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1
Raab, R. Michael. "Genomic analysis of hepatic insulin resistance." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33762.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2006.Includes bibliographical references (leaves 159-191).
Type II Diabetes mellitus is a genetically complex disease characterized by insulin resistance in peripheral tissues, which results in simultaneous hyperglycemia and hyperinsulinemia. Because of the prevalence of type II diabetes, many researchers are investigating the genetics of glucose homeostasis, however, traditional mapping techniques have not been successful in determining all of the genes that regulate glycemia. To complement these efforts, we used DNA microarrays to find differentially expressed genes and combinatorial siRNA screening to investigate the effects of hepatic gene transcription during periods of high and low glucose production. This strategy provides a new approach to studying the molecular mechanisms of disease pathogenesis. Our investigations focused on discovering new genes that influence hepatic metabolism and glucose production. Hepatocytes help maintain whole body glycemia by providing glucose and other substrates during non-feeding periods. DNA microarrays containing 17,000 unique gene probes were used to study hepatic gene transcription during normal, insulin resistant, and fasting states in C57/BL/6J mice. We analyzed this data set using a combination of statistical and multivariate techniques to determine 41 different, genes that are differentially expressed and highly discriminatory of the treatment groups.
(cont.) Hepatocytes perform many physiological roles, thus to investigate which genes from the microarray analysis affected hepatic metabolism, we developed combinatorial RNA-interference (RNAi) based gene silencing techniques. Using combinatorial siRNA screening, we silenced genes that were over-expressed within the microarray data set to study loss of function effects on hepatic metabolism, which was quantified by measuring intracellular metabolite concentrations in relevant metabolic pathways. Based upon the metabolite dependent clustering of experimental and control samples using Fisher Discriminant Analysis, four of the silenced genes had a significant effect on key metabolites involved in hepatic glucose output. Of these four genes, three were shown to influence hepatic glucose output in our primary cell model.
by R. Michael Raab.
Ph.D.
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James, Declan Jonathan. "An analysis of insulin- and non-insulin- stimulated glucose transport in rat skeletal muscle." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394962.
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Kaizik, Stephan Martin. "Analysis of mouse models of insulin secretion disorders." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:4d44b68a-a0a0-4c92-8809-00ddbfe3e636.
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Hernández, Adrian V., Mirella Guarnizo, Yony Miranda, Vinay Pasupuleti, Abhishek Deshpande, Socorro Paico, Hosten Lenti, et al. "Association between Insulin Resistance and Breast Carcinoma: A Systematic Review and Meta-Analysis." Public Library of Science (PLoS), 2014. http://hdl.handle.net/10757/320267.
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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective: This study was undertaken to evaluate the association between components defining insulin resistance and breast cancer in women. Study Design: We conducted a systematic review of four databases (PubMed-Medline, EMBASE, Web of Science, and Scopus) for observational studies evaluating components defining insulin resistance in women with and without breast cancer. A meta-analysis of the association between insulin resistance components and breast cancer was performed using random effects models. Results: Twenty-two studies (n = 33,405) were selected. Fasting insulin levels were not different between women with and without breast cancer (standardized mean difference, SMD 20.03, 95%CI 20.32 to 0.27; p = 0.9). Similarly, non-fasting/ fasting C-peptide levels were not different between the two groups (mean difference, MD 0.07, 20.21 to 0.34; p = 0.6). Using individual odds ratios (ORs) adjusted at least for age, there was no higher risk of breast cancer when upper quartiles were compared with the lowest quartile (Q1) of fasting insulin levels (OR Q2 vs. Q1 0.96, 0.71 to 1.28; OR Q3 vs. Q1 1.22, 0.91 to 1.64; OR Q4 vs. Q1 0.98, 0.70 to 1.38). Likewise, there were no differences for quartiles of non-fasting/fasting C-peptide levels (OR Q2 vs. Q1 1.12, 0.91 to 1.37; OR Q3 vs. Q1 1.20, 0.91 to 1.59; OR Q4 vs. Q1 1.40, 1.03 to 1.92). Homeostatic model assessment (HOMAIR) levels in breast cancer patients were significantly higher than in people without breast cancer (MD 0.22, 0.13 to 0.31, p, 0.00001). Conclusions: Higher levels of fasting insulin or non-fasting/fasting C-peptide are not associated with breast cancer in women. HOMA-IR levels are slightly higher in women with breast cancer.
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Pretty, Christopher Grant. "Analysis, classification and management of insulin sensitivity variability in a glucose-insulin system model for critical illness." Thesis, University of Canterbury. Mechanical Engineering, 2012. http://hdl.handle.net/10092/6580.
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Hyperglycaemia in critical care is common and has been linked to increased mortality and morbidity. Tight control of blood glucose concentrations to more normal levels can significantly reduce the negative outcomes associated with hyperglycaemia. However, hypoglycaemia and glycaemic variability have also been independently shown to increase mortality in critically ill patients. Further complicating the matter, critically ill patients exhibit high inter- and intra patient metabolic variability and thus consistent, safe control of glycaemia has proved very difficult.
Model-based and model-derived tight glycaemic control methods have shown significant ability to provide very tight control with little or no hypoglycaemia in the intensive care unit (ICU). The model-based control practised in the Christchurch Hospital ICU uses a physiological model that relies on a single, time-varying parameter, SI, to capture the patient-specific glycaemic response to insulin. As an identified parameter, SI is prone to also capturing other, unintended, dynamics that add variability on multiple timescales. The objective of this research was to enable enhanced glycaemic control by addressing this variability of the SI parameter through better modelling and implementation.
An improved model of insulin secretion as a function of blood glucose concentration was developed using data collected from a recent study at the Christchurch Hospital ICU. Separate models were identified for non-diabetic patients and diagnosed, or suspected type II diabetic patients, with R2 = 0.61 and 0.69, respectively. The gradients of the functions identified were comparable to data published in a number of other studies on healthy and diabetic subjects.
The transcapilliary diffusion (nI) and cellular clearance (nC) rate parameters were optimised using data from published microdialysis studies. Interactions between these key parameters determine maximum interstitial insulin concentrations available for glucose disposal, and thus directly influence SI. The optimal values of these parameters were determined to be nI = nC = 0.0060 1/min.
