanchnic sympathoinhibitory effects of CCK are dependent on the activation of CCK1 receptors situated on subdiaphragmatic vagal afferents, and subsequent reflex inhibition of a subpopulation of CCK-sensitive presympathetic vasomotor neurons in the RVLM. We used extracellular single unit recording to examine whether the sensitivity of presympathetic vasomotor RVLM neurons to gut peptides is altered in obese hypertensive animals. Typically presympathetic vasomotor neurons inhibited by CCK are fast-firing and fast-conducting, and these were typical characteristics of neurons examined in this study. CCK induced inhibitory responses in RVLM neurons of OR or control animals but these responses were abolished or were excitatory in OP animals (P < 0.05 for all). RVLM neuronal responses to CCK correlated with resting AP and weight gain; animals with lower AP and weight gain tended to have inhibitory responses to CCK, whereas those with higher AP and weight gain had reduced inhibitory or excitatory responses. A further aim was to examine the barosensitivity of RVLM neurons in the different groups of animals. Barosensitivity of the RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. These results suggest that in obese hypertensive animals there is a generalised blunted responsiveness of RVLM neurons to inhibitory inputs. Our second aim was to examine whether subdiaphragmatic vagal responses to CCK and CCK1 receptor mRNA expression on the nodose ganglia are altered in obese hypertensive animals. We examined subdiaphragmatic vagal nerve discharge (SVND) responses to close arterial CCK (0.1 - 4 µg/kg) administration, and evaluated CCK1 receptor mRNA expression using quantitative PCR, respectively. Although CCK evoked a dose-dependent increase in SVND, this was not significantly different between OP, OR or control rats (P > 0.05 for all). Furthermore, there were no differences in CCK1 receptor mRNA expression in the nodose ganglia between the three groups (P > 0.05 for all), suggesting that vagal afferent responses to CCK are intact in obesity. Both the baroreflex and CCK-induced reflex are dependent on the activation of neurons in the nucleus of the solitary tract (NTS) and caudal ventrolateral medulla (CVLM). To investigate whether altered sympathoinhibitory effects in obesity result from aberrant signalling in key cardiovascular medullary centres, we examined whether obese hypertensive rats have reduced Fos-like immunoreactivity (Fos-IR) in response to CCK, using immunohistochemical techniques. Intraperitoneal injection of CCK (8 µg/kg) induced significantly less Fos-IR neurons in the NTS of OP animals when compared to control rats only (P < 0.01). There were significantly fewer Fos-IR neurons in the CVLM neurons of OP animals in response to CCK, when compared to both control or OR rats (P < 0.05). Overall, this study suggests that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due aberrant central but not peripheral signalling mechanisms. In summary, the results of these studies have demonstrated that the sympathoinhibitory and regional vasodilator effects of gut peptides are blunted or abolished in obesity-related hypertension, and that these changes may result from aberrant central signalling mechanisms. Our findings provide evidence of impaired sympathoinhibitory mechanisms from the gut in the development of hypertension in obesity. These studies specifically demonstrate that renal and splanchnic sympathoinhibitory and regional vasodilator effects of CCK and gastric leptin are attenuated or reversed in obese hypertensive animals. Blunted vasodilator responses to CCK were directly correlated with resting AP, weight gain and adiposity index. The typical inhibitory RVLM neuronal responses induced by CCK were blunted or were instead sympathoexcitatory in obese hypertensive animals and RVLM neuronal responses to CCK were directly correlated with resting AP and weight gain. These animals also had attenuated barosensitivity of RVLM neurons, indicative of altered baroreflex gain. Furthermore, in obese hypertensive rats the number of Fos-IR neurons was significantly reduced in key cardiovascular medullary centres involved in sympathoinhibitory reflexes. Nevertheless, subdiaphragmatic vagal transmission and CCK1 receptor mRNA expression in the nodose ganglia were not significantly different between the obese animals and their normotensive counterparts, suggesting that vagal afferent transmission remains intact in obese animals. Collectively, these studies support the notion that central brainstem processing of sympathoinhibitory reflexes is compromised in obese hypertensive animals, at least with respect to the CCK-induced sympathoinhibitory reflex. Altered cardiovascular responses of gut peptides, may have serious implications on postprandial cardiovascular homeostasis and lead to increased vascular resistance in the renal and gastrointestinal beds. In obesity, these changes may disrupt sympathoinhibitory mechanisms and lead to increased sympathoexcitatory mechanisms and subsequently increased vascular resistance in the gut and kidney, contributing to the aetiology of hypertension. The implications of these studies are important in the development of novel targeted therapeutic interventions to better combat and treat hypertension in obesity.
