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1
Smit, Nicolaas Andrias Johannes. "School-Initiated Type-2 Activities in Continuous Professional Teacher Development." Diss., University of Pretoria, 2002. http://hdl.handle.net/2263/78496.
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Professional development is more than marking an attendance register at a workshop.
Professional development is a reflective process of continuous self-development that
should inform the very essence of any learning context. This dissertation builds on
how teachers experience school-initiated type-2 teacher professional development in
secondary public schools and how their experiences may contribute to the work in the
field of teacher professional development and assessment. Although a number of
studies have examined teachers’ comprehension of the Continuous Professional
Development framework in South Africa and the quality management policies, there
is a considerable lack of literature on the relationship between the professional
development of teachers and school improvement.
The purpose of this dissertation is to understand teachers’ experiences with the
implementation of Type-2 Continuous Professional Teacher Development activities in
public high schools. The data for this qualitative study were collected through semistructured
interviews and policy document analysis. The coded data were analysed
and emerging themes were identified. The participants of this study consisted of
teachers and members of the School Management Team.
However, the study found that teachers perceived that there is a gap in the focus of
professional development programmes. Teachers felt that the type-2 developmental
activities seemed only for the benefit and achievement of the school’s goals, and do
not adequately address the developmental needs of teachers themselves.
The findings of this study argue that a culture of shared responsibility and leadership
in secondary schools do indeed improve the development of teachers and the
successful academic achievement of learners.<br>Dissertation (MEd)--University of Pretoria, 2020.<br>Education Management and Policy Studies<br>MEd<br>Unrestricted
2
Sitaraman, Sneha. "Alveolar type 2 epithelial cells in lung development and disease." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1571062200291287.
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3
Rogers, Catherine. "Development of a glycemic index checklist for individuals with type 2 diabetes." Connect to resource, 2009. http://hdl.handle.net/1811/37245.
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4
Khaled, Walid T. "The role of STAT6 and type-2 cytokines in mammary gland development." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612880.
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5
Aljwaid, Husam O. Dakhil. "Relationships between iron, oxidative stress, glycated proteins and the development of atherosclerosis in Type 2 diabetes." Thesis, University of Plymouth, 2015. http://hdl.handle.net/10026.1/3222.
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Hyperglycaemia stimulates a variety of biochemical abnormalities. The area of particular interest in this study is the influence of non-enzymatic glycation of proteins on iron homeostasis, and particularly on non-transferrin-bound iron (NTBI) and its possible relation to atherogenesis in both Type 2 diabetic and obese non diabetic subjects. The link between non-enzymatic glycation of proteins and iron homeostasis, and development of macrovascular disease may be mechanistically different in Type 2 diabetic and obese non diabetic subjects due to a difference in the protein glycation pattern. Because the following in vivo study required storage of samples for up to two years to complete the processing of all the samples, a storage study was carried out using different anticoagulants and addition of reduced glutathione (GSH) to samples to study the effects of storage, thawing and freezing of the samples on the level of malondialdehyde (MDA), a biomarker of lipid peroxidation. This storage study showed that EDTA attenuated the action of lipid oxidation compared with lithium heparin (LiH). A combination of GSH with either EDTA or LiH added more protection from lipid peroxidation in the first week of storage, but due to the thawing and freezing of the sample the action of GSH diminished through its autooxidation, meaning that addition of GSH to samples in the following in vivo study would be useless. An in vivo study was carried out on iron-related parameters in three subject groups: control (non-diabetic, non-obese), Type 2 diabetic and obese non diabetic. Glycated haemoglobin (HbA1C) was strongly correlated with NTBI in the diabetic group. Also the level of NTBI was significantly increased in Type 2 diabetic subjects compared with other groups while the level of total iron was significantly decreased. The study showed a strong positive correlation between NTBI and a biomarker of endothelium dysfunction (E-selectin) in all groups studied. Although it is not possible from the current data to know if there is a causal relationship between these two parameters, it remains a possibility that iron released from its binding sites could initiate oxidative damage to the endothelial cells and begin the process of atherogenesis. Positive correlation at the 90% confidence level between NTBI and a biomarker of inflammation, high sensitivity C-reactive protein, is another indicator in this study of a link between increases in NTBI, inflammation, endothelium dysfunction and atherosclerosis. This study also showed for first time that NTBI is present in higher levels in the plasma of obese subjects compared to controls despite the obese subjects having significantly lower total iron. An in vitro study found that glycation of transferrin half saturated with iron increased with increasing glucose concentration, leading to decreased capacity of transferrin to hold iron and increased release of free iron. Also co-incubation of transferrin half saturated with iron with low density lipoprotein (LDL) and glucose showed oxidation of LDL (measured as MDA). This may be explained by the effect of glycation, leading to release of free iron, which catalyses oxidation of LDL. In addition, glycation of LDL may enhance the oxidation of LDL catalysed by iron. Both studies indicate that the glycation of proteins has a major impact on iron homeostasis leading to release of non-enzymatic glycation and contributing to one of the most common complications of Type 2 diabetes, atherosclerosis.
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Kikkas, Ingrid. "Development of immunoassays for diagnosis of type 1 diabetes." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114824.
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Le diabète de type 1 est une maladie auto-immune caractérisée par la destruction des cellules bêta des îlots de Langerhans du pancréas. Au cours de ce processus auto-immun, des auto-anticorps sont produits contre plusieurs antigènes des cellules bêta, par exemple l'insuline, l'acide glutamique décarboxylase (GAD65), la protéine tyrosine phosphatase (IA-2) et le transporteur de zinc (ZnT8). Au moins un auto-anticorps contre l'un de ces antigènes est présent dans> 95% des personnes atteintes de diabète de type 1 lors de la détection de l'hyperglycémie. Ces auto-anticorps peuvent servir de marqueurs précoces de diabète de type 1, car ils peuvent être présents des années avant l'apparition de la maladie, ce qui permet un diagnostic précoce avant les manifestations cliniques. Dans le cadre de cette thèse, nous avons développé, en partenariat avec une équipe de recherche clinique, une série de tests diagnostiques originaux, basée sur la détection précoce des différents auto-anticorps d’îlots de Langerhans à partir d'échantillons de sérum humain. Ces tests de diagnostic comprennent des tests bridging ELISA pour la détection d'auto-anticorps contre l'insuline, IA-2 et GAD65, qui sont rapides, facile à utiliser et n’utilisent pas de radioactivité. De plus, un test immunochromatographique sur bandelette pour la détection des auto-anticorps contre IA-2 a été développé. Le principal avantage des tests bandelettes est sa convivialité : les résultats peuvent être obtenus en 45 min en utilisant de très petits volumes de sérums et sans l'utilisation d’appareils spécialisés. Tous ces tests développés en interne ont été validés avec des échantillons de sérum de patients atteints de diabète de type 1 et de témoins sains et leurs performances ont été comparées avec celles de tests disponibles sur le marché. En outre, nous avons développé un test multiplex pour la détection simultanée de plusieurs auto-anticorps associés au diabète de type 1, ce qui permet de gagner du temps et d’augmenter la valeur diagnostic et prédictive du test par rapport à la détection d’un seul autoanticorps. Ce test multiplex a été validé pour la détection de deux autoanticorps (IA-2A et GADA) et comparé à nos tests ELISA de IA-2A et GADA<br>Type 1 diabetes is an autoimmune disease characterized by the destruction of pancreatic beta cells within the islets of Langerhans. In the course of this autoimmune process, autoantibodies are generated against several beta-cell antigens, e.g. insulin, glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA-2) and zinc transporter 8 (ZnT8). At least one autoantibody against one of these antigens is present in >95% of individuals with type 1 diabetes upon hyperglycemia detection. These autoantibodies can serve as early markers of type 1 diabetes, since they can be present years before disease onset, allowing for an early diagnosis before clinical manifestations. In the course of this thesis we have developed, in partnership with a clinical research team, a series of original diagnostic tests, based on the early detection of the different anti-Langerhans islet autoantibodies from human serum samples. These diagnostic tests include bridging ELISAs for the detection of autoantibodies to insulin, IA-2 and GAD65, which are rapid, non-radioactive and easy-to-use. Moreover, a lateral flow immunoassay (dipstick) for detection of autoantibodies to IA-2 was developed. The key advantage of lateral flow immunoassay is its user-friendly format: results can be obtained within 45 min using very small volumes of sera and without the use of any specialized apparatus. All these in-house assays were validated with diabetic and healthy human serum samples and the assay performances were compared to commercially available tests on the market. In addition, we have developed a multiplex assay for simultaneous detection of multiple diabetes-associated autoantibodies, which is time-effective and increases the diagnostic and predictive values of the assay, comparing to single autoantibody detection. This multiplex assay was validated for detection of two autoantibodies i.e. IA-2A and GADA and compared to in-house IA-2A and GADA bridging ELISAs
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Yiannakas, Adonis. "The role of central IL-6 signalling in the development of Type 2 diabetes." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/fc156760-f5ac-4f02-8b8e-42cb58decd63.
