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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

The role of skeletal muscle energetics in the symptoms and metabolic characteristics of growth hormone deficiency and vitamin D deficiency : a functional MRS approach

Sinha, Akash January 2013 (has links)
Both growth hormone deficient (GHD) and vitamin D deficient adults complain of fatigue. Suboptimal skeletal muscle mitochondrial function has been implicated in several disorders where fatigue is a prominent feature. I examined in vivo dynamic skeletal muscle metabolism in GHD and vitamin D deficient adults using a non-invasive tool called phosphorus-31 magnetic resonance spectroscopy (31P MRS). 31P MRS can quantify abnormalities in metabolic work-cost relationship during exercise. In the first study, skeletal muscle metabolism was assessed in age, gender and physical activity matched untreated GHD adults, GH treated GHD adults and healthy volunteers. Fatigue perception was compared across the 3 groups using specific domains within a validated quality of life questionnaire (QoL-AGHDA). Whilst untreated GHD adults experienced more fatigue compared to treated GHD adults and normal volunteers, they did not demonstrate any perturbations in peripheral skeletal muscle metabolism as determined by 31P MRS: maximal mitochondrial oxidative function, anaerobic glycolysis and proton clearance. In the second study, the effect of cholecalciferol therapy on skeletal muscle mitochondrial function in vitamin D deficient adults who had presented to their local primary care team with fatigue was examined. 31P MRS assessments were undertaken in 12 symptomatic, severely vitamin D deficient subjects before and after treatment with cholecalciferol. Cholecalciferol therapy was found to augment skeletal muscle mitochondrial oxidative phosphorylation in these individuals. To summarise, I have examined dynamic skeletal muscle metabolism in two common endocrine disorders with contrasting results. There was no detectable perturbation in skeletal muscle metabolism in untreated GHD patients when compared to both matched GH replaced GHD patients and healthy controls. On the other hand, I have found that maximal mitochondrial function is improved and altered by vitamin D repletion in symptomatic vitamin D deficient adults, thereby suggesting a peripheral mechanism for fatigue in vitamin D deficiency. This is the first time that a link has been identified between vitamin D and the mitochondria in human skeletal muscle using 31P MRS.

Development and characterisation of novel proglucagon-derived peptide analogues for the treatment of Type 2 diabetes

Lynch, Aisling Martina January 2013 (has links)
There is an acute medical need for additional drug therapies which offer improved efficacy and better glycaemic control for patients with Type 2 diabetes. Here the antidiabetic potential of several novel pro glucagon-derived peptide analogues were assessed in preclinical studies. Structural modifications, which include variations of glucagon and oxyntomodulin (Oxm), were used to develop novel peptide receptor agonists. Glucagon-based analogues assessed included native glucagon, (N-Acetyl)glucagon, (D-Ser2)glucagon, glucagon-Lys30-y-glutamyl-PAL and (D-Ser2)glucagon-end exendin. Overall, the glucagon agonist with the most potential was (D-Ser2)glucagon as it was stable to DPP-4, significantly increased insulin release in vitro , produced significant beneficial changes in blood glucose and insulin concentrations in vivo in mice and inhibited acute food intake over 3 h. Modified oxyntomodulin analogues tested included (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (DSer2) Oxm, (N-Acetyl)Oxm and (D-Ser2)Oxm-Lys-y-glutamyl-PAL. (Aib2)Oxm showed most benefit and was resistant to DPP-4, significantly increased insulin release in vitro, reduced blood glucose and food intake, whilst increasing insulin concentrations in vivo. Moreover, an acylated analogue (D-Ser2)Oxm-Lys-y-glutamyl-PAL displayed longerlasting biological efficacy by reducing acute blood glucose concentrations in a glucose tolerance test, 4 h after administration. Dogfish glucagon and related analogues were also assessed, including (Tyr')(D-Ala2)dogfish glucagon, (Tyr')(D-Ala2)(Glu3)human glucagon, (D-Ala2)dogfish glucagon, (D-Ala2)dogfish glucagon-Lys '2 -y-glutamyl-PAL, (D-Ala2)dogfish glucagon-Lys20-y-glutamyl-PAL and (D-Ala2)dogfish glucagon-Lys30- y-glutamyl-PAL. (D-Ala2)dogfish glucagon had the best stability profile in mouse plasma and the greatest insulinotropic activity both in vitro and in vivo, whilst reducing blood glucose and food intake in mice. The duration of biological action was enhanced with the acylated analogues, with the most promising analogue being (D-Ala2)dogfish glucagon-Lys30 -y-glutamyl-PAL. Furthermore, chronic administration of dogfish glucagon based analogues were as effective as exendin-4 over a 28 day treatment period. This thesis demonstrates that novel pro glucagon derived peptide analogues display prominent antidiabetic effects both in vitro and in vivo, and should be investigated further for Type 2 diabetic therapies