Models of endogenous glucose production (EGP), as functions of blood glucose concentration and time, were assessed. These models proved unsatisfactory due to difficulties in identifying reliable functions with the available data set. Thus, it was determined that EGP should continue to be treated as a population constant, except during real-time glycaemic control, where the value may be adjusted temporarily to ensure valid SI values.
The first 24 hours of ICU stay proved to be a period of significantly increased SI variability, both in terms of hour-to-hour changes and longer-term evolution of level. This behaviour was evident for the entire study cohort as a whole and was particularly pronounced during the first 12-18 hours. The subgroup of cardiovascular surgery patients, in which there was sufficient data for analysis, mirrored the results of the whole cohort, but was found to have even lower and more variable SI. Glucocorticoid steroids were also found to be associated with clinically significant reductions in overall level and increases in hour-to-hour variability of SI.
To manage variability caused by factors external to the physiological model, the use of several stochastic models was proposed. Using different models for the early part of ICU stay and for different diagnostic subgroups as well as when patients were receiving certain drug therapies would permit control algorithms to reduce the impact of the SI variability on outcome glycaemia.
The impact of measurement timing and BG concentration errors on the variability of SI was assessed. Results indicated that the impact of both sources of errors on SI level was unlikely to be clinically significant. The impact of BG sensor errors on hour-to-hour SI variability was more pronounced. Understanding the effect of sensor and timing errors on SI allows their impact to be reduced by using the 5-95 percentile forecast range of stochastic models during glycaemic control.
The performance of the model incorporating the proposed insulin kinetic parameters and secretion enhancements was validated for clinical glycaemic control and virtual trial purposes. This validation was conducted by self- and cross validation on a cohort independent to that with which the model was developed. The use of multiple stochastic models to reduce the impact of this extrinsic variability during glycaemic control was validated using virtual trials.
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Reed, Peter Wayne. "Genetic analysis of Type 1 (insulin-dependent) diabetes mellitus." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325788.
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Pearson, James. "Analysis of the repertoire of insulin-reactive CD8+ T cells." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/68395/.
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Proinsulin is an auto-antigen in type 1 diabetes in the Non-obese Diabetic (NOD) mouse. The CD8+ T cell clone, G9C8, which utilises a T cell receptor (TCR) comprising TRAV8-1*01TRAJ9 and TRBV19*01TRBD1TRBJ2-3, recognises insulin B15-23 presented by H-2Kd, escapes negative selection and rapidly causes diabetes upon adoptive transfer into immunocompromised NODscid mice. To understand how these insulin B15-23 reactive CD8+ T cells develop, G9C8-derived single TCR TRAV8-1*01TRAJ9 chain transgenic NOD mice were generated. These mice were bred with different proinsulin-expressing NOD mice to generate proinsulin1 deficient, proinsulin2 deficient, proinsulin2 over-expressing and proinsulin1 and 2 deficient mice with a mutated proinsulin transgene, preventing G9C8 antigen recognition. Although proinsulin-specific CD8+ TCR repertoire changes in TRBV19 were seen in these mice, the proportion of insulin B15-23 reactive CD8+ T cells was unaffected by proinsulin expression. Interestingly, TCR clonotyping of these insulin B15-23 reactive T cells revealed minimal shared sequences between the strains, with mice exhibiting individual clonal expansions. However, by isolating TRBV19-expressing insulin B15-23-responsive T cells, shared sequences across the different proinsulin-expressing mice were identified, with a requirement of TRBJ2-3 for insulin recognition (used by the original G9C8 T cell clone). Furthermore, male proinsulin2 deficient TRAV8-1*01TRAJ9 mice developed diabetes, with a higher incidence seen upon antibiotic administration. Although the TCR repertoire was unaffected by antibiotics, the gut microbial diversity was greatly reduced in all the mice with age, independent of antibiotic use, with firmicutes bacteria comprising 90-97% of the microbiota. In summary, proinsulin expression and antibiotics modify diabetes susceptibility; however, insulin B15-23 reactive T cells develop independently of antigen expression and are not directly affected by antibiotics. This data suggests that iii non-antigen dependent mechanisms exist in controlling the development of auto-reactive T cells, but T cell activation and pathogenicity is influenced indirectly by a combination of antigen expression and gut microbiota.
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Thota, P., F. R. Perez-Lopez, Vicente A. Benítes-Zapata, V. Pasupuleti, and Adrian V. Hernandez. "Obesity-related insulin resistance in adolescents: a systematic review and meta-analysis of observational studies." Taylor and Francis Ltd, 2017. http://hdl.handle.net/10757/622281.
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El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.Insulin resistance is common among obese adolescents; however, the extent of this problem is not clear. We conducted a systematic review of PubMed-Medline, CINAHL, The Web of Science, EMBASE and Scopus for observational studies evaluating components defining insulin resistance (insulin, C-peptide and homeostatic model assessment-insulin resistance [HOMA-IR]) in obese adolescents (12–18 years) versus non-obese adolescents. Our systematic review and meta-analysis followed the PRISMA guidelines. Data were combined using a random-effects model and summary statistics were calculated using the mean differences (MDs). 31 studies were included (n = 8655). In 26 studies, fasting insulin levels were higher in obese adolescents when compared to non-obese adolescents (MD = 64.11 pmol/L, 95%CI 49.48–78.75, p < 0.00001). In three studies, fasting C-peptide levels were higher in obese adolescents when compared to non-obese adolescents (MD = 0.29 nmol/L, 95%CI 0.22–0.36, p < 0.00001). In 24 studies, HOMA-IR values were higher in obese adolescents when compared to non-obese adolescents (MD = 2.22, 95%CI 1.78–2.67, p < 0.00001). Heterogeneity of effects among studies was moderate to high. Subgroup analyses showed similar results to the main analyses. Circulating insulin and C-peptide levels and HOMA-IR values were significantly higher in obese adolescents compared to those non-obese.
Revisión por pares
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Derewenda, Urszula. "X-ray analysis of dimeric and hexameric insulins." Thesis, University of York, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.276517.
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Lunt, Helen. "Analysis of a system used to detect islet cell stimulating antibodies." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385080.