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Diet induced obesity and Type 2 diabetes affect an alarming number of people in the world. Patients exhibit a number of associated co-morbidities that require treatment and reduce life expectancy. The development of Type 2 diabetes results from a chronic disruption of glucose homeostasis as a consequence of environmental and genetic factors. The regulation of hypothalamic metabolic signalling is understood to be critical to the dynamic and long-term maintenance of glucose homeostasis by virtue of its influence on peripheral effectors (pancreas, liver, muscle and fat). Prolonged periods of inflammation observed in the development of diet-induced obesity and diabetes and accumulating evidence suggests this may negatively affect the maintenance of these neuroendocrine networks. Interleukin 6 (IL-6) is a pleiotropic cytokine involved in the acute, as well as the resolving and adaptive phase of inflammatory responses. The IL-6 receptor has recently been shown to exhibit extensive localization in key regions of the human and rodent hypothalamus involved in glucose and energy homeostasis regulation. Recent work at Prof. Rory McCrimmon's lab investigating the role of IL-6 in the development of hypoglycaemia unawareness in Type 1 Diabetes identified the development of a glucose-sensing defect in hypothalamic glucose-sensing mouse cultures (GT1-7) in response to antecedent IL-6. These studies provided preliminary evidence to suggest that inflammatory cytokines such as IL-6 could directly modulate hypothalamic glucose sensing neurons and therefore might influence whole body glucose and energy homeostasis. The body of work contained in this thesis sets out to examine the hypothesis that down-regulation of central IL-6 signaling would disturb the ability of mammals to regulate energy homeostasis, and would exacerbate defects in glucose clearance, insulin sensitivity and body composition typically observed in during the development of Type 2 Diabetes through chronic energy excess. To test this hypothesis cre-lox technology was used to generate a CRE-mediated nervous-system specific NesCreIL-6R knock-down (KD) mouse. Chronic administration of high-fat diet (>40% fat) in mice is commonly used to model the effects of diet-induced obesity and the progression to type 2 diabetes in humans. To examine the effects of this intervention in the development of diet induced obesity and diabetes, age (8-10 weeks old) and sex-matched KD and control animals on standard chow (SC -15% fat) and high fat diet (HFD - 60% fat) were characterized using an array of in vivo metabolic phenotyping tests over a period of 20 weeks. To generate a brain-specific IL-6R KD, heterozygous B6.Cg-Tg (Nes-cre) 1Kln/J mice were crossed with B6 (SJL)-Il6ratm.1.1Drew/J animals (IL-6Rflox/flox). The Nestin promoter exhibits brain-specific expression, while the IL-6R gene is flanked by 2 loxP sites in IL-6Rflox/flox mice that would theoretically allow for brain-specific disruption of the receptor gene in offspring of this cross. Incorporation of the CRE gene in NesCre+ mice, and the presence of loxP sites in the genome of IL-6Rflox/flox colony were confirmed by standard PCR (Figures 1.1, 1.2). Offspring of the cross bearing the CRE gene were classified as KD, while the rest were considered wild-type littermates. Disruption of the IL-6R gene was confirmed at the mRNA level using real-time PCR (Figure 1.3.2), with KD mice exhibiting down-regulation of the gene at the hypothalamus (~50%) and hippocampus (~35%). The effects of the NesCremediated down-regulation of the IL-6R were also examined using in vivo and ex vivo approaches, in relation to the induction of the STAT3 phosphorylation typically observed in response to IL-6. Administration of IL-6 in the periphery failed to induce STAT3 phosphorylation in the hypothalamus and hippocampus of KD mice, even though similar responses to control animals were observed in peripheral organs (Figures 1.4, 1.5). Furthermore, examination of IL-6R protein expression by immunohistochemistry, confirmed decreases in the number of IL-6R-positive neuronal cells in NesCreIL-6R KDs compared to control mice (Figures 1.7.1-4). Brain-specific IL-6R down-regulation in NesCreIL-6R KDs was associated with a dramatic suppression of in vivo GSIS (Figure 2.5.4), but was of little consequence to the blood glucose response to insulin (Figures 2.4.1-3). Examination of insulin and glucagon immunohistochemistry and ex vivo hormone release, KD and control islets were found to produce and release similar levels of the hormones in isolation, implicating a central component in the effect observed in vivo (Figures 2.8.1-3). Body weight was closely matched between KD and control animals on SC diet, while dramatic increases observed in control animals on HFD were mirrored in HF-fed KDs (Figure 2.1). Paradoxically, KD SC mice were significantly leaner than control mice, despite being hyperphagic (Figures 2.2.1-5, 2.3, 2.9.1), hypoactive and hypothermogenic (Figure 2.6.2-4). Hyperphagia and suppression of energy expenditure was also observed in the HF-fed KDs, but in this case the leaner phenotype was progressively reversed through the course of 20 weeks of diet (Figures 2.2.1-5, 2.6.2-4). Examination of a separate cohort of SC mice indicated that increases in food intake and body fat in response to chronic diet, were not a consequence of differences in leptin sensitivity between KD and control animals (Figures 2.9.1-2). Collectively, data presented in this thesis suggest central IL-6 to play a fundamental role in the ability of the body to release insulin and regulate glycaemia in response to a glucose challenge. KD mice exhibited increased food intake and decreased energy expenditure and activity, that were only associated with increased body fat following chronic HF-feeding. This would suggest that increases in peripheral IL-6 observed in obese patients are part of a protective response to chronic energy excess, acting centrally to promote energy expenditure at least in part through increases in circulating insulin and thermogenic fat oxidation.
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Fenaux, Martijn. "Molecular Pathogenesis and Development of a Genetically Engineered Vaccine for Type-2 Porcine Circovirus." Diss., Virginia Tech, 2004. http://hdl.handle.net/10919/27171.
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Porcine circovirus type 2 (PCV2) is the primary causative agent of postweaning multisystemic wasting syndrome (PMWS), whereas the ubiquitous porcine circovirus type 1 (PCV1) is nonpathogenic for pigs. Since its initial detection in a Canadian commercial swine herd in 1991, PMWS has been detected in all swine producing regions of the world and is now a serious economic problem to the swine industry. The objectives of this dissertation were to biologically, genetically and experimentally characterize both PCV1 and PCV2, to identify the genetic determinant(s) for virulence and replication, and to develop an effective genetically-engineered vaccine against PCV2 infection and PMWS.
The genetic heterogeneity of PCV2 and PCV1 isolates from different geographic origins were determined. We found that, although PCV1 and PCV2 genomes were very conserved, some minor genomic variation exists among PCV1 isolates and PCV2 isolates. The nonpathogenic PCV1 and pathogenic PCV2 share only about 76% nucleotide sequence identity but have similar genomic organization. The highest sequence variability among PCV isolates is found in the immunogenic ORF2 capsid gene. Based on the sequence data in this dissertation, a universal polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was developed that is capable of detecting all known PCV isolates and differentiating between infections by nonpathogenic PCV1 and pathogenic PCV2.
In order to study the structural and functional relationship of PCV genes and to develop a genetically-engineered vaccine, we constructed infectious DNA clones of both PCV1 and PCV2. By using the PCV2 infectious clone, we showed that pigs can be infected by direct intrahepatic injection of PCV2 infectious DNA clone. The pathological lesions and clinical disease associated with PCV2 infection were more definitively characterized by using the infectious DNA clone. We found that PCV2 is the primary but not the sole causative agent of PMWS, as the full spectrum of clinical PMWS was not reproduced by the infectious PCV2 DNA clone although pathological lesions characteristic of PMWS were reproduced.
A chimeric vaccine was constructed by cloning the immunogenic capsid gene of the pathogenic PCV2 into the genomic backbone of the non-pathogenic PCV1 virus. We showed that the resulting chimeric PCV1-2 vaccine virus, retained the non-pathogenic nature of PCV1 but induced a protective immune response against a wild-type PCV2 challenge. In vaccinated pigs, the chimeric PCV1-2 vaccine reduced PCV2 viremia length and serum virus loads and reduced pathological lesions such as lymphoid depletion (LD) and histiocytic replacement (HR) in lymphoid tissues, inflammation and discoloration of the lymph nodes. The amounts of PCV2 antigen and PCV2 genomic copy loads in lymph node tissues were also significantly reduced. Our results indicated that the attenuated chimeric PCV1-2 virus induces protective immunity against PCV2 infection and thus could serve as an effective vaccine against PCV2 and PMWS.
To improve the safety of the vaccine, we attempted to identify the genetic determinant(s) for PCV2 virulence. An isolate of PCV2 was serially passaged for 120 times in PK-15 cells. After 120 passages, a total of two amino acid mutations were identified in the capsid protein of the passage 120 virus (VP120), P110A and R191S. Compared to other known PCV1 and PCV2 sequences, the two amino acid mutations in PCV2 VP120 are unique. The VP120 virus was biologically characterized in vitro and experimentally characterized in specific-pathogen-free (SPF) pigs. The two amino acid mutations resulted in an enhanced replication ability of PCV2 VP120 in PK-15 cells and an attenuated phenotype in infected pigs. The P110A and R191S mutations in the capsid protein either alone or collectively are likely important for PCV2 virulence and replication.
In summary, we genetically characterized PCV2 isolates from different geographic regions and developed a PCR-RFLP assay. We constructed and characterized infectious DNA clones of PCV1 and PCV2, and developed a genetically engineered vaccine against PCV2 infection. We also identified the genetic determinants for PCV2 virulence and replication. The vaccine developed in this study, when it becomes available, will help the swine industry control this important pathogen.<br>Ph. D.
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Direk, Kenan. "The role of mitochondria in the development of insulin resistance and type 2 diabetes." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-mitochondria-in-the-development-of-insulin-resistance-and-type-2-diabetes(30f426ed-9221-473f-b177-acefda85acaa).html.
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This thesis explores three broad areas of interest in the pathophysiology of type 2 diabetes (T2D). The first part of the thesis examines the relative contributions of body fat measurements on T2D and related morbidities in a large cohort of twins. A proxy measure of visceral fat was constructed from anthropometric and dual-energy X-ray absorptiometry, its heritability was estimated at 58% using the classical twin model and its influence on morbidity was compared to total abdominal fat and the body mass index. The findings from this work show that intra-abdominal adiposity confers the greatest independent risk on morbidity and appears to almost entirely mediate the observed association between morbidity and all the other measures of adiposity investigated. The second part of this thesis is a candidate gene study of the PARL/ABCC5 gene region motivated by prior evidence suggesting a role for PARL in T2D susceptibility. Using a single marker test of association, SNPs in and around the PARL gene showed no evidence of association with T2D. However, analysis based upon SNPs in the entire gene region (184,743-185,548Kb, build 36) using a multi-marker test of association, provided strong evidence that the neighbouring gene (ABCC5) is associated with T2D in both European and African American samples. In addition, ABCC5 expression in subcutaneous adipose tissue was strongly associated with fasting insulin and glucose serum levels, visceral fat accumulation, and T2D with evidence that the disease susceptibility variant(s) is a regulatory element (an expression quantitative trait locus) located at intron 26 in ABCC5. The third component of this thesis is a comprehensive investigation into the potential role of nuclear-encoded mitochondrial (NEM) genes in the aetiology of T2D. A pathway analysis approach is used to test for enrichment of T2D association signals across the genome in defined NEM gene sets. From this analysis, the biological pathways of glycolysis, the tricarboxylic acid cycle, and mitochondrial translation all show evidence of pathway enrichment. These findings demonstrate for the first time, potential associations between these pathways and T2D susceptibility in European and African American samples.
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Bowden, Davies K. A. "Physical inactivity and sedentary time : impact on metabolic health and development of type 2 diabetes." Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3019572/.
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11
Pal, K. "Development of an online self-management intervention for adults with type 2 diabetes (HeLP-Diabetes)." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1559564/.