Nanoparticles as potential drug delivery systems for anti-diabetic peptide therapeutics

Craythorne, Natalie Louise January 2014 (has links)
Exenatide is a potent glucagon-like peptide-1 receptor agonist used in clinical practice for the management of type 2 diabetes. Exenatide is administered subcutaneously twice daily, or once weekly in the form of poly (Iactide-coglycolide) PLGA microspheres. This study investigated the benefit of using encapsulated nanoparticulate exenatide as an intraperitoneal and oral treatment compared to native peptide. To optomise the encapsulation process and determine its suitability to other peptide or protein formulations, ovalbumin and glucose-dependent insulinotrophic polypeptide (GIP) were used. The intial formulation data was collected using ovalbumin as the encapsulant and further optomised using GIP. Following method development with the model protein and peptide, exenatide was successfully encapsulated within the polymeric nanoparticles using the double emulsion/solvent evaporation method, resulting in particles of 122.98 ± 1.65 nm in mean diameter, with a 25.0 ± 1.76% encapsulation efficiency of exenatide. Analysis of the peptide using MALDI-MS confirmed the encapsulated peptide to be the same as the native peptide. Stability analysis determined that the material was stable for a period of 12 weeks, the duration of the trails. In vitro drug release in simulated physiological environments representative of the stomach, small and large intestines suggests that the formulation is most suited to drug delivery in the large intestine. In vitro analysis in BRIN-BD11 cells showed exenatide-Ioaded nanoparticles to have limited cytotoxicity and an ability to produce more insulin than native exenatide. In vivo glucose homeostasis results revealed that the oral administration of exenatide-loaded nanoparticles was superior to intraperitoneal administration and native exenatide in reducing blood glucose. Orally administered exenatide was released from nanoparticles in an environment representative of the small intestine over a period of 96 hours, remaining in the blood at low concentrations over the same period of time. The aforementioned results prove that this delivery system has the potential to change diabetes treatment, allowing for the administration of an oral anti-diabetic peptide. Collectively, these results indicate the need for further investigation of the oral administration and release of anti -diabetic peptides from orally administered nanoparticles.

Pro-glucagon derived peptide therapies for type 2 diabetes and obesity

Bhat, Kattathila Vikas January 2014 (has links)
Pro-glucagon derived peptides, namely glucagon like peptide-l (GLP- I), oxyntomodulin, glucagon and the structurally related peptide, glucose dependent insulinotropic polypeptide (GIP) work to maintain glucose homeostasis, energy balance and body weight. In diabetes the action of GIP is attenuated and the secretion of GLP-I is reduced. Glucagon release aggravates the hyperglycaemic state and promotes progression to type 2 diabetes; being assisted by insulin resistance caused by obesity. Peptide mimetic development is impeded by degradation with dipeptidyl peptidases as well as endopeptidases and subsequently renal clearance. To date no peptide mimetic has exhibited stringent control of glycaemia in addition to providing effective weight loss. This thesis investigates the efficacy of various hybrid combinations of pro-glucagon derived and structurally related peptides in counteracting the deleterious effects of obesity-diabetes. Glucagon analogues with strategic amino acid substitutions to promote GIP function, GIP-Oxyntomodulin hybrids with anorectic and insulinotropic abilities and various GLP-I, GIP and glucagon hybrid peptide combinations were tested for in vitro and in vivo activity. Importantly, all hybrid peptides tested were completely stable to the actions ofDPPIV up to and beyond 8 hours and stimulated an enhancement of insulin secretion in BRIN-BDII cells. Furthermore, selected peptides exhibited acute insulin-releasing and glucose-lowering properties in lean mice. Modified glucagon analogues displayed long-term glycaemic control without exerting any changes in body weight. A GIP-Oxyntomodulin hybrid acutely and sub-chronically improved glycaemic state while lowering circulating levels of glucose and increasing levels of insulin and presented with lowered body weight independent of food intake. This was also accompanied by improved insulin sensitivity. [DA2]GLP-I/GCG acutely improved glucose control reflected by enhanced insulin release. This effect was persistent even at 8 hours post-administration. In models of insulin resistance (oblob mice), [DA2]GLP-lIGCG lowered glucose and improved insulin secretion possibly through a mode of peripheral glucagon-induced gluconeogenic inhibition. In HFF mice, long-term administration of [DA2]GLP-lIGCG improved glucose control with higher circulating levels of insulin and ameliorated insulin sensitivity. Glucose tolerance was enhanced with significant weight loss.

