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The effect of acute insulin-induced hypoglycaemia on cognitive function in humans was examined. The principal studies were performed: i) - to examine whether cerebral adaptation to acute neuroglycopenia occurs in normal subjects, ii) - to examine whether the degree of impairment of cognitive function during acute neuroglycopenia is related to the level of cognitive ability of the subject and iii) - to establish whether patients with insulin-treated diabetes, who have impaired awareness of hypoglycaemia exhibit a more severe degree of cognitive impairment during modest hypoglycaemia. In addition to cognitive function testing in patients with impaired awareness, studies of cerebral blood flow during hypoglycaemia were undertaken using Single Photon Emission Tomography (SPET). Mood changes during acute hypoglycaemia were also examined in non-diabetic subjects. During 60 minutes of exposure to moderate hypoglycaemia there was no evidence of short term cerebral adaptation to neuroglycopenia in normal subjects. Cognitive ability did appear to have some influence on cognitive dysfunction during hypoglycaemia: those subjects of lower cognitive ability appeared to suffer a smaller degree of cognitive dysfunction during hypoglycaemia. During acute hypoglycaemia subjects were observed to have marked changes in mood: there was a decrease in hedonic tone, an increase in tense arousal and a decrease in energetic arousal. Diabetic patients with impaired awareness of hypoglycaemia suffered greater and more prolonged cognitive dysfunction during hypoglycaemia than patients with normal awareness.

The prevalence rates of type2 diabetes mellitus (T2DM) continues to rise among British Pakistanis. The aim of this project was to explore T2DM perceptions and any preventative intentions among British Pakistani women and to discover whether they are doing anything to prevent the onset in themselves and their families. Initially a systematic review was conducted to investigate 20 existing prevention interventions and to assess their effectiveness (n=12,419). Mixed methods approach was adopted and three studies were conducted. The first study consisted of two focus groups with T2DM mothers (n=8) and three focus groups with non-T2DM mothers (n=17). The second study consisted of four focus groups young British Pakistani females (n=11). All focus groups were transcribed verbatim and analysed using thematic analysis. Following these a quantitative study was undertaken comprising of a questionnaire survey; 12 prevention-perception items (derived from the qualitative data) and the Illness-Perception Questionnaire Revised (IPQ-R) using participants from the same populations: T2DM mothers (n=41), non-T2DM mother (n=47) and young women (n=42). Results were analysed using multiple/hierarchical regression. The systematic review highlighted that the most effective prevention programmes focussed on behaviour and lifestyle with a combination of support and education to participants. The research studies demonstrated that T2DM was seen as an older person’s disease to be dealt with if/when it happens. T2DM mothers demonstrated knowledge and prevention understanding. There were non-significant relationships between prevention perceptions and T2DM illness perceptions across all three groups. The finding of this thesis emphasised that lifestyle interventions are crucial to aiding T2DM preventions as a good healthy diet and regular physical activity are the key components to T2DM prevention, and the importance of personal experience in perceived severity and lay-beliefs regarding T2DM and on family/cultural influences in British-Pakistanis. The findings of this project can be used to design culturally specific interventions towards preventing T2DM in the British Pakistani community.

Previous studies in our lab have reported that CB1 and CB2 cannabinoid receptors are expressed by islet -cells where they regulate insulin secretion. A novel cannabinoid receptor, GPR55, is also activated by cannabinoids, but its physiological role in islets of Langerhans has not been established: this was investigated in this thesis, which described the expression and function of this novel receptor in islets. Initial studies of this PhD project demonstrated that GPR55 is expressed at both mRNA and protein levels in isolated mouse and human islets. Pharmacological activation of GPR55 using either a pharmacological agonist (O-1602) or the putative endogenous agonist lysophosphatidylinositol (LPI) elevated intracellular Ca2+ levels ([Ca2+]i) in Fura-2-loaded mouse and human islet cells. In addition, both agonists also stimulated insulin secretion from perifused mouse and human islets at a sub-stimulatory glucose concentration (2mM) and potentiated glucose-stimulated insulin secretion. The stimulatory effects of O-1602 were abolished in islets isolated from GPR55 knockout mice, while the LPI-induced effects on [Ca2+]i and insulin secretion were maintained following GPR55 deletion. The second phase of this PhD project demonstrated that cannabidiol (CBD), which competes with agonists at GPR55 receptors and is commonly used as a GPR55 antagonist, unexpectedly increased [Ca2+]i in mouse islet cells. Stimulatory effects in response to CBD were also observed in perifusion experiments using isolated mouse and human islets, with observations of both initiation of insulin secretion at 2mM glucose and potentiation of glucose-stimulated insulin secretion. The effects of CBD on insulin secretion were also observed in experiments using islets isolated from GPR55 knockout mice. The effects of pharmacological regulation of GPR55 on islet apoptosis were also investigated. Exposure of mouse islets to O-1602 and LPI reduced basal apoptosis and these agents also promoted islet survival in the presence of cytokines, and the GPR55 ‘antagonist’ CBD also reduced apoptosis in the absence and presence of cytokines. In addition, islets from GPR55 knockout mice showed elevations in basal and cytokine-induced apoptosis compared to wildtype mouse islets. In conclusion, the studies carried out during this PhD project indicate that GPR55 is expressed by islets and its activation stimulates increases in intracellular Ca2+ and insulin secretion, and promotes islet survival. Studies using islets isolated from GPR55 knockout mice have shown that the effect of O-1602 is dependent on the presence of GPR55, but LPI and CBD exert GPR55-independent effects in islets. These results suggest that GPR55 plays an important role in the regulation of islet physiology, and that it may contribute to the peripheral regulation of energy balance and glucose homeostasis by cannabinoids.