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Eriksson, Susanne Elisabeth. "To live with insulin dependent diabetes." Thesis, Mälardalens högskola, Akademin för hälsa, vård och välfärd, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-41014.
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Background: Diabetes mellitus is a common disease and people with diabetes have doubled the last 20 years. Individual’s experiences in living with diabetes is useful to increase the understanding of persons with diabetes ability to manage, accept and possibilities to reconcile with a life with diabetes. Aim: The aim of this study was to describe person’s experiences of living with insulin dependent diabetes. Method: The study is a qualitative descriptive study with an inductive approach. Nineteen persons with insulin dependent diabetes mellitus was recruited from diabetic clinics at two hospitals in the middle of Sweden. The analysis was made with a qualitative content analysis. Findings: Time around the diagnosis living with diabetes was losing control of self and life. By flexible strategies they could regain control of self and life. By living in the present they found a way to live with illness as a part of life. Conclusions: Persons with insulin dependent diabetes needed to develop flexible strategies for daily life. With the help of strategies and a positive attitude they could continuously re-evaluate their planning for outer form of reconciliation. The threat of future complications constitutes an obstacle to inner form of reconciliation.
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CARVALHO, Dayse Cabral de. "Custo-utilidade da insulina glargina e insulina isófana (NPH) para o tratamento de pacientes com diabetes mellitus tipo 2 atendidos no Sistema Único de Saúde do Município de Recife." Universidade Federal de Pernambuco, 2014. https://repositorio.ufpe.br/handle/123456789/19711.
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CUSTO UTILIDADE DA INSULINA GLARGINA E NPH REV 4.pdf: 871032 bytes, checksum: 61243dd09cce2d9260cb9239a873d2ca (MD5)Made available in DSpace on 2017-07-17T15:08:06Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) CUSTO UTILIDADE DA INSULINA GLARGINA E NPH REV 4.pdf: 871032 bytes, checksum: 61243dd09cce2d9260cb9239a873d2ca (MD5) Previous issue date: 2014-10-31
INTRODUÇÃO: O Diabetes Mellitus é um transtorno metabólico, caracterizado por hiperglicemia. É considerada condição sensível à Atenção Primária, tendo impacto por reduzir ou retardar as complicações da doença. A reposição de insulina para o diabete mellitus tipo 2 é indicada quando somente mudanças no estilo de vida associados a hipoglicemiante oral forem insuficientes para obter controle glicêmico. OBJETIVOS: Determinar o custo-utilidade da insulina glargina e insulina NPH para o tratamento de pacientes com diabetes mellitus tipo 2 atendidos no Sistema Único de Saúde do Município de Recife – PE. MÉTODOS: Foi realizada comparação da categoria custos médicos diretos de duas intervenções terapêuticas indicadas para o tratamento do diabete mellitus tipo 2. A avaliação de custo-utilidade foi realizada a partir da perspectiva do Sistema Único de Saúde. Foi considerado um horizonte analítico de 10 anos. Os dados coletados foram de fontes secundárias, de sistema de informação em saúde, dados dos relatórios emitidos nos sistemas de informatização das Farmácias do Recife e da Farmácia do Estado de Pernambuco e fontes da literatura. Para a análise de decisão, foram consideradas as hipoglicemias noturnas e não noturnas graves e não graves. RESULTADOS: O indivíduo médio, representante de Pernambuco, apresenta 8,7 anos de diagnóstico do DM2, recebem aproximadamente 14,4 frascos de insulina NPH ou Glargina ao ano, dados estes, utilizados na probabilidade de transição. Para o cenário das complicações agudas, o custo do usuário foi calculado para 2013: sem complicação em uso da insulina NPH foi de R$ 1.237,95 e para insulina Glargina R$ 4.935,42. Foi considerado 12 episódios de hipoglicemia noturna grave ao ano. A redução de risco de hipoglicemia para pacientes em uso da insulina Glargina é de 50,9% apresentando cinco episódios ao ano. A razão de custo incremental (RCEI) do presente estudo, indica um valor agregado adicionado de R$ 12.987,4892 por AVAQ ganho a cada ano de tratamento com a insulina glargina em relação a NPH. CONCLUSÕES: Houve redução de episódio de hipoglicemia noturna grave da insulina glargina comparado com a insulina NPH. Os dados apresentados não permite afirmar qual da intervenção é mais efetiva, apenas mostra que a insulina glargina tem um maior custo-utilidade e um custo médico direto maior. Os custos incrementais e os benefícios alcançados em anos de vidas ganhos produziu uma Razão de R$ 12.987,4892 ao ano para a insulina glargina. Diante das incertezas acerca da efetividade das insulinas analisadas, faz-se necessário a realização de estudos aprofundados entre estas intervenções terapêuticas.
INTRODUCTION: Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. It is considered sensitive to Primary Health Care, considering its impacting to reduce or delay complications of the disease. Replacement of insulin for diabetes mellitus type 2 is indicated only when changes in lifestyle associated with oral hypoglycemic agents are insufficient to obtain glycemic control. OBJECTIVES: To determine the cost-utility of insulin glargine and NPH insulin for the treatment of patients with type 2 diabetes mellitus treated at the Unified Health System of the Municipality of Recife - Pernambuco. METHODS: We compared the direct medical costs of category two therapeutic interventions indicated for the treatment of diabetes mellitus type 2 was performed Assessment of cost-utility analysis was performed from the perspective of the Health System was considered an analytic horizon of 10 years.. The data were collected from secondary sources of health information system data reports issued in the computerization of Pharmacies and Pharmacy Recife Pernambuco State and literature sources systems. For decision analysis, were considered nocturnal hypoglycemia and nocturnal not serious and not serious. RESULTS AND DISCUSSION: The average individual, representative of Pernambuco, has 8.7 years of diagnosis of T2DM, receive approximately 14.4 vials of NPH or glargine per year, these data are used in the transition probability. For the setting of acute complications, the user cost was calculated for 2013: Uncomplicated in use NPH insulin was R$ 1,237.95 and R$ 4,935.42 insulin glargine. Was considered 12 episodes of severe nocturnal hypoglycemia per year. The reduced risk of hypoglycemia for patients on insulin glargine is 50.9% with five episodes per year. The ratio of incremental cost (ICER) of this study, indicates a value added of R$ 12,987.4892 per QALY gained every year of treatment with insulin glargine compared to NPH. CONCLUSION: There was a reduction of severe nocturnal hypoglycemia episode of insulin glargine compared with NPH insulin. The data presented allows not say which intervention is most effective, just shows that insulin glargine has a higher utility cost and a direct medical cost higher. Incremental costs and benefits achieved gains in years of life produced a ratio of R$ 12.987,4892 year to insulin glargine. Given the uncertainties about the effectiveness of insulin analyzed, it is necessary to conduct in-depth studies of these therapeutic interventions.