The validity and application of self-monitoring of blood glucose in diabetes

Given, Joanne Emma January 2014 (has links)
This thesis has explored the validity and application of self-monitoring of blood glucose (SMBG) in diabetes mellitus from a range of perspectives, using a variety of methods. Initially, a systematic literature review was conducted to evaluate the validity of patient generated blood glucose diaries. Concern was raised over their clinical utility as, allowing for a minimal amount of 'error', just over 50% of adult diaries could be considered 'accurate/reliable'. There was also a lack of information relating to the diaries of those with type 2 diabetes and study follow-up was of short duration. As a result, a secondary data analysis was conducted to explore the validity of diaries, over a year, in a sample of patients with type 2 diabetes. Using a range of statistical techniques, and a novel approach to determining the clinical significance of recording errors, this identified an initial learning curve for 5MBG record keeping. Our understanding of the validity of 5MBG was furthered by subsequently using this database to explore the impact of measurement error on the estimation of the relationship between mean plasma glucose and glycated haemoglobin. Measurement error led to an underestimation of the relationship. When combined with biological variation this draws into question the potential for one regression equation to represent this relationship across diverse populations. The final section of this thesis concentrates on the validity and application of SMBG when telemedicine is used between antenatal women with gestational diabetes and the diabetes team. A feasibility study was conducted for a randomised controlled trial and telemedicine review was found to allow comparable management decisions to be made in less time than face-to-face review. Staff and patients found the equipment easy to use and were positive about the potential for telemedicine to be used to replace alternate outpatient diabetes review appointments.

Investigation of the antidiabetic actions and function of insulin, glucagon and glucagon-like peptide 1 secreting cells for transplantation therapy of diabetes

Green, Alastair David January 2015 (has links)
Diabetic patients who cannot adequately maintain glucose homeostasis using other agents often have to rely on exogenous insulin treatment. This can have side effects such as hypoglycaemia. Islet transplantation has been shown to provide improved glucose management with lower risk of hypoglycaemia in patients with brittle diabetes. Unfortunately this therapy is greatly limited by the lack of availability of primary tissue, and poor long term survival of grafts. Recently, cell therapy has shown great promise as a potential treatment for diabetes. In this project, the effects of cell communication on survival and function of human insulin secreting 1.1 B4 cells in vitro and in vivo were investigated. Additionally, the effects of co-agonism of GLP- 1 and glucagon receptors by cell therapy using mouse L-cell and alpha cell models in diabetic SCID mice were examined. To improve survival and function of grafts, effects of co-culturing mouse GLP-1 secreting GLUTag cells along with mouse insulin secreting MIN6 cells to form heterotypic pseudoislets were also investigated. Such studies might help understand the role of homotypic and heterotypic cellular interactions in maintenance of l3-cell function and survival. The configuration of 1.1 B4 cells as pseudoislets increased insulin secretory function, and enhanced resistance to cytotoxicity. These changes were accompanied by significant increases in the expression of genes for insulin production and secretion, cellcommunication and anti-oxidant defence. Implanted 1.1 B4 cells grew into well vascularised cell masses within approximately 2-3 weeks. As expected, in normoglycaemic animals the cells had no detectable metabolic effects. However, diabetic animals receiving 1.1 B4 cell suspensions or pseudoislet implants also grew cell masses without measurable metabolic effects. It has been shown that 1.1 B4 cells are sensitive to high glucose toxicity, and so the study was repeated, but prior to and during implantation and the cell growth period, hyperglycaemia was ameliorated with intensive insulin therapy. On this occasion both monolayers and pseudoislets yielded well vascularised, insulin positive cell masses which reversed hyperglycaemia in the animals. The therapeutic effect of 1.1 B4 cell suspensions and pseudoislets was similar, though pseudoislet cell masses grew more slowly. Implantation of GLUTag cells and a combination of GLUTag and TC1.9 cells both had profound restorative effects on pancreatic islet beta cells, and caused significant decreases in circulating blood glucose, and increases in glucose tolerance. TC 1.9 cells implanted alone did not form cell masses, and did not significantly affect islet morphology or metabolic parameters. While, GLUTag and TC1.9 combined implants did produce as strong an anti-hyperglycaemic effect as GLUTag alone, half the number of GLUTag cells were implanted in this group, indicating that some degree of dual agonism may have occurred and contributed to the metabolic effects observed. MIN6 and GLUTag pseudoislets were shown to be responsive to glucose and secretagogues and were significantly more resilient to cytotoxic agents than homotypic MIN6 pseudoislets, although the latter were more resistant to glucotoxicity. Additionally, implantation of both types of pseudoislet had profound anti-hyperglycaemic effects on diabetic SCID mice, although the heterotypic pseudoislets appeared to precipitate a more controlled and gradually improvement than MIN6 pseudoislets. Current observations suggest that cell communication greatly enhances human beta cell function and survival. Chronic co-agonism of GLP-1 and glucagon receptors by cell therapy holds significant potential in type diabetes therapy. Lastly, there is clear promise for the improvement of islet function and survival by co-transplantation with GLP-1 secreting cells.