The aim of this research was to investigate the characteristics of leucocyte- rich platelet-rich plasma (LR-PRP) from three groups of participants; healthy diabetics, healthy controls and a group of diabetics with an active foot ulcer. ELISAs were used to measure the concentrations of a number of intrinsic growth factors in LR-PRP. No significant differences were found between groups for the levels of any growth factor. The pH and redox potential of the unsupplemented LR-PRP from the three groups of study participants were determined using a hand-held ArrowDOX pH/redox meter. There was no significant difference in the pH values or redox potential found between the three groups of participants. Experiments using a well diffusion assay and seeded lawns of bacteria frequently identified in diabetic foot infections were conducted to investigate antimicrobial properties of either pure or supplemented LRPRP. The inherent antimicrobial properties of LR-PRP were measured. Some plates which had lawns of Staphylococcus aureus, MRSA, Streptococcus pyogenes, Proteus vulgaris and E.coli had zones of inhibition caused by LR- PRP from all three study groups. Antibiotics (co amoxiclav, clindamycin, doxycycline and pip I taz) frequently used to manage diabetic foot infections were used to supplement the LR-PRP. Zones of inhibition were found for the dilutions in LR-PRP for some of the antibiotics against some bacteria, which were greater than the zones of inhibition obtained for LR - PRP and Ringers solution alone. Some differences were found in size of the ZOI between participant groups. The LR -PRP encouraged enhanced bacterial growth on the plates with Pseudomonas aeruginosa indicating that clinicians should consider assessing the wound for the presence of this organism prior to application. Enhanced bacterial growth rather than inhibited bacterial growth was found in all three study groups, with all challenge bacteria used when LR-PRP was supplemented with insulin.

The prevalence of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) continues to rise. Physical activity (PA) guidelines for health are often prescribed in an effort to reduce physical inactivity and improve health in overweight adults at risk of T2DM and CVD. However, freeliving individuals struggle to regulate PA intensity. Primarily this research aims to examine the effects of walking on T2DM and CVD risk in overweight adults with intermediate hyperglycaemia (IHG). A pilot study (Appendix 1) was undertaken to investigate the usefulness of 13C stable isotope as a method of assessing glucose disposal in this population; as results did not support this methodology it was not explored further within the thesis. The systematic review (Study 1; Chapter Four) highlights that aerobic exercise, particularly walking, is an effective method of reducing T2DM and CVD risk in overweight adults. Study 2 (Chapter Five) uses objective accelerometer data to identify ambulatory activity habits of a cohort of overweight IHG adults from Northern Ireland. Study 2 highlights this population spend the majority of time in sedentary-to-light-intensity activity, do not meet current PA guidelines and concluded that time spent in sedentary activity is significantly correlated with two-hour glucose concentration. Study 3 (Chapter Six) assessed the ability of overweight IHG adults to regulate their walking intensity to self-selected music with a predetermined tempo. Results proved this is a useful method to help this population regulate their walking intensity. This study also found that using music with a predetermined beat helps adults to attain at least moderate intensity walking. Study 4 (Chapter Seven) concluded that a novel walking intervention (music with a predetermined beat using a mobile application) with behaviour change support was not more effective than usual care for improving glycaemic control in overweight IHG adults. This nine month study found significant improvements in perceived quality of life and flow mediated dilation (FMD), however this latter result should be cautiously accepted. Future research incorporating greater sample sizes should investigate if this novel intervention achieves statistical significance in various parameters as primary outcome measures.