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Background: The prevalence of type 2 diabetes is increasing and estimates suggest that by 2030 nearly 1 in 10 adults worldwide will be living with this condition. 10% of the NHS budget is spent on treating diabetes and related complications like heart attacks, strokes and blindness. Improving self-management in people living with type 2 diabetes is crucial in reducing the morbidity and mortality associated with this disease. Uptake of group-based self-management training is low and there is an urgent need for evidence based and effective alternatives. Computer-based interventions have the potential to provide cost-effective self-management training and improve outcomes for people with type 2 diabetes. The eHealth Unit was awarded a 5 year NIHR Programme grant for Applied Research to develop, evaluate and implement an online self-management intervention for adults with type 2 diabetes. This thesis describes my contribution towards developing the intervention. Aims/objectives: To describe the development of an online self-management intervention for adults with type 2 diabetes. Methods: The intervention development process was modelled on the MRC guidelines for developing complex interventions. This started with a systematic review of the literature on computer-based self-management interventions for adults with type 2 diabetes. Suitable theories to underpin the intervention were identified and used to construct a logic model to describe the potential mode of action. Qualitative work with people living with type 2 diabetes and health professionals was used to explore patient and professional defined wants and needs from such interventions. This data was then synthesized to inform the development of a theory-based online intervention called HeLP-Diabetes, designed to improve self-management in people living with type 2 diabetes. Conclusions: The synthesis of previous evidence with new qualitative data from patients and health professionals has helped to create a unique online intervention that will hopefully help bridge current gaps in the delivery of self-management training and improve outcomes for people with type 2 diabetes.
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Thurner, Matthias. "The role of novel genetic and epigenetic mechanisms in the development of Type 2 diabetes." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:7ae45a54-45ea-4cdc-9c65-0068adb9ce67.
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Type 2 diabetes (T2D) is a metabolic disease characterised by insulin resistance and beta-cell failure and a leading cause of mortality and morbidity. GWAS have identified pancreatic beta-cell dysfunction as a major player in T2D pathogenesis, but since the majority of signals reside in non- coding sequence the causal variant(s) and effector transcripts often remain undefined. Combining human genetic discoveries with genomic interrogation of relevant tissues was shown to provide a powerful strategy to understand the molecular disease mechanisms. Thus, the main aim of my DPhil project is to generate and integrate genetic data, such as rare coding CNVs, and epigenomic data, including human pancreatic islet DNA methylation and chromatin state data, to characterise existing T2D GWAS loci and identify novel genetic T2D susceptibility signals. Using WGBS (n=10) and ATAC-seq (n=29), I extended the epigenomic characterisation of human pancreatic islets. Specifically, I characterised for the first time the whole-genome human islet DNA methylome and provided information about the variability in open chromatin in human islets. Enrichment analysis in T2D-related GWAS data showed that hypomethylated enhancer-like regions (n=37.1k, FE=3.2) and open chromatin (n=247.2k, FE=3.1) regulatory regions are strongly enriched in T2D GWAS data. These annotations were integrated with existing islet ChIP-seq annotations to extend islet chromatin states. Through this approach, I identified enhancer subtypes based on DNA methylation and accessibility, which differed markedly in their enrichment levels in T2D-related GWAS signals. The refined enhancer states were then used to prioritise T2D-associated variants for testing of allelic imbalance in open chromatin. After correcting for technical artefacts, significant allelic (FDR < 0.05) imbalance in open chromatin was discovered at 3 T2D GWAS loci (ADCY5, CDC123, KLHDC5); thus highlighting potential molecular mechanisms at these loci governing T2D risk. I also used ATAC-seq to characterise the epigenomic landscape of human iPSC subtypes derived from beta- and fibroblast-cells that differed in their ability to differentiate into endodermal tissue. The identification of significant (FDR < 0.05) differentially open chromatin sites (n=8.3k) in these iPSCs, which were found to be associated with genes linked to both pancreas development and mature function, could be used to improve current in vivo 'iPSC to endodermal' differentiation protocols. Ultimately, this may lead to enhanced generation of human islet cells relevant for both T2D disease modelling and potential clinical use. Finally, I determined the role of rare coding CNVs, identified from large-scale T2D-case-control exome-sequencing (n=14.5k) and exome chip array (n=11.6k) datasets, in T2D development. This analysis found at the known C2CD4A/VPS13C T2D GWAS locus, rare VPS13C gene deletions and duplications consistently associated with increased and decreased T2D-risk, respectively; hence, prioritising VPS13C for potential functional follow-up at this GWAS locus. These data have extended the catalogue of genetic variants (rare coding CNVs) and the epigenomic landscape of human islets and iPSCs to improve understanding of islet development and regulation as well as T2D genetic susceptibility.
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Lin, Chih-Wei. "Modeling glucose-insulin kinetics and development of type 2 diabetes in offspring of diabetic parents." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2741.
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Type 2 diabetes (T2D) has been studied for decades. Many risk factors of T2D have been identified, but few studies were designed to investigate the pharmacokinetics/ pharmacodynamics (PK/PD) risk factors preceding the onset of T2D. Moreover, although the disease progression of T2D has received considerable attention, little is known about the disease development of T2D. It is important to understand the temporal changes of the risk factors of glucose and insulin kinetics during the development of T2D for a better understanding of the etiology of T2D. The objectives of this work are: 1) to develop a population-based glucose-insulin PK/PD model and identify the PK/PD risk factors preceding the onset of T2D, 2) to develop a methodology to evaluate the development of T2D, 3) model the time-course of the disease development based on the disease development variables (DDVs) derived from repeated intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT). The central hypothesis is that the development of T2D can be described and characterized by the glucose-insulin kinetics by employing a population-PK/PD based disease development analysis.
To summarize, a glucose-insulin kinetic model was developed and presented in Chapter 2. The pharmacokinetics/pharmacodynamics (PK/PD) risk factors preceding the onset of T2D were investigated using a population-based Bayesian nonlinear hierarchical model. In Chapter 3, a methodology describing the disease development of T2D was developed based on four important DDVs of T2D, namely fasting blood glucose (FBG), fasting serum insulin (FSI), homeostatic model assessment of insulin resistance (HOMA-IR) and body mass index (BMI). These DDVs were investigated for their temporal patterns and relationships to the time-course of the development of T2D. The proposed model enables a quantitative, time-based evaluation of the development of T2D in this high risk population. In Chapter 4, the DDVs derived from repeated IVGTTs were evaluated. By applying the mixed effect analysis, important DDVs were identified as potential new biomarkers of T2D. Chapter 5 is an extension of application of the disease development analysis based on the DDVs derived from OGTTs. Chapter 6 is the conclusions and future works of this thesis. The proposed population model of glucose-insulin kinetics has demonstrated that pharmacokinetic differences exists for the high risk population and can be helpful for prediction of T2D. By applying the proposed disease development analysis, the time-dependency and temporal patterns of the DDVs can be identified. An examination of the temporal changes in DDVs for the glucose-insulin system before the diagnosis of the disease provides a quantitative evaluation of the pathophysiological evolution of T2D and is valuable in predicting T2D.
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Shah, Urjita H. "A Roadmap for Development of Novel Antipsychotic Agents Based on a Risperidone Scaffold." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4804.
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Schizophrenia is a chronic psychotic illness affecting ~21 million people globally. Currently available antipsychotic agents act through a dopamine D2 receptor mechanism, and produce extrapyramidal or metabolic side effects. Hence, there is a need for novel targets and agents. The mGlu2/5-HT2A receptor heteromer has been implicated in the action of antipsychotic agents, and represents a novel and attractive therapeutic target for the treatment of schizophrenia. A long-term goal of this project is to synthesize bivalent ligands where a 5-HT2A receptor antagonist is tethered to an mGlu2 PAM via a linker.
The goals of the investigation were to study the SAR of risperidone (an atypical antipsychotic agent) at 5-HT2A receptors using a “deconstruction-reconstruction-elaboration” approach to determine the minimal structural features of risperidone that contribute to its 5-HT2A receptor affinity and antagonism, and to determine where on the “minimized risperidone” structure an mGlu2 PAM can be introduced. Additional goals included studying the binding modes of various mGlu2 PAMs and identifying where on an mGlu2 PAM a risperidone “partial” structure could be introduced.
Biological studies of deconstructed/elaborated analogs of risperidone suggest that the entire structure of risperidone is not necessary for 5-HT2A receptor affinity and antagonism, and that a fluoro group contributes to 5-HT2A binding. 6-Fluoro-3-(4-piperidinyl)-1,2-benz[d]isoxazole that has only half the structural features of risperidone retains 5-HT2A receptor affinity and antagonist activity, and represents the “minimized risperidone” structure with the piperidine nitrogen atom representing a potential linker site for eventual construction of bivalent ligands. Molecular modeling studies at 5-HT2A receptors suggest that risperidone and its analogs have more than one binding mode.
Modeling studies to evaluate binding modes of various PAMs at mGlu2 receptors, coupled with known SAR information, were used to identify a PAM (JNJ-40411813), and the pyridone nitrogen atom of JNJ-40411813 as a potential linker site. Additionally, potential synthetic routes for JNJ-40411813 were explored that might be of value in the synthesis of bivalent ligands.
Based on the structural features of 6-fluoro-3-(4-piperidinyl)-1,2-benz[d]isoxazole, a new pharmacophore for 5-HT2A receptor antagonists, consisting of one aromatic region, a basic protonated amine and hydrogen bond acceptors, has been proposed.
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Hess, Melody L. "Development of a Nutrition Education Program Aimed at Diabetes Prevention and Management in an Urban Appalachian Population." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378109309.
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Tudor-Locke, Catrine Elizabeth. "Development, implementation and evaluation of a daily physical activity intervention for individuals with Type 2 diabetes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ51234.pdf.
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Lynch, Aisling Martina. "Development and characterisation of novel proglucagon-derived peptide analogues for the treatment of Type 2 diabetes." Thesis, Ulster University, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.674964.
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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
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Power, Ailsa M. "Community pharmacy type 2 diabetes care : design and evaluation of a model to support continuous professional development." Thesis, University of Strathclyde, 2008. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=23484.
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To develop a competency based continuous professional development (CPD) support package based on a workbook of competencies for community pharmacists working with patients with diabetes mellitus type 2 in primary care. To monitor the competencies attempted and evaluate by means of a pre and post measurement of views and attitudes to CPD. Subjects and settings: (a) 19 health care team members in the model of care design, (b) 18 community pharmacists in consensus building, (c) 60 pharmacists in a controlled study to monitor and evaluate the package. Main outcome measures: (a) Model of Care, (b) Measured consensus on pharmacist activities, (c) Uptake of elements of the Support Model; changes in pharmacist views and attitudes to CPD; investigation of pharmacists' CPD priorities. Results: Findings established an agreed model of care and a set of activities (behavioural statements). These statements linked to nationally agreed multiprofessional competencies producing a CPD diabetes workbook.