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Dash, Satya. "Analysis of TBC1D4 genetic variants in patients with severe insulin resistance." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609172.
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Ong, Kenneth Kian Leong. "Longitudinal analysis of the insulin gene minisatellite and insulin-like growth factors in human size at birth and early childhood growth." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619807.
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Hernández, Adrian V., Vinay Pasupuleti, Zapata Vicente A. Benites, Priyaleela Thota, Abhishek Deshpande, and Lopez Faustino R. Perez. "Insulin resistance and endometrial cancer risk: A systematic review and meta-analysis." Elsevier B.V, 2015. http://hdl.handle.net/10757/582697.
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Abstract Aim: It has been suggested that chronic hyperinsulinemia from insulin resistance is
involved in the etiology of endometrial cancer (EC). We performed a systematic review and
meta-analysis to assess whether insulin resistance is associated with the risk of EC.
Methods: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles
published from database inception through 30th September 2014. We included all observational
studies evaluating components defining insulin resistance in women with and without
EC. Quality of the included studies was assessed by NewcastleeOttawa scale. Randomeffects
models and inverse variance method were used to meta-analyze the association between
insulin resistance components and EC.
Results: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies,
n Z 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confi-
dence interval [CI] 15.04e52.85, p Z 0.0004). No differences were seen in postmenopausal
versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide
levels (five studies, n Z 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08e0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR)
values (six studies, n Z 1859) in EC patients were significantly higher than in women without
EC (MD 1.13, 95% CI 0.20e2.06, p Z 0.02). There was moderate-to-high heterogeneity
among the included studies.
Conclusion: Currently available epidemiologic evidence is suggestive of significantly higher
risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMAIR
values.
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Hernandez, Adrian V., Vinay Pasupuleti, Vicente A. Benítes-Zapata, Priyaleela Thota, Abhishek Deshpande, and Lopez Faustino R. Perez. "Insulin resistance and endometrial cancer risk: A systematic review and meta-analysis." Elsevier B.V, 2015. http://hdl.handle.net/10757/621216.
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Abstract Aim: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. Methods: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by NewcastleeOttawa scale. Randomeffects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. Results: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n Z 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confi- dence interval [CI] 15.04e52.85, p Z 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n Z 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08e0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n Z 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20e2.06, p Z 0.02). There was moderate-to-high heterogeneity among the included studies. Conclusion: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMAIR values.Revisión por pares
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Rubino, Maria. "Second trimester amniotic fluid insulin and glucose as predictors of macrosomia." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111582.
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Using second trimester amniotic fluid (AF), the objectives of this study were two-fold: 1) to investigate the relationship between AF glucose and insulin levels as a predictor of macrosomia and 2) to create a risk profile for macrosomia (LGA> 90th percentile) using a combination of AF glucose and insulin concentrations. Amniotic fluid samples were obtained from non-diabetic women (n = 542) undergoing age-related amniocentesis (12th to 22nd week). AF glucose was quantified using a standard hexokinase assay and AF insulin was quantified using the Beckman Access ultrasensitive assay system. Although LGA infants were found to have significantly higher concentrations of insulin and glucose in their 2nd trimester AF, logistic regressions showed that neither alone predicted the outcome of macrosomia. However, a Bayesian two-dimensional contour map plotted the risk for LGA using both AF glucose and insulin. The two-dimensional contour map illustrated the value in considering AF glucose and insulin together to predict LGA in newborns.
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Lim, Kang-Il. "Insulin stimulated glucose uptake : the influence of hyperglycemia and protein kinase C inhibition." Virtual Press, 2002. http://liblink.bsu.edu/uhtbin/catkey/1236582.
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The glucose toxicity has been recognized over the last several years as a factor contributing to both impaired insulin secretion and insulin resistance in patients with diabetes. However, the molecular mechanisms that underlie the changes in glucose transport activity induced by hyperglycemia have not been fully understood. The purpose of the present investigation is to determine if acute hyperglycemia affects an activation of glucose transport and also if hyperglycemic-induced change in insulinstimulated glucose transport is mediated via a PKC-dependent signaling system. Animals were anesthetized, and the soleus (SOL) muscles were isolated and clamped at their resting length. After a 10 minute recovery period the muscles were transferred to preincubation vials containing KHB supplemented with 4 or 16 mmol of glucose and 16 mmol/1 mannitol with or without insulin and/or inhibitors for 30 minutes. Following an incubation series to prepare the muscle, the muscle was incubated in radioactive 3-0- [3H] methylglucose and [14C] mannitol for 10 min. in the presence/absence of insulin and inhibitors, and the amount of glucose transport was measured. A total of 100µU/ml insulin with 4 mM glucose led to increase glucose transport by 155%, whereas the same amount of insulin with 16 MM glucose led to 80% increment in glucose transport. Also, 16 mM glucose in the absence of insulin induced an increase of glucose uptake by apporoximately 50% compared with 4 MM glucose. However, the addition of insulin reduced that difference to 5.3%. The conventional PKC inhibitor GF 109203X in the muscle incubated with 16 MM glucose led to a decrease in insulin-stimulated glucose transport (1l%), whereas the inhibitor with 4 mM glucose induced a decrease in insulin-stimulated glucose transport (24%). These findings suggest that glucose can directly regulate glucose transport activity by a mechanism that possibly involves a facilitated GLUT1 transporter activity. In addition to the mass action of glucose, the hyperglycemic-induced increase in insulin stimulated glucose transport may be partially mediated via a PKC-dependent signaling system.School of Physical Education
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Camargo, Rafael Ludemann 1986. "Taurine supplementation in malnourished obese animals = analysis of the molecular mechanisms of the hypothalamic action of insulin and leptin and the repercusion upon energy metabolism = Suplementação de taurina em animais desnutridos obesos: análise dos mecanismos moleculares da ação hipotalâmica da insulina e leptina e repercussões no metabolismo energético." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314187.