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ItemMechanisms of altered sodium transport in obesity-related hypertension( 2014)As rates of obesity continue to rise, obesity related hypertension (ORH) is becoming an increasing health burden on a global scale. Multiple mechanisms underlie the development of hypertension in obesity but important common end-pathways are vasoconstriction and volume expansion due to enhanced tubular reabsorption of sodium. The mechanisms that lead to obesity-related sodium retention at a tubular level are largely unknown. The effects of high fat diet (HFD) induced obesity on distal tubular sodium transporters were studied at different time points. At 2.5 weeks the key sodium-retaining change identified was increased expression of NCC (the target for thiazide diuretics). In contrast, at 14 weeks, NCC expression had returned to baseline but the activities of NKCC2 (the target for frusemide) and ENaC (the target for amiloride) were increased. The increase in NKCC2 activity was shown to be due to increased activating-phosphorylation. There was a marked increase at S126-NKCC2, which identifies a new role for this site in the regulation of blood pressure. A smaller phosphorylation change at T96/T101 due to increased activity of SPAK/OSR1 was also noted in the cortex. This suggests that different mechanisms underlie the establishment and maintenance of sodium retention in obesity. The energy-sensing kinase AMPK has been implicated as a mediator of several adverse consequences of obesity. AMPK has previously been found to phosphorylate S126-NKCC2 in vitro. AMPK activity was reduced in the renal cortex and in cells of the thick ascending limb after 14 weeks of HFD, making it unlikely AMPK was responsible for phosphorylation change at S126-NKCC2 noted at this time. However, in vitro studies employing activation of AMPK and the WNK/SPAK/OSR1 pathway in wild type and AMPK-null murine embryonic fibroblasts have revealed a role for AMPK in negatively regulating activating-phosphorylation of SPAK/OSR1. This suggests obesity-related AMPK suppression is responsible for the enhanced T96/T101-NKCC2 found in the renal cortex after 14 weeks of HFD through activation of SPAK/OSR1. The widely expressed basolateral sodium potassium 2 chloride co-transporter NKCC1 is closely related to NKCC2 and shares many structural and functional properties. A role for NKCC1 in regulating blood pressure through effects on vascular tone has previously been identified. A role for AMPK in regulating the function of NKCC1 was studied. AMPK was found to negatively regulate NKCC1 activity through inhibiting activating-phosphorylation at T212/217. This was due to reduced activity of SPAK/OSR1; phosphatase activity and surface expression were unchanged by activation of AMPK. In summary, the current study has revealed that different tubular mechanisms are involved in the establishment and maintenance of sodium retention in obesity. Increased phosphorylation of S126-NKCC2 has been identified as a hitherto unrecognized mediator of enhanced sodium reabsorption in ORH. Furthermore, for the first time, obesity-related suppression of AMPK has been linked to activation of SPAK/OSR1. Through downstream effects on NKCC2 and NKCC1, respectively, this links AMPK suppression with sodium retention and vasoconstriction, the key mechanisms that drive the development of ORH.
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ItemClinical and physiological differences in obese individuals with and without diabetes mellitus undergoing a very-low-calorie diet program.( 2012)In Australia, the rising prevalence of obesity and type 2 diabetes mellitus represents the major health challenge of the 21st Century. Weight reduction is a cornerstone of modern management of overweight and obese patients with type 2 diabetes; however, management of the obese diabetic patient remains one of the most challenging in clinical medicine. Very-low-calorie diets (VLCDs) – defined as diets limiting energy intake to 800 kcal (3.35 MJ) per day while providing at least 50 g of high-quality protein and amino acids, essential fatty acids and daily requirements of trace elements, vitamins and minerals – have been advanced as a therapeutic intervention for weight loss in overweight and obese individuals with type 2 diabetes mellitus. However, whether obese individuals with diabetes lose as much weight as non-diabetic individuals using VLCDs remains uncertain, as earlier studies had significant limitations. The aim of this thesis was to examine the question: are obese individuals with type 2 diabetes mellitus as “successful” as obese individuals without diabetes participating in a VLCD program? Success may variably be defined in terms of weight loss, decreases in anthropometric measurements such as waist circumference, improvements in body composition such as reductions in percentage body fat or visceral adipose tissue, improvements in metabolic parameters or insulin dosage, or improvements in renal and cardiac function. While previous studies have been primarily focused upon weight loss, the focus of this thesis is to explore the effects of VLCDs in this broader context of successes that may be attributable to participation in these weight loss programs. Importantly, the comparison of diabetic and non-diabetic individuals using VLCDs is an area hitherto under-investigated. Chapter 2 presents the results of a single centre, prospective, case-control study investigating change in weight and body composition in obese subjects with