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Afemikhe, Juliana Ayafegbeh. "Development of a health education programme for self-management of Type 2 diabetes in Edo State, Nigeria." University of the Western Cape, 2016. http://hdl.handle.net/11394/4910.
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Philosophiae Doctor - PhD<br>Diabetes is a chronic, metabolic disease that requires lifelong medical management, health education and self-management. According to a World Health Organisation report, there is a global increase in the prevalence of diabetes and even more so in the low-and middle-income countries, specifically Nigeria, which has the highest number of people with diabetes in the African region of the World Health Organisation. As a global issue, the positive health outcomes of diabetes are tied to health education and self-management of the disease and using the health resources of nations. However, in the context of limited resources in Nigeria, there is a need for improvement of health education in self-management of Type 2 diabetes. Health education that is provided in some Nigerian health facilities is reported to be unstructured, without patients’ active participation, not tailored to the needs and the interests of the patients and limited collaboration between multi-disciplinary professionals. In this context, the aim of the study was to develop a structured health education programme for self-management of patients with Type 2 diabetes, to facilitate the quality of the lives of these patients .An adapted intervention mapping framework provided a structured process for development of an evidenced based programme. A mixed method approach was followed. In the first phase of the study an exploratory descriptive qualitative research design was followed. A purposive sampling approach was used in selecting (i) participants, who were patients with Type 2 diabetes and (ii) health-care professionals working in two health-care institutions in Benin City, Edo State, Nigeria. In phase 1, Step1 of the research was a situation analysis, which consisted of conducting 30 semi-structured interviews with patients; observation of nurses providing health education; and five focus group discussions with health-care professionals (nurses, dieticians and social workers). Qualitative data analysis was accomplished through using Tesch’s (1990) steps of analysis to identify themes and categories. The situation analysis revealed, firstly, that there was a lack in the knowledge and self-management of Type 2 diabetes among patients. Secondly, that the health-care professionals acknowledged their collective role in health education and were burdened with the patients who were non-adherent to self-management. The result also revealed the necessity to change from a traditional teaching method to a structured educational process that is patient-centred. The second phase of the research was the stage of developing the educational programme through collaboration with the stakeholders (health-care professionals and patients with Type 2 diabetes) using the findings from the data-analysis of the first phase supported with literature. In phase 2, Step 2 was to develop matrices from the data analysis in Phase 1 for the programme. Step 3 added theory-based intervention methods and practical applications to the preliminary program and in Step 4 the programme was described. This was followed in Step 5 by preparing health-care professionals for offering the programme to patients and implementing and evaluating the programme. The evaluation of the programme was by means of a quantitative pilot study in which a pre-post-test in a quasi-experiment was conducted with 28 patients and qualitative interviews after the program and post intervention interviews with the participants. The evaluation showed that the program was effective in meeting its objectives. In Step 6 a plan for the adoption, implementation, sustainability and evaluation of future implementations was developed.
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Su, Men. "Type 2 Diabetes Mellitus Acts as a Risk Factor for the Development of Early Stage Alzheimer’s Disease." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS121.
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Après le vieillissement, le diabète Mellitus de type 2 (DMT2) est le facteur de risque le plus important pour développer la maladie d'Alzheimer (MA). Le DMT2 est une maladie métabolique caractérisée par une hyperglycémie et une résistance à l’insuline qui se développe vers la cinquantaine et est fortement favorisée par l’obésité. Nous avons exploré l’impact potentiel du DMT2 sur le développement de la MA chez le Rat. Pour cela, nous avons utilisé un régime alimentaire cafétéria (RC) couplé à des injections de faibles doses de Streptozotocine (STZ) (STZ-CD). Les rats STZ-CD montrent des signes classiques de DMT2 et des déficits légers de consolidation en mémoire de reconnaissance spatiale. Afin d'imiter le développement des stades précoces de la MA, la moitié des rats reçoivent une infusion intracérébrale de peptides β-amyloïdes solubles (Aβ) qui ne conduisent pas à des déficits mnésiques durables. Par contre, le phénotype DMT2 chez les rats STZ-CD exacerbe les déficits mnésiques observés avec le peptide Aβ en les prolongeant dans le temps. L’enrichissement environnemental pendant une période critique de 2 semaines après l’infusion d’Aβ est capable de compenser les déficits mnésiques induits par le peptide Aβ et/ou le traitement STZ-CD ; mais d’une manière limitée dans le temps. Des analyses biochimiques dans l’aire CA1 de l’hippocampe ont été effectuées pour explorer de possibles altérations de la voie PI3K, de marqueurs de la cascade amyloïde et du DMT2. Le peptide Aβ seul induit peu de changements durables ; le phénotype DMT2 seul est associé à des changements pour quelques protéines-clé, largement en liaison avec le régime cafétéria. Par contre, la majorité des modifications dysfonctionnelles de protéines est observée chez les rats montrant un phénotype de type DMT2 et recevant le peptide Aβ. Ces altérations, similaires à celles rapportées chez des patients atteints de la MA et chez des modèles animaux de la MA, concernent notamment des protéines de la voie PI3K-Akt impliquée dans des fonctions comme l’autophagie et l’inflammation et des marqueurs de la MA. L’altération de ces protéines pourrait contribuer aux déficits mnésiques durables observés et mettre en lumière des mécanismes moléculaires induits par le DMT2 et promouvant un milieu neuronal favorisant le développement d’un stade précoce de la maladie d'Alzheimer<br>Following aging, type 2 Diabetes Mellitus (T2DM) is the most important risk factor of developing Alzheimer’s disease (AD). It is a metabolic disorder characterised by hyperglycemia and insulin resistance that develops in middle age and is promoted largely by obesity. In this study, we used a T2DM rat model to assess the potential impact T2DM may have on the development of AD. Rats were fed cafeteria-style diet (CD) coupled with low dose injections of Streptozotocin (STZ)(STZ-CD). We found that STZ-CD treated rats showed classic signs of T2DM and a modest deficit in consolidation of spatial recognition memory. In order to mimic the development of early stage AD, half of the rats were infused with a soluble oligomeric amyloid beta (Aβ), which alone was not sufficient to induce long-lasting memory deficits. Interestingly, the T2DM phenotype exacerbated the memory deficits induced by Aβ infusion by prolonging these deficits. Environmental enrichment during a critical two-week period following infusion of Aβ rescued memory deficits induced by Aβ and/or STZ-CD treatment; however, this was time-limited. Biochemical analyses were conducted mainly in proteins involved in the PI3K-Akt signalling pathway and markers of AD and T2DM in CA1 of the hippocampus. Aβ alone induced few long-lasting changes; T2DM phenotype alone induced some changes that were largely mediated by CD treatment alone; however, the majority of dysfunctional regulation of proteins was observed in rats showing a T2DM phenotype that were infused with Aβ. More importantly, many of these changes are similar to those reported in brains of AD patients or rodent models of the disease; notably key proteins in the PI3K-Akt signaling pathway that mediate functions such as autophagy, inflammation and markers of AD. Dysregulation of these proteins may contribute to the long-lasting memory deficits seen in this model, which may provide evidence of molecular mechanisms induced by T2DM that could promote a dysfunctional neuronal environment favouring the development of early stages of Alzheimer’s disease
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Cowan, Elaine. "Development of obestatin analogues and investigation of their effects on metabolism in obesity and type 2 diabetes." Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706299.
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Obestatin is a 23 residue gastrointestinal peptide with alpha-helical structure, short half-life, and as yet, no identified receptor. Since discovery in 2005, it has been reported to have many beneficial metabolic and cardiovascular actions in normal physiology and experimental obesity/diabetes, a number of which have been confirmed and disputed. This thesis aimed to characterise the structure and activity of obestatin (1-23) and obestatin analogues in vitro, and to undertake in vivo studies to examine their metabolic actions and biochemical pathways. Initially, N-PEGylated obestatin (PEG-OB(1-23)) was chronically assessed and found to have no significant effects in standard diet fed rats of normal physiology and in high fat diet fed (HFF) rats of mild obesity without metabolic dysfunction. Subsequent in vitro investigations with three novel N-PEGylated analogues incorporated with disulphide bridges, PEG-OB(1-23) and native obestatin showed that whilst none of these could activate putative receptors, novel analogue PEG-OB(Cys10,Cys13) with less alpha-helicity had the most promising stability (>4 times) and activity profile (effects slightly improved or comparable in pancreatic beta-cells, isolated mouse aorta and endothelial cells) compared to native obestatin. This analogue was assessed chronically in a more severe animal model of obesity/diabetes and found to inhibit cumulative weight gain, improve glucose tolerance and reduce diet induced increases in pancreas and white adipose tissue (WAT) weights, terminal insulin, c-peptide 2, HOMA-IR and HOMA-B levels in diet induced obesity (DIO) mice. Furthermore it induced decreasing trends in pancreatic morphology parameters in lean and DIO mice, reduced surface body temperature in lean animals, and (via metabolomics analysis of terminal plasma) demonstrated obestatin involvement in phospholipid turnover, lipid homeostasis, insulin sensitivity, inflammation, steroid, bile acid, PAF and glutathione metabolism. Interestingly concurrent investigations also demonstrated improvements in animal vascular function and we propose that obestatin enhances nutrient disposal and insulin sensitivity at least partially via its vascular actions.
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Dumas, Karine. "Implication de la protéine REDD1 dans les maladies métaboliques associées à l’obésité : REDD1 = Regulated in Development and DNA damage responses 1." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4045.