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Orientador: Everardo Magalhães CarneiroTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O balanço energético é preponderantemente controlado por regiões hipotalâmicas que recebem informações aferentes oriundas da periferia. Os estoques de energia sensibilizam neurônios hipotalâmicos que controlam a ingestão e o gasto energético, regulando assim o peso corporal. A desnutrição e a obesidade estão relacionadas ao desequilíbrio da homeostase energética. Evidências mostram que o consumo de dieta hiperlipídica (DHL) ativa vias inflamatórias no hipotálamo que prejudicam ações da insulina no controle do balanço energético. Além disso, o consumo de DHL também prejudica ações anorexigênicas da leptina e sua sinalização hipotalâmica. Neste estudo, avaliamos o consumo e o gasto energético, bem como os mecanismos moleculares e genéticos envolvidos na sinalização da insulina e leptina hipotalâmica e seu controle sobre o padrão alimentar e metabólico de camundongos submetidos à restrição protéica e alimentados com DHL. Além disso, verificamos os possíveis efeitos benéficos da suplementação com o aminoácido taurina (Tau), associado a DHL, nos perfis moleculares e fisiológicos analisados neste estudo. Para isso, logo após o desmame, camundongos C57BL/6 foram alimentados com dieta controle (14% de proteína ¿ grupo C) ou hipoprotéica (6% de proteína ¿ grupo R), sendo suplementados ou não com 5% de Tau na água de beber (grupos CT e RT). Após 6 semanas, os grupos receberam ou não DHL durante 8 semanas (grupos CHT e RHT). Animais submetidos a restrição protéica apresentaram maior sensibilidade periférica a insulina, apesar da deficiência na sensibilidade hipotalâmica deste hormônio. Os grupos em estudo apresentaram modificações na expressão de genes hipotalâmicos relacionados a defesa celular, apoptose, stress do retículo endoplasmático e controle da ingestão alimentar. Houve maior expressão gênica dos neuropeptidios orexigênicos em camundongos submetidos a restrição protéica, caracterizando hiperfagia, apesar de uma ingestão calórica normal. Camundongos DHL apresentaram hipofagia e menor expressão gênica dos neuropeptídeos anorexigênicos. Entretanto, o consumo de DHL em animais controles e desnutrido, propiciou maior ingestão calórica, culminando com aumento de peso e dos estoques de gordura. Camundongos DHL apresentaram também comprometimento da ação anorexigênica da leptina. Além disso, houve aumento da expressão protéica da uncoupling protein 1 (UCP1) no tecido adiposo marrom (TAM), assim como do quociente respiratório (QR) durante o período escuro em camundongos submetidos a restrição protéica. Por outro lado, houve diminuição da expressão protéica da UCP1 no TAM e do QR em camundongos DHL. Houve diminuição no gasto energético (GE) de animais DHL apenas na fase clara. Em conclusão, camundongos submetidos a restrição protéica apresentaram comprometimento da ação da insulina no hipotálamo, aumento da expessão dos neuropeptídios orexigênicos e do consumo alimentar. Além disso, o consumo de DHL promoveu obesidade, hipercolesterolamia, intolerância a glicose, aumento da ingestão calórica e prejuízo na ação da insulina e leptina. Entretanto, a suplementação com Tau preveniu alterações na homeostase glicêmica, no consumo calórico, na ação hipotalâmica da insulina e leptina em camundongos DHL. Por outro lado, a melhora desses padrões metabólicos mostrou-se menos eficaz em camundongos submetidos a restrição protéica. Por fim, o comprometimento do gasto energético e da atividade locomotora em animais obesos não foram restabelecidos com a suplementação de Tau
Abstract: The energy balance is mainly controlled by hypothalamic regions that receive afferent information arising from the periphery. Energy stocks sensitize hypothalamic neurons that control food intake and energy expenditure, thus regulating body weight. Malnutrition and obesity are related to an imbalance of energy homeostasis. Evidence shows that consumption of high-fat diet (HFD) activates inflammatory pathways in the hypothalamus that affect the actions of insulin in the control of energy balance. Moreover, consumption of HFD also impairs anorexigenic actions of leptin and its hypothalamic signaling. In this study, we evaluated the consumption and energy expenditure, as well as the molecular and genetic mechanisms involved in insulin and leptin signaling in the hypothalamus and its control over the food and metabolic pattern of malnourished mice fed with HFD. Furthermore, we verified the possible beneficial effects of supplementation with the amino acid taurine (Tau) associated with HFD in molecular and physiological profiles analyzed in this study. Thereunto, soon after weaning, C57BL/6 mice were fed with control diet (14% protein ¿ group C) or low protein diet (6% protein ¿ group R) and supplemented or not with 5% of Tau in the drinking water (CT and RT groups). After 6 weeks, the groups received or not HFD for 8 weeks (CHT and RHT groups). Animals subjected to protein restriction had a higher peripheral insulin sensitivity, despite the deficiency of this hormone in hypothalamic sensitivity. The study groups showed changes in hypothalamic expression of genes related to cellular defense, apoptosis, endoplasmic reticulum stress and the control of food intake. There was a higher gene expression of orexigenic neuropeptides in mice subjected to protein restriction, featuring a hyperphagia despite a normal caloric intake. HFD mice showed hypophagia and reduced gene expression of anorexigenic neuropeptides. However, consumption of HFD in controls and malnourished animals provided higher caloric intake, leading to weight gain and fat stores. HFD mice also exhibited an impaired anorexigenic effect of leptin. In addition, there was an increase in protein expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) and respiratory quotient (RQ) during the dark period in mice subjected to protein malnutrition. On the other hand, there was a decrease in the protein expression of UCP1 in the BAT and RQ in HFD fed mice. There was a decrease in energy expenditure (EE) in HFD animals only during the light phase. In conclusion, mice subjected to protein restriction showed an impairment of insulin action in the hypothalamus and an increase of the orexigenics neuropeptides genes expressions as well as food intake. Moreover, consumption of HFD promoted obesity, hipercolesterolamia, glucose intolerance, increased caloric intake and impaired of hypothalamic action of insulin and leptin. However, Tau supplementation prevented alterations in glucose homeostasis, caloric intake and hypothalamic action of insulin and leptin signaling in HFD mice. Moreover, the improvement in these metabolic patterns was less effective in mice subjected to protein restriction. Finally, the impairment of energy expenditure in obese animals and spontaneous locomotor activity were not restored by supplementation of Tau
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular
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Melvin, Derek Robert. "Analysis of trafficking motifs in the insulin-responsive glucose transporter isoform, GLUT4." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264144.
