An exploration of the management of blood glucose in hospital patients with diabetes at the end-of-life. Investigate current practice through retrospective medical notes review and focus group discussion with palliative care, diabetes and generalist ~ specialties to explore their perspectives of end-of-life diabetes care. The aim is to inform service development guidelines to improve the quality of care for patients with diabetes. An evaluation research method using a mixed method approach was conducted within an acute care setting. Deceased patient's records (n=71) were reviewed and data were abstracted for Glycaemic variables, advocacy, diabetes and admission variables to determine the factors influencing admission and end-of-life diabetes management. Descriptive statistics were used to compare the management of cancer and non-cancer patients and referral patterns to palliative care and diabetes specialists. Four focus groups were convened from the individual specialities, and a final mixed specialty group was convened. The participants were predominantly senior medical, nursing, pharmacy and dietician professionals within the hospital. Results The focus group· perception of care ideals was not reflected in the medical notes. Capillary Blood Glucose (CBG) is not routinely managed at the end-of-life due to rapid deterioration and death in the majority of patients. Diabetes is apparently treated generically without due consideration to its type or in those patients whose survival goes beyond 72 hours up to 16 days. Patients and relatives views are not routinely sought. The Liverpool Care Pathway (LCP) and limited knowledge for the management of diabetes was found to be a barrier to personalised diabetes care. Conclusion Guidelines have been suggested. Education for practice is required for optimal end-of-life care for patients hospitalised with diabetes.

No description available.

In individuals with diabetes mellitus, foot ulceration presents one of the most important risk factors in lower limb amputation. The investigation of foot ulceration is in-turn dependent on the study of plantar pressure and shear forces acting at the foot. The purpose of this study was to determine and assess the feasibility of the available methods and techniques to measure 'plantar pressure' and 'shear stresses' acting at the foot/shoe interface. From earlier studies using force-plate systems it can be concluded that the simultaneous measurement of 'shear stress' and 'pressure' is crucial in the diagnosis of plantar ulceration. However, methods to quantify both in conjunction with each other in an in-shoe situation are not well demonstrated. Investigations revealed various methods and processes to measure 'pressure' but on the other hand there seems to be a comparative lack in information of the procedures to 'measure shear stresses.

The glycaemic environment within the pancreatic beta cell is reflective of prevailing, circulating glucose conditions. Furthermore, within the pancreatic beta cell, glucose and glucose metabolites provide a suitable environment for non-enzymatic glycation to occur. Insulin which is produced and secreted from the beta cell has been shown to readily undergo glycation and is detectable within the beta cell. Under hyperglycaemic conditions, such as in diabetes, it has been proposed that the glycation of insulin is augmented and as such will provide a novel means of identifying diabetes. This thesis examines the secretion of glycated insulin from healthy and diabetic individuals, how secretion is modulated following treatment with anti-diabetic medication using a novel immunoassay and furthermore, proposes potential mechanistic routes through which glycated insulin affects insulin secretion. Pre-clinical studies in pancreatic BRIN-BDII cells and murine islets have demonstrated an autocrine inhibitory effect of insulin release. At physiologically relevant intra-islet concentrations, insulin suppressed the insulin-secretory responses of a range of secretagogues acting at different points in the beta cell stimulus-secretion coupling pathway including tolbutamide (43% inhibition), alanine (45% inhibition), IBMX (35% inhibition), forskolin (28% inhibition), and arginine (41 % inhibition). In addition, alanine and IBMX- up-regulation of insulin gene expression was decreased in the presence of insulin. Furthermore, insulin decreased gene expression of the potassium channel pore forming proteins, KIR6.2 and SUR-I, and also expression of the insulin receptor. A similar inhibitory effect on insulin release and through tolbutamide-mediated pathway was demonstrated with glycated insulin albeit to a lesser degree. Insulin (10 urnol/l) inhibited its pancreatic secretion by 65% at high glucose concentrations compared to glycated insulin which exhibited 77% inhibition at the same concentration. Importantly, glycated insulin also inhibited the autocrine release of insulin and had diminished action through the tolbutamide stimulated pathway, which may contribute to insulin resistance. Furthermore, these studies suggest inhibition by glycated insulin and insulin may be mediated through impaired membrane depolarisation. As part of this thesis, an ELISA was optimised for the quantification of circulating glycated insulin in a number of human clinical studies to assess glycated insulin as a novel biomarker for diabetes. Following optimisation, the assay was determined to be specific (spike recovery 90-97.5%, (ECso 0.37 nmol/l) and sensitive «19.1 pmol/l) for glycated insulin detection. The assay was found to be reproducible with intra and inter-assay variations of 7.9% and 8.9%, respectively. In vitro studies in pancreatic beta-cells demonstrated augmented insulin release and suppression of glycated insulin release following treatment with metformin at hyperglycaemic conditions. Furthermore, the combination of metformin with GLP-1, further augmented metformin induced insulin release while glycated insulin release remained suppressed. These findings highlight an important supplementary benefit of metformin. In clinical studies, this thesis has for the first time, demonstrated circulating glycated insulin release to be raised 3-fold in type 2 diabetic subjects and 2-fold in pre- diabetes confirming a role for glycated insulin in identifying asymptomatic diabetes and those with impaired glucose tolerance. Importantly, in studies of pregnant women, circulating concentrations of glycated insulin were found to be augmented lO-fold and may present a novel means of monitoring the beta-cell expansion during pregnancy. In type 2 diabetes, glycated insulin exhibited a rapid release from the beta-cell following a mixed meal. Circulating glycated insulin concentrations were found to be similar between fasting or non-fasting however post-prandial sampling should be carried out at least 30 min following meal ingestion to avoid any post-prandial spikes. To further examine the drug induced changes to glycated insulin secretion in a clinical setting, the effect of anti-diabetic drugs on post-prandial glycated insulin were assessed in pre-diabetic and type 2 diabetic subjects. Metformin reduced glycated insulin excursion by 48% in pre-diabetes and 60% in diabetes. Additionally, Nateglinide inhibited the glycated insulin excursion by 65% in type 2 diabetes. Studies herein have demonstrated that glycated insulin is dynamically secreted from the beta-cell in pre-diabetes, diabetes and gestational diabetes, and is affected by anti-diabetic therapeutic agents. Collectively these studies confirm a putative role for glycated insulin as a biomarker for diabetes however further work to investigate the natural history of glycated insulin secretion, in diabetes is required.