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L’obésité est définie comme une accumulation excessive de graisse pouvant conduire à des problèmes de santé et sa prévalence mondiale ne cesse d’augmenter. L’obésité s’accompagne de désordres métaboliques comme la résistance à l’insuline, la stéatose hépatique et le diabète de type 2. REDD1 (Regulated in Development DNA damages responses 1) régule de nombreuses voies de signalisation impliquées dans la modulation de la balance énergétique cellulaire. Dans mon laboratoire d’accueil, nous avons montré que REDD1 est impliqué dans la voie de signalisation de l’insuline. L’objectif de ma thèse est d’étudier l’implication de REDD1 dans les complications métaboliques induites par l’obésité. L’expression de REDD1 est augmentée dans le tissu adipeux épididymaire et le foie de souris contrôles (WT) nourries avec un régime obésogène (HFD). De plus, son expression est augmentée dans le foie de patients obèses atteints de stéatose hépatique et est corrélée avec le degré de la pathologie et la résistance à l’insuline des patients. Afin d’identifier le rôle de REDD1 dans le développement des pathologies induites par l’obésité, nous avons caractérisé le phénotype de souris invalidées pour REDD1 (KO) soumises à un régime HFD. Lors d’un régime HFD, les souris REDD1-KO développent une obésité et une résistance à l’insuline identique aux souris WT. Cependant, les souris REDD1-KO sont protégées du développement de la stéatose hépatique. Aucune modification de l’expression des protéines impliquées dans l’import et l’export hépatiques des acides gras n’a été mise en évidence. Dans le foie des souris REDD1- KO, l’expression des protéines impliquées dans la lipogenèse est diminuée alors que l’expression des protéines qui régulent la β-oxydation des acides gras est augmentée. Dans le foie des souris WT, le développement de la stéatose hépatique s’accompagne d’une augmentation de la taille des mitochondries. Par contre, dans le foie des souris REDD1-KO, le régime HFD n’induit pas d’augmentation de la taille des mitochondries et l’expression des protéines impliquées dans la régulation de la mitophagie est augmentée. Ces résultats suggèrent que lors d’un stress métabolique comme un régime obésogène, le foie des souris invalidées pour REDD1 pourrait être protégé d’un dysfonctionnement mitochondrial grâce à une exacerbation de l’autophagie. Dans la seconde partie de ma thèse, nous avons étudié le phénotype des souris hétérozygotes pour REDD1 (REDD1-He) soumises à un régime HFD. La diminution partielle de REDD1 n’affecte pas le développement de l’obésité par rapport aux souris WT, ni le développement de la stéatose hépatique. Cependant, sous régime HFD, l’intolérance au glucose et la résistance à l’insuline des souris REDD1-He sont augmentées par rapport aux souris WT-HFD. Les souris REDD1-He semblent oxyder difficilement les lipides en période de jeûne et ont une répartition des tissus adipeux différente que les souris WT. En conclusion, mes travaux de thèse ont permis de montrer pour la première fois l’implication de REDD1 dans le développement de la stéatose hépatique lors de l’obésité<br>Obesity is defined as an abnormal fat accumulation which could lead to health disorders and its prevalence is in constant increase worldwide. Obesity is associated with insulin resistance, hepatic steatosis and type 2 diabetes. REDD1 (Regulated in Development DNA damages responses 1) regulates most of signaling pathways implicated in cell energetic balance. In my host lab, we have demonstrated that REDD1 is implicated in insulin signaling pathway. The goal of my thesis was to study the REDD1 implication in obesity associated metabolic diseases. We observed that REDD1 expression was increased in epidydimal adipose tissue and in liver of control high fat diet (HFD) fed-mice (WT). Furthermore, REDD1 expression was increased in liver biopsies from obese patients with hepatic steatosis and its expression was correlated with the severity of the pathology and insulin resistance. To identify the role of REDD1 in the development of obesity-induced diseases, we have characterized the phenotype of REDD1 knockout mice (REDD1-KO) fed with HFD. Under HFD, the REDD1-KO mice showed a similar weight gain and insulin resistance compared to WT mice. Interestingly, REDD1-KO mice were protected from hepatic steatosis under HFD. In liver of REDD1-KO mice, no modification of protein expression implicated in hepatic lipid flux was observed. In REDD1-KO mice liver, we observed a decrease of protein expression implicated in lipogenesis pathways associated to an increase of the expression of proteins involved in β-oxydation. In WT mice, hepatic steatosis is correlated with an increase of mitochondrial size. In REDD1-KO mice, HFD did not induce an enlargement of mitochondria. Moreover, the expression pattern of proteins involved in autophagy and mitophagy is increased in HFD REDD1-KO livers. Our results suggest that in HFD conditions, liver of REDD1- KO mice could be protected from mitochondrial dysfunction because of an increase of mitophagy. In a second part of my thesis, we have studied the effect of partial decrease of REDD1 expression on obesity-induced complications using REDD1 heterozygous mice (REDD1-He). Partial decrease of REDD1 did not influence weight gain and hepatic steatosis development under HFD compared to WT mice. However, REDD1-He mice have developed an important glucose and insulin resistance under HFD compared to WT mice. This is associated with an impairment of the use of lipid as substrate during fasting. To conclude, my thesis research project allows us to show for the first time that REDD1 is implicated in hepatic steatosis under obesity
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Buckley, Patrick. "Development and Application of Microarray-Based Comparative Genomic Hybridization : Analysis of Neurofibromatosis Type-2, Schwannomatosis and Related Tumors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4786.
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Alemán, José O. (José Orlando). "Gluconeogenesis as a system : development of in vivo flux analysis of hepatic glucose production in Type 2 Diabetes." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/43743.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008.<br>This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.<br>Vita.<br>Includes bibliographical references (p. 289-300).<br>Metabolic diseases are an increasing health concern in the developed world. Type 2 Diabetes, (T2D) affects over 100 million people worldwide and significantly contributes to chronic diseases such as atherosclerosis and kidney failure. This condition is characterized by deregulation of glucose homeostasis through the development of insulin resistance, manifested as increased glucose production in the liver. Hepatic gluconeogenesis provides de novo formation of glucose from three carbon precursors such as glycerol, lactate, pyruvate and alanine. The upregulation of this pathway underlies the persistent hyperglycemia observed in diabetic patients. We have developed stable isotope tracer methods to reconstruct hepatic glucose production fluxes by infusion of [13C, 2H]-glycerol and mass spectrometry analysis of plasma metabolites. Using this methodology we observe physiologic changes in liver cell lines and primary hepatocyte cultures in the presence of hormones insulin/glucagon and in response to gluconeogenic precursor availability. We put forth the hypothesis that in the presence of glycerol as a gluconeogenic substrate, glucose-6-phosphatase has an important role in modulating metabolic flux through upper gluconeogenesis. Infusion of simultaneous tracer combinations in vivo including a novel [U-13C,2H5]-glycerol allow detailed net flux and reversibility reconstruction of upper gluconeogenesis to an unprecedented degree in a single experiment. We deployed the developed methods to probe glucose overproduction in the liver insulin receptor knockout (LIRKO) transgenic model of Type 2 Diabetes, and found unexpected similarities in the metabolic flux profile not observed by genomic, protein or metabolite measurements.<br>(cont.) Our results underscore the importance of flux measurement as a physiologic parameter akin to gene and protein expression in revealing the metabolic phenotype of cells, tissues and organisms. These methods have the potential to contribute as clinical assays to characterize excess glucose production as well as in drug development for new targets to control hepatic glucose production.<br>by José O. Alemán.<br>Ph.D.
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Mutsago, Bernard. "Development and application of diabetes care (Type 2) indicators at primary level in the Cape Town metropole region." Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/9365.
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Includes bibliographical references (leaves 68-75).<br>Since many of the diabetic complications can be prevented by good management, healthcare delivery ought to be of the highest quality possible. Therefore, continuous assessment and improvement of quality of care is important in order to give people with diabetes the care they deserve. This study aimed to develop a multi-faceted, indicator-based audit tool to evaluate the structural, process and outcome dimensions of quality of care for Type 2 diabetes at primary level in Cape Town metropole region.
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Docherty, Paul David. "Evaluation and Development of the Dynamic Insulin Sensitivity and Secretion Test for Numerous Clinical Applications." Thesis, University of Canterbury. Department of Mechanical Engineering, 2011. http://hdl.handle.net/10092/5525.
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Given the high and increasing social, health and economic costs of type 2 diabetes, early diagnosis and prevention are critical. Insulin sensitivity and insulin secretion are important etiological factors of type 2 diabetes and are used to define an individual’s risk or progression to the disease state. The dynamic insulin sensitivity and secretion test (DISST) concurrently measures insulin sensitivity and insulin secretion. The protocol uses glucose and insulin boluses as stimulus, and the participant response is observed during a relatively short protocol via glucose, insulin and C-peptide assays.
In this research, the DISST insulin sensitivity value was successfully validated against the gold standard euglycaemic clamp with a high correlation (R=0.82), a high insulin resistance diagnostic equivalence (ROC c-unit=0.96), and low bias (-10.6%). Endogenous insulin secretion metrics obtained via the DISST were able to describe clinically important distinctions in participant physiology that were not observed with euglycaemic clamp, and are not available via most established insulin sensitivity tests.
The quick dynamic insulin sensitivity test (DISTq) is a major extension of the DISST that uses the same protocol but uses only glucose assays. As glucose assays are usually available immediately, the DISTq is capable of providing insulin sensitivity results immediately after the final blood sample, creating a real-time clinical diagnostic. The DISTq correlated well with the euglycaemic clamp (R=0.76), had a high insulin resistance diagnostic equivalence (ROC c-unit=0.89), and limited bias (0.7%). These DISTq results meet or exceed the outcomes of most validation studies from established insulin sensitivity tests such as the IVGTT, HOMA and OGTT metrics. Furthermore, none of the established insulin sensitivity tests are capable of providing immediate or real-time results. Finally, and most of the established tests require considerably more intense clinical protocols than the DISTq.
A range of DISST-based tests that used the DISST protocol and varying assay regimens were generated to provide optimum compromises for any given clinical or screening application. Eight DISST-based variants were postulated and assessed via their ability to replicate the fully sampled DISST results. The variants that utilised insulin assays correlated well to the fully sampled DISST insulin sensitivity values R~0.90 and the variants that assayed C-peptide produced endogenous insulin secretion metrics that correlated well to the fully-sampled DISST values (R~0.90 to 1). By taking advantage of the common clinical protocol, tests in the spectrum could be used in a hierarchical system. For example, if a DISTq result is close to a diagnostic threshold, stored samples could be re-assayed for insulin, and the insulin sensitivity value could be ‘upgraded’ without an additional protocol. Equally, adding C-peptide assays would provide additional insulin secretion information. Importantly, one clinical procedure thus yields potentially several test results.
In-silico investigations were undertaken to evaluate the efficacy of two additional, specific DISTq protocol variations and to observe the pharmacokinetics of anti-diabetic drugs. The first variation combined the boluses used in the DISTq and reduced the overall test time to 20 minutes with only two glucose assays. The results of this investigation implied no significant degradation of insulin sensitivity values is caused by the change in protocol and suggested that clinical trials of this protocol are warranted. The second protocol variant added glucose content to the insulin bolus to enable observation of first phase insulin secretion concurrently with insulin sensitivity from glucose data alone. Although concurrent observation was possible without simulated assay noise, when clinically realistic noise was added, model identifiability was lost. Hence, this protocol is not recommended for clinical investigation.
Similar analyses are used to apply the overall dynamic, model-based clinical test approach to other therapeutics. In-silico analysis showed that although the pharmacokinetics of insulin sensitizers drugs were described well by the dynamic protocol. However, the pharmacokinetics of insulin secretion enhancement drugs were less observable.