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Lee, Adrian. "Analysis of insulin-like growth factor-II in human breast cancer cells." Thesis, University of Surrey, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335638.
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Bellows, William D. (William Devereaux). "Analysis of randomly occurring high injection forces in an insulin delivery device." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/92226.
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Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2014. In conjunction with the Leaders for Global Operations Program at MIT.Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, 2014. In conjunction with the Leaders for Global Operations Program at MIT.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 57-58).
During manufacturing scale-up of a new product, new failure modes often surface which require corrective action. However, as production numbers of an insulin injection device pass 200 million per year, testing continues to find sub-assemblies with too-high injection forces, seemingly at random. Up until now, no corrective action has been effective in preventing these problems. These non-conforming sub-assemblies cause batches to be rejected, reducing the production yield at Sanofi's Site Frankfurt Devices (SFD) production facility. This thesis describes the current state of rejected batch problem solving and explores the application of new methods to better understand the root problems and improve the process. Frequency spectra analysis of testing data using the Fast Fourier Transform (FFT), combined with device physics, identified the key interaction points within the sub-assemblies. This model of part interactions has been verified through testing of purpose-built defective pieces and examination of defective parts. The verified model was then used to identify which components within sub-assemblies cause non-conformances. The root causes of several failure codes were determined, and results were further confirmed by rebuilding and retesting subassemblies with the identified problem components. These results confirm the usefulness of this novel application of frequency analysis to a new field of industrial troubleshooting. Various improvement and control methods are explored and next steps recommended for Sanofi to further improve quality control processes and thereby the production yield. The opinions expressed herein are solely those of the author and do not necessarily reflect those of Sanofi S.A.
by William D. Bellows.
S.M.
M.B.A.
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Olinski, Robert Piotr. "Evolutionary Analysis of the Insulin-Relaxin Gene Family from the Perspective of Gene and Genome Duplication Events." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7892.
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Patel, Dhaval Subhas. "Analysis of the daf-2 insulin/igf-1 receptor gene in Caenorhabditis elegans." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445066/.
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The daf-2 gene is a key regulator of growth, metabolism and longevity in the nematode Caenorhabditis elegans. The DAF-2 receptor functions in a pathway that is analogous to mammalian insulin/insulin-like growth factor signalling and determines whether animals proceed with full reproductive development or arrest in a long-lived diapausal state known as the dauer larva. Temperature-sensitive hypomorphic mutants of daf-2 constitutively arrest as dauers when raised at non-permissive temperatures. At permissive temperatures the animals develop into adults that are long-lived compared to wild-type adults. These alleles of daf-2 can be separated into two distinct classes (1 and 2) based on their pleiotropic phenotypes. In addition to their phenotypic differences, the two classes also differ in their epistatic interactions with other genes involved in dauer formation, suggesting that the DAF-2 receptor has multiple signalling outputs. In this thesis I have investigated the nature of the daf-2 allele class difference using a range of methods, including sequence analysis and homology modelling of mutant receptors. This generated the prediction that signalling flux through the receptor is a determinant of the class difference, with class 2 alleles having an asymmetrical alteration in signal transduction through DAF-2. Experimental testing of these predictions suggest that some phenotypes such Eat and Unc may be associated with asymmetrical signalling, while others such as early larval arrest may be correlated with a reduction in receptor level at the plasma membrane. A comparative analysis of the DAF-2 receptor with its homologues from Caenorhabditis briggsae, Caenorhabditis remanei and the parasitic nematode Brugia malayi suggests the large C-terminal extension in the Caenorhabditis species, which shorter in Brugia and not present in vertebrates, is an adaptive trait that has evolved by exon duplication for rapid growth and development and may contribute to the shortevity of these species. In addition, I have also performed an analysis of ins-7 and ins-35, two putative ligands of DAF-2 that are differentially regulated by the transcription factor DAF-16, using RNAi. Knockdown of both these genes lead to slight lifespan extension (10-20%) at 20 °C in all genetic backgrounds and slight suppression (-10%) at 25 °C in long-lived daf-2 mutant backgrounds compared to controls. This suggests that INS peptides may function as agonists a 20 °C and antagonists at 25 °C, and that this behaviour may be independent of their transcriptional regulation.
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Tang, Lei. "The determination and structural analysis of site-directed dihydrofolate reductase and insulin mutants." Thesis, Open University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338337.
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Malvezzi, Maria Aparecida Pereira Nunes. "Efeito dose-resposta do fluoreto em parâmetros relacionados à resistência à insulina e na expressão de proteínas hepáticas e musculares em camundongos NOD." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/25/25149/tde-24012019-090227/.