Analysis of the repertoire of insulin-reactive CD8+ T cells

Pearson, James January 2014 (has links)
Proinsulin is an auto-antigen in type 1 diabetes in the Non-obese Diabetic (NOD) mouse. The CD8+ T cell clone, G9C8, which utilises a T cell receptor (TCR) comprising TRAV8-1*01TRAJ9 and TRBV19*01TRBD1TRBJ2-3, recognises insulin B15-23 presented by H-2Kd, escapes negative selection and rapidly causes diabetes upon adoptive transfer into immunocompromised NODscid mice. To understand how these insulin B15-23 reactive CD8+ T cells develop, G9C8-derived single TCR TRAV8-1*01TRAJ9 chain transgenic NOD mice were generated. These mice were bred with different proinsulin-expressing NOD mice to generate proinsulin1 deficient, proinsulin2 deficient, proinsulin2 over-expressing and proinsulin1 and 2 deficient mice with a mutated proinsulin transgene, preventing G9C8 antigen recognition. Although proinsulin-specific CD8+ TCR repertoire changes in TRBV19 were seen in these mice, the proportion of insulin B15-23 reactive CD8+ T cells was unaffected by proinsulin expression. Interestingly, TCR clonotyping of these insulin B15-23 reactive T cells revealed minimal shared sequences between the strains, with mice exhibiting individual clonal expansions. However, by isolating TRBV19-expressing insulin B15-23-responsive T cells, shared sequences across the different proinsulin-expressing mice were identified, with a requirement of TRBJ2-3 for insulin recognition (used by the original G9C8 T cell clone). Furthermore, male proinsulin2 deficient TRAV8-1*01TRAJ9 mice developed diabetes, with a higher incidence seen upon antibiotic administration. Although the TCR repertoire was unaffected by antibiotics, the gut microbial diversity was greatly reduced in all the mice with age, independent of antibiotic use, with firmicutes bacteria comprising 90-97% of the microbiota. In summary, proinsulin expression and antibiotics modify diabetes susceptibility; however, insulin B15-23 reactive T cells develop independently of antigen expression and are not directly affected by antibiotics. This data suggests that iii non-antigen dependent mechanisms exist in controlling the development of auto-reactive T cells, but T cell activation and pathogenicity is influenced indirectly by a combination of antigen expression and gut microbiota.

Defective regulatory T cell function in type 1 diabetes : a trait under genetic control?

Tyler, Jennie January 2013 (has links)
Type 1 diabetes (T1D) is an autoimmune disease, resulting from the specific destruction of the insulin‐producing beta‐cells in the islets of the pancreas. Islet‐specific autoreactive T cells are instrumental in this process and although these cells are present in individuals with and without T1D, their exhibition of a memory phenotype in diabetic individuals indicates they may have been previously activated in these patients. This suggests a breakdown in peripheral tolerance, implying regulatory T cells (Tregs) may be involved. Indeed, CD4+ CD25hi FOXP3+ Tregs do not differ in frequency in T1D, but their function is impeded. This defect is present in both recentonset type‐1 diabetics (ROT1D) and long‐standing type 1 diabetics (LST1D) suggesting it is a stable phenotype, possibly under genetic control. Also, it is known that the production and signalling of interleukin‐2 (IL‐2); a cytokine essential for the maintenance of Tregs, is defective in T1D. The aim of this thesis was to ascertain whether defective Treg function in T1D is genetically determined or a consequence of the disease. The first section of this thesis examined the effect of a T1D‐associated IL2RA single nucleotide polymorphism (SNP) on Treg function, by means of a genotype‐immunophenotype study. Non‐diabetic donors homozygous for the susceptible allele at this SNP exhibited diminished Treg fitness and suppressive action, suggesting that defective Treg function is a contributing factor in T1D. The latter section utilised T1D‐discordant monozygotic twins and healthy controls to examine Treg function and the IL‐2‐dependent generation of regulatory type 1 (Tr1) cells. Due to the low number of twins obtained nothing conclusive can be drawn from the study on Treg function. However, the results from the Tr1 generation assay suggest the possible existence of an IL‐2 signalling defect in non‐diabetic twins.