The overall thesis is supported by a common model parameter identification method. The iterative integral parameter identification method is a development of a single, simple integral method. The iterative method was compared to the established non-linear Levenberg-Marquardt parameter identification method. Although the iterative integral method is limited in the type of models it can be used with, it is more robust, accurate and less computationally intense than the Levenberg-Marquardt method.
Finally, a novel, integral-based method for the evaluation of a-priori structural model identifiability is also presented. This method differs significantly from established, derivative based approaches as it accounts for sample placement, measurement error, and probable system responses. Hence, it is capable of defining the true nature of identifiability, which is analogous, not binary as assumed by the established methods.
The investigations described in this thesis were centred on model-based insulin sensitivity and secretion identification from dynamic insulin sensitivity tests with a strong focus on maximising clinical efficacy. The low intensity and informative DISST was successfully validated against the euglycaemic clamp. DISTq further reduces the clinical cost and burden, and was also validated against the euglycaemic clamp. DISTq represents a new paradigm in the field of low-cost insulin sensitivity testing as it does not require insulin assays. A number of in-silico investigations were undertaken and provided insight regarding the suitability of the methods for clinical trials. Finally, two novel mathematical methods were developed to identify model parameters and asses their identifiability, respectively.
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Provenzano, Lucy. "The role of cellular prion protein in the development of schwannomas and other Merlin-deficient tumours." Thesis, University of Plymouth, 2018. http://hdl.handle.net/10026.1/10784.
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Neurofibromatosis type 2 (NF2) is an inherited, multiple tumour disease caused by loss of the tumour suppressor protein, Merlin. There are several tumours associated with NF2 including; ependymomas, meningiomas and schwannomas. Merlin loss can also occur sporadically in all of these tumours and is associated with upregulation of various growth factor receptors and their relevant signalling pathways. At present the only treatment options for NF2 are surgery or radiosurgery, both of which incur serious morbidity and are unable to prevent recurrence of tumours. Either new drug treatments, or re-profiling of other drugs already commercially available, are urgently needed to improve outcome for NF2 patients. Cellular prion protein (PrPC), encoded by PRNP gene, is involved in tumour development by altering proliferation, adhesion, and survival in some cancers via focal adhesion kinase (FAK) /Src/ NFκB, cyclin D1 and p53 -proteins. Our group previously showed a strong elevation of PRNP gene activity in schwannoma. I hypothesise that PrPC may contribute to schwannoma development. To study the role of PrPC in schwannoma development I have used the well-established in vitro model of schwannoma that comprises primary human Schwann and schwannoma cells. I show that PrPC is upregulated in schwannoma as well as in Merlin-deficient meningiomas and human malignant mesotheliomas. In schwannoma PrPC is released both via exosomes and by α-cleavage which forms biologically active N- and C-terminal portions of the protein. PrPC contributes to pathological proliferation, adhesion and survival of schwannoma cells by activating ERK1/2, PI3K/AKT, cyclin D1, FAK, p53 pathways via the 37/67kDa non-integrin laminin receptor (LR/37/67kDa) and CD44. Furthermore, schwannoma cells appear to be intrinsically drug-resistant due to upregulation of MDR1 protein p-glycoprotein (p-gp) expression. P-gp expression is dependent on PrPC thus, inhibiting PrPC may be a good potential new therapeutic option for schwannoma patients, either alone or in combination with Sorafenib and p-gp inhibitor Valspodar (PSC833). An inhibitor of LR/37/67kDa/PrP interaction, NSC47924, or Bortezomib, a proteasome/NFκB inhibitor which has been approved for the treatment of multiple myeloma, could also be of beneficial therapeutic effect and is something to investigate in future work. I conclude that PrPC is an interesting new therapeutic target through its involvement with schwannoma patholgenesis and resistance to drug treatments PrPC may prove to be a good therapeutic target in other NF2-related tumours like meningiomas and schwannomas.
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Ryan, Alexander. "The role of PtdIns(4,5)P2 and its regulatory proteins in the development of insulin resistance in cell culture models." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-ptdins45p2-and-its-regulatory-proteins-in-the-development-of-insulin-resistance-in-cell-culture-models(1d0f500c-7b21-46a3-9eee-ad53588344c9).html.
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Insulin resistance, a key risk factor for type 2 diabetes, can be defined as when cells fail to respond effectively to insulin. In striated muscle and fat, this manifests as impaired insulin-stimulated glucose uptake due to reduced plasma membrane insertion of the glucose transporter GLUT4. In cell culture models, insulin resistance induced by chronic exposure to insulin, endothelin-1 or glucosamine, is correlated with reduced immunoreactivity of the lipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) in plasma membrane sheets. However, the reason for this decrease, and whether other factors that induce insulin resistance affect PtdIns(4,5)P2 levels, is unknown. Using L6 skeletal muscle myotubes and 3T3-L1 adipocytes, this project has investigated whether PtdIns(4,5)P2 levels are perturbed in insulin resistance induced by several factors, including exposure to insulin, oxidative stress, and treatment with tumour necrosis factor α, endothelin-1 or angiotensin II (Ang II).All these pre-treatments were found to abolish insulin-stimulated 3H 2-deoxy-glucose uptake, and significantly decrease PtdIns(4,5)P2 levels, measured in cell extracts by quantitative blotting using a PtdIns(4,5)P2-specific probe, developed from the PH domain of phospholipase C (PLC) δ. Importantly the ability of insulin to stimulate glucose uptake can be restored by replenishing PtdIns(4,5)P2 in L6 myotubes treated with insulin and Ang II. PtdIns(4,5)P2 levels are regulated by three families of proteins; PIP kinases, which synthesise it, phosphatases, which remove phosphate groups from the inositol headgroup, and PLCs, which hydrolyse it. Membrane preparations from Ang II- and insulin-induced insulin resistant L6 myotubes showed no differences in PtdIns(4,5)P2 production or dephosphorylation. However a significant increase in PLC activity was detected in membranes from insulin resistant cells and membrane localisation of PLCβ family members was increased in insulin resistant cells. Furthermore, studies using PLC inhibitors show a restoration of PtdIns(4,5)P2 levels in insulin resistant cells, leading to partial reversal of insulin resistance.This study therefore shows a causal link between decreased PtdIns(4,5)P2 levels and insulin resistance in L6 myotubes, and that PLCs are the reason for the PtdIns(4,5)P2 decrease in Ang II- and insulin-induced insulin resistance. PLCs, or their activation pathways, may thus be a novel target for combating insulin resistance, and preventing type 2 diabetes.
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Rudenski, A. "Development of a model of insulin/glucose regulation to assist elucidation of the pathophysiology of type 2 diabetes mellitus." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382881.
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Parry, Helen. "The roles of genetics and glycaemic control in the development of LVH and Heart Failure in Type 2 Diabetes." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/b7000b88-606c-4675-afe7-b720e33d7952.
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Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Not everyone with diabetes develops either LVH or HF, proposed factors influencing this include glycaemic control and genetic factors. No studies to date have looked at the genetics of LVH and HF specifically in T2DM.This thesis investigates the importance of glycaemic control and genetic factors in HF and LVH in T2DM. Data from patients with T2DM in the Go-DARTS study were used to identify individuals with HF, non-HF controls, individuals with LVH and non-LVH controls. Weighted mean HbA1C was calculated for each of them. Logistic regression analysis and proportional hazard regression analysis were performed to investigate whether glycaemic control was independently related to LVH and HF. Genetic typing for published loci associated with glycaemic control was performed and included in the proportional hazard regression analysis. Genotyping for published SNPs associated with LVH was also performed and included survival analysis looking at LVH. Proportional hazard regression analysis showed weighted mean HbA1C >=8% was associated with LVH (HbA1C >=8 to 9% HR 1.25, CI 1.04-1.50, HbA1C >=9 to 10% HR 1.64, CI 1.29-2.09, HbA1C>=10% HR 1.80, CI 1.32-2.44, all p-values <0.05) and also demonstrated weighted mean HbA1C <6% was associated with LVH in T2DM (HR 1.95, CI 1.57-2.43, p-value <0.05). Two out of 9 published SNPs were associated with LVH in our cohort with T2DM: rs17132261 and rs2292462 (p-value <0.05).Proportional hazard regression analysis showed HbA1C >=8% was associated with HF development and HbA1C<6% was also associated with HF development in T2DM (HbA1C<6% HR 2.2, CI 1.7-2.9, >=8 to 9% HR 1.6, CI 1.2-2.0, >=9 to 10% HR 2.5, CI 1.8-3.4 and weighted mean HbA1C>=10% HR 4.82, CI 3.6-7.0, all p-values <0.05). Conditional logistic regression analysis also showed 3 SNPs previously associated with fasting glucose were associated with HF development here (rs560887, rs7944584 and rs10885122).19These results suggest glycaemic variation and genetic factors are important factors in HF and LVH in T2DM.
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Wade, Louise S. "Development of Assessment and Screening Tool to Assist with Prevention and Identification of Charcot Foot in Type 2 Diabetics." ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2770.
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Abstract
Development of Assessment and Screening Tool
to Assist with Prevention and Identification of Charcot Foot in Type 2 Diabetics
by
Louise Wade MSN, RN
MS, West Texas A&M University, 2010
BS, West Texas A&M University, 2010
Project Submitted in Partial Fulfillment
of the Requirements for the Degree of
Doctor of Nursing Practice
Walden University
August 2016
Abstract
According to the World Health Organization, up to 50% of type 2 diabetic patients
develop neuropathy, which may cause major infections, amputation, and Charcot foot due
to impaired sensation. Early recognition and care is essential for treatment of Charcot
foot and prevention of further injury. Due to the complexity of this potentially life
threatening complication, assessment is challenging, especially when practitioners who
treat adult diabetic patients may not be familiar with Charcot foot. The purpose of this
scholarly project was to develop an assessment, screening tool, and algorithm for
detecting Charcot foot; an additional goal was to develop practice guidelines for
practitioners to assist in the early recognition, treatment, and referral of adult diabetic
patients at risk for Charcot foot. Lippitt's theory of change was used to guide the project.
An interdisciplinary team of stakeholders was assembled to guide development of the
tool, algorithm, and practice guidelines. Products were developed in accordance with
evidence in current peer-reviewed literature and American Diabetes Association
recommendations for Charcot foot diagnosis, treatment, and referral. Content was
validated using a scale content validation instrument process to obtain input from experts
in the care of Charcot foot. An implementation plan was developed to guide introduction
of the products into practice, and an evaluation plan created to determine the extent to
which intermediate term outcomes are met using these products. The project may
contribute to social change by identifying patients at risk for Charcot foot prior to the
onset of the complication, therefore preventing further injury, deformity, or amputation in
populations that are often unable to afford quality healthcare.