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Enquanto alguns trabalhos relatam que a administração crônica de F causa resistência à insulina, estudo recente do nosso grupo revelou que em animais com diabetes previamente induzido por estreptozotocina, a administração crônica de baixas doses de F aumenta a sensibilidade à insulina, por interferir em vias metabólicas musculares e hepáticas. Entretanto, o diabetes induzido por estreptozotocina causa alterações metabólicas diferentes do diabetes tipo 1. Desta forma, seria interessante verificar se o aumento da sensibilidade à insulina induzido por baixas doses de F também ocorreria utilizando um modelo de diabetes que mimetiza melhor o diabetes tipo 1 (camundongos NOD non-obese diabetic). Com base no exposto, o presente estudo investigou, em camundongos NOD recémdesmamados e expostos cronicamente a doses de F na água de beber que simulam a ingestão de F pela água artificial ou naturalmente fluoretada, se ocorrem alterações relacionadas à resistência à insulina, bem como na expressão de proteínas hepáticas e musculares. Para tanto, 24 camundongos NOD (não obesos diabéticos), obtidos imediatamente após o desmame, foram divididos em 3 grupos, de acordo com a concentração de F presente na água de beber (0, 10 ou 50 ppm), que foi administrada por um período de 21 dias. Decorrido o período experimental, os animais foram eutanasiados, sendo coletado o sangue para análise de F (eletrodo íon específico), glicose (método da glicose-oxidase) e insulina (ELISA), bem como o fígado e músculo gastrocnêmio, para análise proteômica quantitativa livre de marcadores (software Protein Linx Global Service). Os dados foram analisados por ANOVA e teste de Tukey, ou teste de Kruskal-Wallis e teste de Dunn (p<0,05). Apenas o grupo tratado com 50 ppm F apresentou concentração plasmática de F significativamente maior que o controle. Os animais tratados com 10 ppm F tiveram glicemia significativamente menor que o grupo controle, mas não houve diferença significativa entre os grupos em relação à insulinemia. A % de função das células pancreáticas foi significativamente maior no grupo tratado com 10 ppm F, quando comparado aos demais. A análise proteômica revelou alterações no perfil proteômico tanto do tecido muscular quanto do hepático. No tecido muscular, o grupo de 10 ppmF apresentou, em relação ao controle, expressão aumentada de proteínas envolvidas no metabolismo energético. Já o grupo de 50 ppm F, em relação ao controle, apresentou expressão aumentada de proteínas relacionadas à contração muscular, diferenciação do tecido adiposo marrom e apoptose. Para o tecido hepático, também foi observada expressão aumentada no grupo submetido a 10 ppm F em relação ao controle de proteínas envolvidas no metabolismo energético e síntese proteica, com destaque ainda para o aumento de isoformas de Glutathione S transferase, bem como de Heat shock-related 70 kDa protein 2. No grupo submetido a 50 ppmF foi observada alteração de proteínas envolvidas no metabolismo de espécies reativas de oxigênio e metabolismo energético. O aumento na expressão de proteínas antioxidantes, mediante tratamento com a baixa concentração de F, pode ajudar a explicar a proteção contra o desenvolvimento do diabetes, o que deve ser comprovado em estudos mecanísticos futuros.While some studies report that chronic administration of fluoride (F) causes insulin resistance, a recent study in our group found that in animals with diabetes previously induced by streptozotocin diabetes, chronic low-dose F administration increases insulin sensitivity by interfering with metabolic pathways in muscle and liver. However, streptozotocin-induced diabetes causes different metabolic changes from type 1 diabetes. Thus, it would be interesting to see whether increased insulin sensitivity induced by low doses of F would also occur using a diabetes model that better mimics type1 diabetes (NOD mice - non-obese diabetic). Based on the foregoing, the present study investigated in NOD mice chronically exposed to doses of F in drinking water that simulate the ingestion of F by artificial or naturally fluoridated water, if there are changes related to insulin resistance as well as in the expression of liver and muscle proteins. Twenty-four NOD mice, obtained immediately after weaning, were divided into three groups, according to the concentration of F present in the drinking water (0, 10 or 50 ppm), which was administered by a period of 21 days. After the experimental period, the animals were euthanized and the blood was collected for analysis of F (ionspecific electrode), glucose (glucose oxidase method) and insulin (ELISA), as well as the liver and gastrocnemius muscle, for quantitative proteomic analysis (Protein Linx Global Service software). Data were analyzed by ANOVA and Tukey\'s test, or Kruskal- Wallis and Dunn\'s test (p <0.05). Only the group treated with 50 ppm F had plasma F concentration significantly higher than the control group. Animals treated with 10 ppm F had significantly lower glycemia than the control group, but there was no significant difference between the groups in relation to insulinemia. The % of pancreatic -cell function was significantly higher in the group treated with 10 ppm F compared to the others. Proteomic analysis revealed changes in the proteomic profile of both muscle and hepatic tissue. In the muscle tissue, the group of 10 ppm presented, in relation to the control, increased expression of proteins involved in energy metabolism. The group of 50 ppm F, in relation to 7control, presented increased expression of proteins related to muscle contraction, differentiation of brown adipose tissue and apoptosis. For hepatic tissue, increased expression was also observed in the group of 10 ppm F in relation to the control of proteins involved in energetic metabolism and protein synthesis, with emphasis also on the increase of Glutahione S transferase isoforms as well as Heat shock-related 70 kDa protein 2. In the group treated with 50 ppm F proteins related to ROS metabolism and energetic metabolism were altered. Increased expression of antioxidant proteins by treatment with low F concentration may help explain protection against the development of diabetes, which should be demonstrated in future mechanistic studies.
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McGarry, Robert Gerard. "Modelling insulin/glucose dynamics and application to the analysis of oral glucose tolerance tests." Thesis, Queen's University Belfast, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335562.
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Millar, Caroline Ann. "Analysis of the subcellular distribution and trafficking of the insulin-responsive glucose transporter, GLUT4." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284933.
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Watson, Nicol D. "A biochemical and proteomic analysis of glucosamine-treated, insulin-resistant cultured human muscle cells." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432496.
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Kiefer, Julie Christine. "Analysis of myogenic regulatory factors and insulin-like growth factors in early somite myogenesis /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/9227.
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Griffiths, Matthew Rhodri. "Analysis of signal transduction pathways involved in the activation of gene transcription by the insulin receptor." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265456.
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Sit, Kei Chun. "Investigation of the binding interactions between insulin and its receptor." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/87276/1/Kei_Sit_Thesis.pdf.
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This project investigated the interactions between insulin and its receptor. A combination of computational and experimental investigations resulted in the identification of four residues in non-canonical sites that, when mutated, had detrimental effects on insulin binding. An increased understanding of the binding mechanism will aid future research into diseases involving the insulin receptor and its relatives and could potentially lead to new therapeutic avenues to combat these health related issues.