type 2 diabetes mellitus or normal fasting glucose concentrations undergoing a 24-week VLCD program. It was found that while following a 24-week VLCD program, obese subjects with and without diabetes achieved comparable weight loss but the decrease in adiposity per unit weight loss was attenuated in diabetic subjects. Hyperinsulinemia may have inhibited lipolysis in the diabetic group; however, other factors may also have contributed. Chapter 3 extends the findings of Chapter 2 by reporting on change in abdominal adipose tissue compartments, namely visceral and subcutaneous adipose tissue depots, and the changes in adipokines associated with change in visceral fat. In diabetic subjects, increased VAT volume at baseline, not baseline BMI, predicted greater weight loss. Reduction in VAT relative to abdominal SAT was attenuated in the diabetic compared to control group. Differences between the groups related to insulin and adiponectin concentrations may have contributed to this observation. Chapter 4 reports on a pilot study of abdominal magnetic resonance imaging, originally performed to image visceral adiposity, to measure skeletal muscle area at the 3rd lumbar vertebral level, allowing estimation of whole body skeletal muscle mass derived by dual-energy X-ray absorptiometry. The use of formulae previously developed in a cancer patient population was verified, with suggestions for improving these calculations for use in an obese population. Chapters 5, 6 and 7 present data on changes in renal and cardiac function and reproductive hormone profiles. Renal function was measured using the plasma clearance of the radioisotope 99mTc-diethylene-triamine-penta-acetic acid (DTPA) technique, with the Brochner-Mortensen correction. Change in advanced glycation end-products was also documented. Cardiac function was measured using transthoracic echocardiography, adding to the existing literature which is largely derived from studies of bariatric surgery. In summary, the efficacy of VLCDs in facilitating weight loss was shown to be preserved in obese individuals with diabetes. However, significant differences in the change in body composition including reductions in body fat and visceral adiposity were found. The findings of this study have implications for the management of obese individuals with diabetes undergoing intensive dietary therapies, with a greater clinical focus on fat reduction and attention to antidiabetic and weight loss pharmacotherapies mandatory in this difficult to treat population.
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ItemAn investigation of physiological adaptations to weight loss( 2012)Although dietary restriction usually results in weight loss, the majority of obese dieters eventually regain the weight that they have lost. Body weight is centrally regulated, with peripheral hormonal signals released from the gastrointestinal tract, pancreas and adipose tissue being integrated, primarily in the hypothalamus, to regulate food intake and energy expenditure. The peripheral modulators of appetite include leptin, ghrelin, cholecystokinin (CCK), peptide YY (PYY), insulin, pancreatic polypeptide (PP) and glucagon-like peptide 1 (GLP-1). Caloric restriction results in acute compensatory changes, including profound reductions in energy expenditure and circulating satiety hormones such as leptin, with increases in ghrelin and appetite, which encourage weight regain. The regulation of body weight is not completely understood, and the present study was conducted to contribute to knowledge in the following areas: 1. Whether changes in appetite-regulating hormones after weight loss are sustained following prolonged weight maintenance. 2. Ketosis thought to suppresses hunger, but its effect on circulating hormonal mediators of appetite is largely unknown. 3. Few studies have examined psychological and behavioural factors as predictors of weight loss maintenance. In the present study, 50 overweight or obese non-diabetic men and post-menopausal women undertook an 8-week ketogenic very low energy diet (VLED), in order to lose ≥10% of their initial weight. This was followed by a 2 week transition to regular foods (to maintain weight loss while reducing circulating ketones), and 52 weeks of follow-up, during which they were aiming to maintain their reduced weight. Prior to the commencement of the VLED, subjects completed five questionnaires assessing eating behaviours and psychosocial factors, which were used to predict eventual weight outcome. Participants lost an average of 14% of their starting weight during the initial weight loss period. This was accompanied by significant reductions in the anorexigenic hormones leptin, insulin, CCK, PYY, GLP-1 and amylin, and increases in ghrelin, GIP and PP. Subjective ratings of appetite increased after weight loss. The majority of changes were in a direction which would encourage weight regain, and most persisted 12 months after initial weight loss. When weight-reduced subjects were ketotic, the circulating concentrations of several hormones and nutrients which influence appetite were altered compared with after resolution of ketosis. Although there appeared to be a combination of orexigenic and anorexigenic effects of ketosis on circulating factors, subjective ratings of appetite were clearly lower in weight-reduced subjects during ketosis. Several baseline predictors of weight outcome 12 months after initial weight loss were identified, including initial heart rate, ways of coping with stress, and perceived social support.