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Grgano, Emanuele Marco [Verfasser], та Rolf W. [Akademischer Betreuer] Hartmann. "Development of 17β-hydroxysteroid dehydrogenase type 2 and type 1 inhibitors for the treatment of osteoporosis and estrogen dependent diseases / Emanuele Marco Grgano ; Betreuer: Rolf W. Hartmann". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2016. http://d-nb.info/1120985005/34.
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Lødøen, Silje Drabløs. "Genetic Predisposition and Changes in Dietary Patterns may contribute to increased Development of Type 2 Diabetes in the Chinese Population." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-23291.
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Lifestyle diseases, such as type 2 diabetes (T2D) and cardiovascular diseases (CVDs), arerelated to overweight in the western world. Although lower occurrence of overweight hasbeen documented in China compared to western countries, an increase in such lifestylediseases has been observed during the last decades. The aim of this thesis was to study therelationship between lifestyle and the development of T2D and CVDs in the Chinesepopulation. The results may provide further knowledge concerning lifestyle diseases and maytherefore contribute to reduce disease development in the future. The experimental datapresented in this thesis was extracted from various research areas within molecular biology,genetics and epidemiology.Asian populations show higher concentrations of the pro-inflammatory mediator PAI-1 andlower concentrations of the anti-inflammatory mediator adiponectin compared to other ethnicgroups. These differences suggest that Asians may be genetically predisposed to developingmetabolic inflammation, which may increase the risk of developing T2D and CVDs. In China,the inflammation is most likely amplified due to altered nutritional patterns. Urbanpopulations in China have increased rapidly during the last decades. Highly influenced bywesternization processes, dietary changes have been introduced to these urban areas. Westerndiets include high consumption of fat, resulting in high kilocalorie (kcal) intake that mighttrigger overnutrition. Furthermore, an altered dietary carbohydrate composition has beenobserved through increased consumption of high glycemic indexed (GI) carbohydrates. Thetraditionally northern Chinese diet contains more kcal than the southern diet and has a higherGI content. These dietary differences might provide an explanation for higher prevalence ofT2D and CVDs observed in north China compared to south China.Genetic changes in utero and during childhood due to the Chinese Famine in the mid1940shas proven to explain a small part of the increased development of T2D in China. Individualswho during early development were subjected to malnutrition and later consume a richwestern diet are at increased risk of developing T2D. However, these genetic differences donot explain the disease development in Chinese children and adolescents. The one-childpolicy has been blamed for the increase as it reduces competition between siblings. None ofthe results in this thesis support the hypothesis that the one-child family policy is to be blamedfor the disease development. Therefore, the main factors contributing to the lifestyle diseasedevelopment in China appear to be genetic predisposition and dietary changes.
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Hadjiconstantinou, Michelle. "The development of an online emotional support programme to improve diabetes-related distress and well-being in type 2 diabetes." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42526.
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Background: Emotional support in type 2 diabetes (T2DM) is limited, however online-based programmes can be used as supplements for the emotional management of this condition. This research aimed to explore the emotional impact of T2DM and aimed to design a prototype of an evidence- and theory-based online programme to improve the emotional management of T2DM, especially well-being and diabetes-related distress. Methods: This thesis adopted a user-centered approach. A review of existing literature was undertaken to determine current concepts of well-being, diabetes-related distress (DRD) and stigma. A systematic review and meta-analysis were conducted to review the existing evidence on online-based interventions and well-being in T2DM. A secondary qualitative analysis was carried out to gain insight into the emotional impact of living with the condition. A series of patient and public involvement (PPI) and research advisory meetings were held regularly to inform early stages of the programme design. Focus groups were conducted with both people with T2DM (2 groups, n=10) and healthcare professionals (2 groups, n=10). The aim was to explore views living with T2DM, views on the use of the internet as a source for emotional support, and to evaluate the acceptability and feasibility of the online programme. All qualitative data in the methods section was analysed using framework analysis. Results: The systematic review and meta-analysis reported non-significant results for depression and DRD scores in online-based interventions, however these results were considered with caution. The secondary analysis identified key emotional challenges contributing to DRD. Overall, the qualitative studies reported a strong need for emotional support in T2DM; and verified the acceptability and feasibility of the online programme. Overall, information support, professional support and peer support were identified as important features for inclusion in an online emotional management programme. Discussion: Recommendations for clinical practice and further research are discussed in order to ensure future usability testing and effective implementation of the ‘My Well-being’ online programme.
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England, Clare. "Development of a brief evidence-based dietary assessment tool to promote healthy dietary change for people with Type 2 diabetes." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683701.
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Background Individualised dietary advice is essential for management of Type 2 diabetes (T2DM). In the DK dietary advice is often delivered by health professionals with limited nutrition training. It is not clear which dietary changes are most beneficial for adults with T2DM. Tools are needed to assist in providing individualised dietary advice. The aim of this thesis was to develop a brief dietary assessment tool, for use in the DK, for people with T2DM. Methods A questionnaire was developed. Item development was infonned by analysis of food diaries from people with T2DM who took part in a dietary intervention and a systematic review of existing measures. Items were refined via a Delphi study and a final scale was produced. A pilot test-retest reliability study and a comparison with food diaries were conducted in people with, or at high risk of, T2DM. Results Participants in the intervention reported dietary changes that produced a modest reduction in energy intake. Men and women changed their diets differently, but both made changes that limited impact on household members. Observed associations between changes to macronutrients and metabolic outcomes were clinically insignificant. The Delphi panel favoured food frequency and meal patterning questions. The pilot suggested that the resulting questionnaire had excellent test-retest reliability and showed similar agreement with food diaries and brief questionnaires developed internationally. Conclusion Dietary advice should focus on changes that reduce energy intake. This study found this advice should focus on reducing snack foods, high-energy drinks and portion sizes. However, more research is needed into which changes have the most benefit and why people choose to make the changes that they do make. A brief dietary assessment tool has been developed which shows promising test-retest reliability and comparability with food diaries. Evaluation of the tool in clinical practice is warranted.
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Hamrén, Bengt. "Safety and Efficacy Modelling in Anti-Diabetic Drug Development." Doctoral thesis, Uppsala University, Division of Pharmacokinetics and Drug Therapy, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8648.
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<p>A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population.</p><p>Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development. </p><p>Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar.</p><p>The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment. </p><p>The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population. </p><p>The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs. </p>
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Ghadzi, Siti Maisharah Sheikh. "Pharmacometrics Modelling in Type 2 Diabetes Mellitus : Implications on Study Design and Diabetes Disease Progression." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-317040.
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Pharmacometric modelling is widely used in many aspects related to type 2 diabetes mellitus (T2DM), for instance in the anti-diabetes drug development, and in quantifying the disease progression of T2DM. The aim of this thesis were to improve the design of early phase anti-diabetes drug development studies with the focus on the power to identify mechanism of drug action (MoA), and to characterize and quantify the progression from prediabetes to overt diabetes, both the natural progression and the progression with diet and exercise interventions, using pharmacometrics modelling. The appropriateness of a study design depends on the MoAs of the anti-hyperglycaemic drug. Depending on if the focus is power to identify drug effect or accuracy and precision of drug effect, the best design will be different. Using insulin measurements on top of glucose has increase the power to identify a correct drug effect, distinguish a correct MoA from the incorrect, and to identify a secondary MoA in most cases. The accuracy and precision of drug parameter estimates, however, was not affected by insulin. A natural diabetes disease progression model was successfully added in a previously developed model to describe parameter changes of glucose and insulin regulation among impaired glucose tolerance (IGT) subjects, with the quantification of the lifestyle intervention. In this model, the assessment of multiple short-term provocations was combined to predict the long-term disease progression, and offers apart from the assessment of the onset of T2DM also the framework for how to perform similar analysis. Another previously published model was further developed to characterize the weight change in driving the changes in glucose homeostasis in subjects with IGT. This model includes the complex relationship between dropout from study and weight and glucose changes. This thesis has provided a first written guidance in designing a study for pharmacometrics analysis when characterizing drug effects, for early phase anti-diabetes drug development. The characterisation of the progression from prediabetes to overt diabetes using pharmacometrics modelling was successfully performed. Both the natural progression and the progression with diet and exercise interventions were quantified in this thesis.
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Connelly, Jennifer. "The development and feasibility testing of a virtual health trainer in the promotion of physical activity in people with Type 2 diabetes living in remote and/or rural areas." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230174.
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The purpose of this thesis was to aid in the development of a web-based physical activity intervention for people with type 2 diabetes living in remote and rural areas. Chapter 1 introduces the research area, the design of the thesis and the key research questions. The thesis is then made up of 5 key studies. Study one, a systematic review of the literature was conducted and reported in chapter 2. This review identified the technologies that have previously been used to promote physical activity in type 2 diabetes, it identified the methodological quality of each included technology and the key components for effective change. Web based technology was the most commonly used and the most effective in increasing physical activity using components such as goal setting and physical activity trackers. These results informed study 2 (chapter 3) which explored patient and health professional's views on diabetes, physical activity and use of the internet. The need for clear information was identified with regard to diabetes as well as the call for accurate physical activity advice in relation to diabetes for both patients and health professionals. Study 3 (chapter 4) explored key information and components for an effective website. Included features were the need for a personalised approach; detailed advice on how the body responds to physical activity; a physical activity tracker and goal setting. The need for a 'virtual trainer' for support, advice and help with goal setting and interactive maps showing physical activity opportunities were all deemed important. The fourth study, chapter 5 described the design of the website and its features as well as the protocol for a six month pilot randomised controlled trial to examine the effectiveness of the development website, with and without interactive design elements. The final study in this thesis (chapter 6), describes the physical activity, physiological and biochemical results from a randomised controlled trial to test the effectiveness of the website and its features. The final chapter summarises the findings in response to the research questions and the future recommendations based on the outcomes.
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New, Nelda F. "The development and outcomes of a co-created diabetes self-management education intervention : a pilot study /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Nursing) -- University of Colorado Denver, 2007.<br>Typescript. Includes bibliographical references (leaves 154-162). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Al-Lenjawi, Badriya. "Development, implementation and evaluation of a diabetes patient education toolkit (DPET) for self-management of type 2 diabetes mellitus in Doha, Qatar." Thesis, University of Greenwich, 2010. http://gala.gre.ac.uk/5714/.