This thesis analysed the associations between several clinical and psychometric variables that can determine glycaemic control: nutritional intake, barriers to nutrition therapy adherence, postprandial glycaemia, and diabetes complications perception. A group of 66 patients previously diagnosed with type 2 diabetes mellitus was recruited and categorized into patients with HbA1c below 7% (proper glycaemic control) and patients with HbA1c of 7% or above (poor glycaemic control). All subjects were interviewed and offered a nutritionally controlled breakfast. The glucose response to the experimental breakfast was monitored for 120 minutes after the meal, in order to record postprandial glycaemia levels The results show that subjects with adequate glycaemic control have a better compliance of nutrition recommendations, but all patients have excess intakes of energy, total cholesterol, saturated fatty acids, and sugars. There are no significant differences in postprandial glycaemia between patients with adequate glycaemic control and those with poor glycaemic control, which may imply that some subjects are unaware that they exceed the recommended rise in postprandial glucose, and thus may be at a higher than expected risk for macro and microvascular events. As self-monitoring is the only practical way to detect postprandial hyperglycaemia, efforts should be made to promote regular glucose self-monitoring. Patients with poor glycaemic control have a more biased opinion of their likelihood of personal disease risk. Additionally, exposures such as medical tests, air pollution, pesticides, or household chemicals, are considered as likely to cause health problems as several known and common diabetes complications, like high blood pressure or cardiovascular disease. Younger age, high body mass index, and biased personal disease risk perceptions are important predictors of glycaemic control and should be addressed by education interventions. Health professionals need to consider specific patient characteristics in order to provide proper continued medical care, and nutrition education should be tailored to the perceptions of patients and should positively discriminate subjects above or below the internationally proposed HbA1c cut-points for glycaemic control.

Flavonoids are a broad collection of polyphenolic compounds ubiquitously found in foods of plant origin. Previous studies suggested that they are beneficial in protecting against many chronic diseases, such as cancers, cardiovascular diseases and neurological disorders. There is also evidence that flavonoids have beneficial effects on modifying glucose absorption and are thus regarded as potential anti-diabetic agents. To address this we investigated the effects of a flavonoid-rich berry extract on glucose transport in intestinal epithelial Caco-2 cells and C2C12 muscle cells. In Caco-2 cells, acute exposure to berry extract inhibited glucose uptake. Prolonged incubation down-regulated the gene expression of SLUT2 and SGLT1, with a concomitant up-regulation of <i>let-7a</i> miRNA. Using bioinformatic tools, <i>let-7a</i> is predicted to target the mRNA of GLUT2, potentially down-regulating its expression. In C2C12 myotubes, chronic incubation of berry extract did not have any effect on basal or insulin-stimulated glucose uptake. Taken together, these data suggested that the acute inhibitory effects of berry flavonoids on glucose transport are specific to intestinal glucose transporters. These compounds may be useful for regulating the rate of glucose absorption from the diet; however, they are less effective modifiers of peripheral glucose transport. Studies were also carried out on the molecular basis of alcoholic myopathy, using the C2C12 muscle cell model. This provides not only an opportunity to study the pathogenic basis of a common disorder but also to compare putative pathways that may be modulated my myotoxins and myoprotectants. The results of microarray studies showed that alcohol altered the expression of genes related to multiple cellular functions, including insulin signalling, muscle contraction and protein synthesis. On the other hand, microarray studies demonstrated that berry extract was a potent inducer of cellular antioxidant defence system. This indicated that berry extract might act as a dietary strategy to protect cells against ethanol-induced oxidative damage.

Survivors of bone marrow transplant (BMT) with total body irradiation (TBI) in childhood are known to suffer late-effects due to toxicities of malignancy and its treatments including chemotherapy, glucocorticoids and TBI. Well described late-effects include short stature, gonadal failure, growth hormone deficiency (GHD), fatigue and reduced quality oflife (QOL). Emerging late-effects include increased central adiposity, reduced lean mass, increased risk of metabolic syndrome and cardiovascular mortality. Many features are shared with the GHD phenotype but the effects of growth hormone (GH) treatment are unknown. Aims of the research were as follows: - To describe the BMT/TBI phenotype in more detail in reference to body composition, insulin resistance, cytokines and cardiovascular risk markers. To investigate the GH axis in further detail using overnight growth hormone profiles, IGF-l generation tests, and the response to GH treatment over the first year. To examine the HP A axis using overnight cortisol profiles. To investigate the effects of an exercise intervention on body composition, insulin resistance, and cardiovascular risk. Results confirmed increased adiposity and reduced lean mass in BMT/TBI survivors with and without GHD and ameliorated by GH treatment. Increased risk of diabetes, metabolic syndrome and dyslipidaemia were demonstrated. Data showed a high prevalence of GHD in BMT/TBI survivors after adjustment for adiposity and that this persisted into adulthood and evolved with time since BMT/TBI. GH treatment resulted in improved height velocity and body composition but not improved metabolic and cardiovascular risk factors. There were no differences in response to GH treatment between BMT/TBI survivors and controls. The HPA axis studies showed novel changes in BMT/TBI survivors with clear gender differences in free cortisol index levels, including raised overnight levels in male survivors and blunted morning levels in female survivors. The exercise intervention showed improvements in fitness and insulin resistance but not body composition or cardiovascular risk markers. Further studies are required to investigate the mechanism of the development of diabetes and the metabolic syndrome in this group and further secondary prevention strategies are required to improve long-term cardiovascular outcomes