This study aimed to implement and explore the use of coaching as a method of supporting people to change their health behaviours. Coaching was delivered using the transtheoretical model of behaviour change, motivational interviewing and appreciative inquiry as underpinning theories. Ten participants were coached individually via the telephone over a three month period and the calls were taped. Thematic analysis was carried out using both an inductive and deductive approach. The core concepts of the behaviour change theories were used to develop the coding framework. In addition an interpretive analysis was carried out on two cases. A within subject design was used to assess the impact of coaching at baseline, three months, six months and 12 months on HbA1c, blood pressure, weight, BMI, waist circumference, self-reported physical activity levels, stage of change in relation to exercise, diabetes empowerment and diabetes distress. Focus group interviews were held with five participants and an ongoing coaching log was kept to formulate an account of the implementation and management of the intervention. The main study findings demonstrated that the transtheoretical model was a useful underpinning framework for use in coaching with participants moving through the stages of change although not in a linear fashion. All processes of change used can be linked to the transtheoretical model but not always as the model predicts. An increase in self-efficacy and a decrease in diabetes distress were found. The participants reported behaviour changes with coaching and identified the attributes of the coaching relationship that are essential to supporting change. Short term benefits were seen in physiological variables at three months but these deteriorated with the cessation of the intervention indicating the need for continuous support. The intervention showed high acceptability and low attrition and warrants further exploration in a clinical trial.

The health and socio-economic burdens of the current diabesity epidemic present significant challenges worldwide. This thesis evaluates the therapeutic potential of two approaches to diabesity therapy namely; sustained GIP receptor antagonism and prolonged CCK receptor activation. Active immunisation against (Pro3)GIP in high-fat mice resulted in the generation of GIP specific neutralising antibodies, resulting in decreased circulating blood glucose, plasma insulin, LDL-cholesterol, tissue triglyceride content and improved glucose tolerance and insulin sensitivity. In an extension of this work, GIP signalling blockade by active immunisation against GIP or (Pro3)GIP resulted in similar significant improvements in metabolic status of high-fat fed mice, but was devoid of changes in energy expenditure, indirect calorimetry, behaviour and cognitive function. Furthermore, results were comparatively similar to the more established therapeutic regime of once-daily treatment with the stable and specific GIP receptor antagonist, (Pro3)GIP. Contrastingly, while acute administration of the small molecular weight GIP receptor antagonist, 4H2BH, effectively inhibited the acute in vitro and in vivo actions of GIP, chronic treatment was not associated with metabolic benefits in obese diabetic (ob/ob) mice. In a separate series of experiments, chronic treatment with the stable CCK receptor agonist, p(Glu,Gln)CCK-8, reduced food intake, decreased body weight and improved metabolic control without appreciable adverse effects in high-fat fed mice. Early treatment with p(Glu,Gln)CCK-8 also prevented the onset of obesity in high fat fed mice, and benefits persisted despite cessation of treatment. Finally, combined p(Glu,Gln)CCK-8 treatment with the stable GIP agonist, GIP [mPEG] , demonstrated some beneficial additive effects, however combination therapy with the leptin fragment, [D-Leu-4]-OB3, was associated with clear additive and synergistic benefits in high fat fed mice, including inhibition of food intake and curtailment of hyperglycaemia. This thesis demonstrates that modulation of gut hormones that regulate energy homeostasis may provide novel and effective means to treat obesity-diabetes.