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The randomised controlled education intervention study recruited 430 adults aged 25-65 years with established diagnosis of T2DM (M = 130, F = 309) via a multi-stage double-blind stratified sampling procedure from 22 hospitals and health centres in Doha, Qatar. The intervention group (n = 215) were assigned to a six-week, 2-hourly structured educational class based on the specifically designed DPET, plus their usual one-to-one routine clinical care; the control group (n = 215) used the DPET for home self-study, plus their usual one-to-one routine clinical care. Adherence to the programme in the intervention group (n = 109; M = 40, F = 69) was 50.7% compared to 84% among controls (n = 181; M = 50, F = 131); an overall non-adherence rate of 32.6%. Repeated measures ANOVA showed a highly significant change in each of diabetes knowledge, attitudes and practice among intervention compared to controls at 12 month follow-up (p<0.0001). The intervention had no significant overall impact on systolic blood pressure (p = 0.632) nor diastolic BP (p = 0.421) but improvements in BMI among the intervention group (p = 0.001). Repeated measures ANOVA also showed differences in overall change in HbA1c (p = 0.012), fasting blood glucose (p = 0.022), HDL-cholesterol (p<0.0001) and albumin-creatinine ratio (p<0.0001) in the intervention group but not total cholesterol (p=0.204), LDL-cholesterol (p = 0.203) and total triaclyglycerol (p = 0.200) from baseline values after 12 months follow-up. Post-sessional self-assessment tests of knowledge, attitudes, practices and goal-setting used as a proxy measurement of empowerment showed a significant improvement in the empowerment scores from baseline in the intervention group (p<0.0001).
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Burghes, Susan E. Coulson. "Development and characterization of a Murine Model of Autoimmune Encephalitis with the Type 2 Central Nervous Voltage-gated Sodium Channel as the autoantigen /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486400446371923.
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Weymann, Nina [Verfasser], and Martin [Akademischer Betreuer] Härter. "A web-based Interactive Health Communication Application System for Patients with Type 2 Diabetes : Development and Randomized Controlled Trial. / Nina Weymann. Betreuer: Martin Härter." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1084213214/34.
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Meyer, Catharina Margaretha. "The development of recommendations for the implementation of nutrition therapy for coloured women with a type 2 diabetes attending CHC's in the Cape Metropole." Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3267.
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El, Sanadi Caroline Elizabeth. "DEVELOPMENT AND VALIDATION OF CLINICAL PREDICTION TOOLS FOR AIDING IN SELECTION OF 2ND LINE THERAPIES ADDED TO METFORMIN IN TREATMENT OF TYPE 2 DIABETES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1607604907339227.
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Hsiao, Wen-Yu. "The Lipid Handling Capacity of Subcutaneous Fat Requires mTORC2 during Development." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1087.
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Overweight and obesity are associated with Type 2 Diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictorexpress mature adipocyte markers but develop a striking lipid storage defect. In vivo,this results in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness. Mechanistically, mTORC2 promotes transcriptional upregulation of select lipid metabolism genes controlled by PPARgand ChREBP. These include genes that control lipid uptake, synthesis, and degradation pathways as well as Akt2, the gene encoding its substrate and insulin effector. Finally, we reveal a potential novel mTORC2 target, ACSS2, which might control intracellular acetyl-CoA availability and regulate metabolic gene expression by altering histone modification in white adipocytes. Exploring this pathway may uncover strategies to promote safe lipid storage and improve insulin sensitivity.
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Werfalli, Mahmoud. "Informing the development of a self-management care programme for older people with type 2 diabetes attending community health centres in Cape Town, South Africa." Doctoral thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/30420.
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Diabetes is a growing problem globally, with the major impact being experienced in low and middle-income countries. In 2017, there were an estimated 122.8 million people over the age of 65 years living with diabetes globally, with a prevalence of 18.8% and 3.2 million deaths at this age. If the trends continue, the number of people living with diabetes over the age of 65 years will be 253.4 million in 2045.This is being driven by demographic changes including the ageing of the population. In South Africa, diabetes is a major cause of morbidity and mortality and a burden to the overstretched health services, community, family and people with the disease. Self- care management is a cornerstone of diabetes care. The purpose of this thesis is to inform the development of a self-care management programme for older people attending public sector primary health care services in Cape Town, South Africa by using the PRECEDE planning model. This model provides an eight-phase framework for health care professionals to determine, develop, implement and assess health promotion programmes, as well as the application of health promotion theories systematically within such programmes. The thesis incorporates five interlinked studies, presented as five publications, two published and three in review: The first was a systematic review of studies that assessed the prevalence of type 2 diabetes mellitus among older people in African countries conducted between 2000 and 2015 with the objective of providing data for the monitoring of future trends. This demonstrates that type 2 diabetes is not rare in individuals aged 55 years and older across Africa – the overall prevalence of diabetes was 13.7% (95% CI 11·3–16·3) and was twofold higher in studies based on the oral glucose tolerance test than in those using fasting plasma blood glucose. The second is a secondary analysis of the Study on global AGEing and adult health (SAGE) South Africa Wave 1 data that examined the prevalence of self-reported diabetes and the association between diabetes and each of health-related quality of life and disability amongst South Africa’s older adults. The results were that diabetes was associated with lower quality of life and greater disability: it represented not only a risk factor for disability but was associated with a range of impairments and co-morbidities predisposing to loss of autonomy. The third, a cross-sectional survey, examines the knowledge of older people with diabetes attending primary care clinics in Cape Town, South Africa, about living with and managing their diabetes; and aims to determine the relationship of social support, especially that of family and friends with their self-management. Its major finding is that there was a lack of knowledge about the complications of diabetes, suggesting that the available diabetes educational opportunities have not been effective. Importantly, however, social support was positively associated with both knowledge and a number of self-care aspects. The fourth is a qualitative study consisting of documentary review and individual interviews with key informants to investigate the current policies, programmes and any other interventions as they relate to older people with diabetes. This found that generally older persons face numerous barriers in managing their condition. Further, there are multiple efforts to re-orientate the healthcare system to focus more effectively on non-communicable diseases for the population which would benefit older patients with diabetes. Finally, the study includes a systematic review of peer and non-professional health worker-led diabetes self-management programmes (COMP-DSMP) in low and middle-income country primary health care settings, and also examines the implementation strategies and associated diabetes-related health outcomes This found equivocal evidence supporting the use of COMP-DSMP for people with diabetes in these countries and suggested that the models of a peer/CHW-led programme need to be further explored, especially given the inevitability of a professional healthcare workforce shortage in LMICs. In conclusion, this research study has described the extent of the need for developing and evaluating education programmes that focus on older people with diabetes and emphasises the role of family and friends. Whilst there have been some significant policy interventions pertaining to the protection of the health and welfare of older persons in SA, the needs of this vulnerable group remain relatively low on the list of priorities in terms of focus and resource allocation. In this context, older people, as a distinct group, are also not a strong focus in current health policy relating to the provision of NCD care. This thesis alerts policymakers and clinicians to some of the specific issues considered to be pertinent and important in the care and management of older persons with diabetes. Many of these would also be applicable to older individuals with other chronic conditions.
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Swead, Ramadan. "The development of a study protocol, and ethics and regulatory approval documentation, for evaluation of clinical efficacy of Sutherlandia frutescens in adult type-2 diabetics." University of the Western Cape, 2018. http://hdl.handle.net/11394/5943.
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Magister Scientiae - MSc (Pharmacy Administration and Policy Regulation)<br>The prevalence of diabetes mellitus is increasing worldwide and it is becoming a significant
medical problem in low- and middle-income countries. The condition can be controlled
with a lifelong commitment to blood sugar monitoring, weight management, proper
nutrition, exercise, and pharmacotherapy. Additional new pharmacotherapies are however
needed to combat the increased prevalence and various traditionally used herbs, such as
Sutherlandia frutescens (S, frutescens), are being advocated to supplement the management
of type 2 diabetes mellitus. However, the clinical efficacy of S. frutescens in the
management of type 2 diabetes mellitus has not yet been scientifically established.
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Lundberg, Alexander. "Studying the Oligomerization of the Kinase Domain of Ephrin type-B Receptor 2 Using Analytical Ultracentrifugation and Development of a Program for Analysis of Acquired Data." Thesis, Linköpings universitet, Kemi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-110376.
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Ephrin type-B receptor 2 (EphB2) is a receptor tyrosine kinase which phosphorylates proteins and thereby regulates cell migration, vascular development, axon guidance synaptic plasticity, and formation of borders between tissues. It has been seen overexpressed in several cancers, which make it an interesting protein to study. In this thesis EphB2 kinase domain (KD) and juxtamembrane segment with kinase domain (JMS-KD) have been expressed, purified and studied using analytical ultracentrifugation to evaluate the oligomerisation of the KD and how the double mutation S677/680A affects this. A program for data analysis have been written and used for analysis of the acquired data. The values of the dissociation constant were 2.94±1.04 mM for KD wild type and 3.46±2.26 mM for JMS-KD wild type have been calculated. Due to varied problems with the measurements no data was acquired on the double mutant, and not enough data was gained to draw any conclusions. Additional experiments will be needed to understand the oligomerisation of this intriguing protein.
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Xhakaza, Lettilia. "Development and validation of a pharmacogenomics profiling panel suitable for personalizing Metformin therapy." University of the Western Cape, 2019. http://hdl.handle.net/11394/7225.
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>Magister Scientiae - MSc<br>The burden of non-communicable diseases (NCDs) in South Africa is predicted to increase substantially in the next decades if the necessary preventative measures are not taken. The two most common NCDs associated with rapid mortality increase are diabetes mellitus (DM) and hypertension (HTN). Both of these diseases, i.e DM and HTN, can be a result of a combination of modifiable risk factors (behavioral) and non-modifiable risk factors (genetic, physiological, and environmental). New strategies implemented to manage these diseases should include addressing both modifiable and non-modifiable risk factors for patients with NCDs. The aim of this study was to contribute to the reduction of incidence of uncontrolled T2DM among patients taking metformin as a first-line anti-diabetic drug, through the development of individualized therapy for this drug. When implemented, this could be one of the healthcare strategies to address non-modifiable risk factors for patients with T2DM as an important NCD. The first objective of the study was to explore the prevalence and risk factors of DM and HTN in South Africa, especially within the economically disadvantaged population.
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Wetzel, Marie [Verfasser], та Rolf W. [Akademischer Betreuer] Hartmann. "Development of potent and selective inhibitors of 17β-hydroxysteroid dehydrogenase type 2 : a new target for the treatment of osteoporosis / Marie Wetzel. Betreuer: Rolf W. Hartmann". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1052550991/34.
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