Advice on diet and body weight for the management of type 2 diabetes in adults from different socio-economic status groups

Moore, Helen Joy January 2006 (has links)
Aim: The research has four related aims; 1) to explore the relationship between body weight and diabetic control in patients with type 2 diabetes; 2) to identify whether, and what type of, lifestyle advice for patients with type 2 diabetes related to their diabetic control; 3) to identify whether types of lifestyle advice identified in aim 2 were related to effective diabetic control when tested in randomised controlled trials (RCTs); 4) to identify whether types of lifestyle advice identified in aim 2 were also related to effective prevention of diabetes when tested in RCTs. Variations in all outcomes due to socio-economic status (SES) were also assessed. Methods: An analysis of the James Cook University Hospital (Middlesbrough, UK) Diabetes Care Centre Register was conducted to address research aims 1 and 2. Cochrane systematic reviews were conducted to address research aims 3 and 4. Results: Mean body mass index (BMI) increased and mean glycated haemoglobin (HbA1c) decreased over the course of the research in the type 2 diabetes population; levels of BMI and HbA1c were highest in the lowest SES group. The systematic reviews found that at six and twelve months, advice on diet plus exercise compared with dietary alone was associated with a (pooled weighted mean) decrease from baseline in HbA1c of 0.9% (95% Cl 0.4 to 1.3) and 1.0% (95% Cl 0.4 to 1.5) in patients with type 2 diabetes, and that at twelve months, dietary advice plus exercise, compared with dietary advice alone, was associated with a statistically significant mean (pooled weighted mean) decrease in fasting plasma glucose of 0.2 mmol/l, (95% Cl 0.1 to 0.3), in normoglycaemic people. No analyses on SES in the primary studies included in either review were reported. Conclusion: Levels of BMI and diabetic control are worst in adult type 2 diabetics from low SES groups. Diabetic registers are useful, but additional data should be captured. The evidence base for advice on diet, with or without additional advice on exercise or behaviour, for adults with, or at risk of, type 2 diabetes is poor. However, advice on diet plus exercise, compared with dietary advice alone, does appear to afford some benefit.

Characteristics of Candida isolates from patients with diabetes mellitus

Manfredi, M. January 2006 (has links)
The present research has investigated the molecular characterization of oral yeasts in healthy individuals from different dental clinical settings in the United Kingdom, and patients from the UK and Italy who were affected by diabetes mellitus (DM) to determine the impact of DM upon candidal infection of the mouth. In the present study of patients with DM from the UK and Italy a lower than expected incidence of oral candidal infections (7/249, 2.8%) was observed. The presence of oral yeasts and genotypic diversity of C. albicans was also not influenced by DM. There was no significant difference between the presence of oral yeasts in Italian and UK DM patients. However, more (p=0.04) C. dubliniensis isolates were found in non-DM individuals. Higher levels of Candida adhesion to fibronectin-coated paramagnetic beads were observed in isolates from DM patients. Isolates from patients with low oral yeast loads adhered significantly (p=0.0T) more than those from patients with high oral yeast loads. In general, there was no difference in proteolytic activity of isolates from DM or control patients. Candida isolates from UK DM patients had significantly greater in vitro resistance to azole antifungal agents (miconazole p<0.0001 fluconazole p=0.02 ketoconazole p=0.01) than those from Italian DM patients. In addition, C. albicans isolates from all examined patients were more susceptible to fluconazole (p=0.0008) and miconazole (p=0.01) than non-C. albicans strains. PCR fingerprinting and subsequent phylogenetic analysis revealed that C. albicans isolates from UK DM patients were the most diverse (p<0.0001) in comparison to those from Italian DM patients or from healthy subjects. Finally, it was observed that the activity of a rat IgM monoclonal anti-idiotypic antibody (mAbKlO) and a synthetic decapeptide (KP) had a significant dose- dependant fungicidal activity upon a wide spectrum of C. albicans and non-C albicans isolates from patients with and without DM.

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