The transition from net glucose production by the liver to net glucose uptake after a meal is regulated by glucose, insulin and glucagon and by neurotransmitters via mechanisms that are as yet uncharacterised. This study investigated the direct effects of serotonin on glucose metabolism in freshly isolated hepatocytes. Serotonin (5-hydroxytryptamine, 5-HT) is both a neurotransmitter and a hormone produced by the gut in the postprandial state that exerts its target actions through multiple families of 5-HT receptors (5-HTl-7). 5-HT caused a concentration-dependent stimulation of glycogen synthesis in hepatocytes maintained in short-term culture that was counteracted by antagonists of 5-HTl receptors and enhanced by antagonists of 5-HT2BC receptors. Selective agonists of 5-HTl receptors (5-HTIA, 5-HTIB and 5-HTIF), m-5-HT and 5-HT2 receptors provided evidence for a stimulatory pathway mediated by 5-HTl receptors and an inhibitory pathway mediated by 5-HT2 receptors. The activation of the stimulatory pathway was counteracted by the antipsychotic drug olanzapine. M-5-HT (a-Methyl 5-hydroxytryptamine) and selective agonists for 5-HTl receptors were used to study the stimulatory signalling pathway. The stimulation of glycogen synthesis by m-5-HT (and 5-HTl receptor agonists) was greater than the stimulation induced by insulin and was associated with inactivation of glycogen phosphorylase (conversion of phosphorylase-a to phosphorylase-b) and activation of glycogen synthase without stimulation of glucose phosphorylation or glycolysis. M-5-HT counteracted the activation of glycogen phosphorylase caused by forskolin and dibutyryl-cAMP but it did not counteract the inhibition of glycolysis or the phosphorylation of the protein kinase A (PKA) substrate phosphofructokinase-2/fructose bisphosphatase-2 (Ser32) suggesting a selective effect on the glycogenic pathway as opposed to a signalling pathway upstream of PKA. Unlike insulin action the glycogenic stimulation by m-5-HT was not blocked by wortmannin, a PI 3-kinase inhibitor, and it was not associated with activation of PKB. However, it was partially counteracted by inhibitors of cdk5 including roscovitine, kenpaullone and purvanalol. Overexpression of cdk5 and its eo-regulator p35 mimicked the stimulation of glycogen synthesis by m-5-HT supporting a role for cdk5 in control of glycogen synthesis. M-5-HT caused increased phosphorylation of both protein phosphatase-l (Thr320) and its regulatory protein, inhibitor-2 (Thr72), which are substrates of cdk5. This supports a possible role for cdk5 in the glycogenic stimulation bym-5-HT. This study provides evidence that agonists of 5-HTl receptors stimulate hepatic glycogen synthesis by a novel signalling pathway that is totally distinct from the insulin signalling pathway and involves inactivation of glycogen phosphorylase and possibly activation of cdk5. The counteraction of this pathway by olanzapine provides a possible explanation for the impaired glucose tolerance caused by this currently used drug. 11

Insulin resistance, the primary metabolic abnormality underpinning type 2 diabetes mellitus and obesity, is an important risk factor for the development of cardiovascular disease. Endothelial dysfunction represents one of the earliest phases in the natural . history of atherosclerosis and is normally offset in health by various endogenous repair processes. Circulating endothelial progenitor cells (EPCs) participate in endothelial repair following arterial injury. Type 2 diabetes is associated with fewer circulating EPCs, EPC dysfunction and impaired endothelial-repair. I set out to determine whether insulin-resistance per se adversely affects EPC mediated endothelial-regeneration using mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. The metabolic phenotype of IRKO mice was consistent with compensated insulin resistance. Flow cytometry demonstrated that IRKO mice had fewer circulating EPCs than WT mice. Culture of mononuclear-cells confirmed that IRKO mice had fewer EPCs in peripheral-blood, but not in bone-marrow or spleen, suggesting a mobilization defect. Defective VEGF-stimulated EPC mobilization was confirmed in IRKO mice, consistent with reduced eNOS expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of EPCs from IRKO mice was impaired compared to those from WT animals. Endothelial-regeneration of the femoral artery following denuding wire-injury was delayed in IRKO mice compared to WT. Transfusion of mononuclear-cells and c-kit bone-marrow cells from WT mice normalized the impaired endothelial-regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial-repair. My data suggest that insulin-resistance impairs EPC function and delays endothelial-regeneration following arterial injury. These findings support the hypothesis that insulin-resistance per se is sufficient to jeopardise endogenous vascular repair. Defective endothelial-repair may be normalised by transfusion of EPCs from insulin- sensitive animals but not from insulin-resistant animals. These data may have important implications for the development of therapeutic strategies for insulin- resistance associated cardiovascular disease.

No description available.

No description available.