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McElwee, Joshua J. "A comparative analysis of transcriptional alterations in long-lived insulin/IGF-1-like signaling mutants in Caenorhabditis elegans and Drosophila melanogaster /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/4982.
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Stankūnaitė, Eglė. "Pharmacoepidemiological study and costs analysis of oral antidiabetic drugs and insulins in Lithuania on 2006-2009 year." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092504-76708.
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Objective: To perform pharmacoepidemiological study of the use of oral antidiabetic drugs and insulins in Lithuania on 2006-2009 year and cost-minimization and reference price analysis enabling more rational use of financial resources of national health system.
Material ans methods: The search for all literature relating to pharmacokinetic and pharmacodynamic chareacteristics of drugs for diabetes mellitus was done in MEDLINE database. The data on total sales of oral antidiabetic drugs and insulins in Lithuania over a four-year period (2006-2009) were obtained from Softdent, Lithuania data base. Drugs were classified according to the Anatomic Therapeutic Chemical system. Data were calculated by DDD methodology and expressed in DDDs per 1000 inhabitants per day (DDD/TID). Calculations of drug prices and total expenditures for antidiabetic drugs were made by using retail prices from the National Patient Funds Price List on 2006- 2009 years. Pharmacoeconomic calculations were done according to cost minimization and reference price methodologies.
Results: The total consumption of hypoglycaemic drugs (incl. insulins) increased by 33.33% from 21.54 DDD/TID in 2006 to 28.72 DDD/TID in 2009. The utilization of insulin increased by 30% reaching the value of 9.43 DDDD/TID, similarly the utilization of oral antidiabetic drugs increased by 35% reaching the value of 19.29 DDD/TID in 2009. In comparison with antidiabetic drug consumption in other countries, this meaning was about... [to full text]Tikslai: Įvertinti geriamųjų antidiabetinių vaistų ir insulinų suvartojimo tendencijas Lietuvoje 2006–2009 m. ir atlikti farmakoekonominę analizę kaštų mažinimo ir referentinės kainos metodu siekiant racionaliai panaudoti sveikatos apsaugos lėšas cukriniam diabetui gydyti. Medžiaga ir metodai: Duomenys apie antidiabetinių vaistų farmakokinetines ir farmakodinamines savybes buvo surinkti iš MEDLINE elektroninių duomenų šaltinių. Duomenys apie antidiabetinių vaistų pardavimą Lietuvoje 2006–2009 metais gauti iš UAB SoftDent duomenų bazės. Vaistai klasifikuoti pagal anatominę terapinę cheminę (ATC) klasifikaciją. Vaistų suvartojimas buvo vertinamas pagal apibrėžtos dienos dozės (DDD – angl. defined daily dose) metodiką, o duomenys apskaičiuoti pagal DDD skaičių, tenkantį 1000 gyventojų per vieną dieną.Vaistų kainų skaičiavimai atlikti remiantis mažmenine kaina iš „Kompensuojamų vaistinių preparatų kainynų“. Antidiabetinių vaistų farmakoekonominei analizei atlikti taikytas kaštų mažinimo bei referentinės kainos nustatymo metodas. Rezultatai: Bendras antidiabetinių vaistų suvartojimas padidėjo 33,33% nuo 21,54 DDD/TID 2006 metais iki 28,72 DDD/TID 2009 metais. Insulinų suvartojimas padidėjo 30% ir siekė 9,43 DDDD/TID 2009 metais, o geriamųjų antidiabetinių vaistų suvartojimas pakilo 35% iki 19,29 DDD/TID 2009 metais. Palyginus su kitų Europos šalių duomenimis, Lietuvoje antidiabetinių vaistų suvartojimas buvo du-tris kartus mažesnis, nepaisant to, jog sergamumas cukriniu diabetu... [toliau žr. visą tekstą]
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Zhou, Rui. "Functional analysis of insulin-like growth factor binding protein -4 and -6 in transgenic mice." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-12058.
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Richards, Hannah B. "Functional analysis of type 2 diabetes associated transcripts." Thesis, University of Oxford, 2014. https://ora.ox.ac.uk/objects/uuid:a1da01e0-5e60-4d4a-a621-6f1cae17a1d8.
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Genome wide association studies (GWAS) have transformed the study of the heritability of complex diseases such as type 2 diabetes (T2D), with the current tally of established risk loci close to ninety. Each of these loci has the potential to offer novel insights into the biology of this disease, and opportunities for clinical exploitation. However, the complexity of T2D has often frustrated efforts to achieve these functional and translational advances. This thesis aims to delve into the functional characterisation of two known susceptibility loci, KLF14 and ADCY5, and describe findings relevant to disease pathology. KLF14 and ADCY5 are two loci associated with T2D predisposition working through disparate mechanisms. Variants at the maternally imprinted KLF14 locus are associated with measures of insulin resistance and expression data has implicated KLF14 as a master regulator of genes in adipose tissue. In contrast, variation at the ADCY5 locus is associated with impaired beta cell function, high fasting glucose, and low birth weight suggesting ADCY5 is having an effect on insulin secretion. In this thesis, ENU mouse models of these two genes are investigated functionally to elucidate more about the pathology of common human variation at these loci. A mouse model was derived with an ENU point mutation at Adcy5 Y1064C. Phenotyping of this model revealed improved oral glucose tolerance, and secretion studies from isolated islet cells demonstrated impaired glucagon secretion from mice homozygous for the Y1064C mutation in the presence of adrenaline. These results suggest that Adcy5 is involved in glucagon regulation in the alpha cell. The Adcy5 Y1064C confers a protective effect against hyperglycaemia in mouse indicating that the T2D risk allele at the ADCY5 locus in humans may have the opposite direction of effect. A mouse model containing the ENU point mutation Klf14 R238L predicted to be disruptive to KLF14 protein function showed no significant difference in body weight, measures of insulin resistance, or blood cholesterol. However, expression of several genes associated in trans with variation near KLF14 in humans was changed in adipose tissue and skeletal muscle when the R238L mutation was inherited maternally compared to mice which had inherited the mutation paternally or carried two wild type alleles. This result suggests a mechanism by which Klf14 is regulating genes across metabolic tissues.
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Mabugana, Matamela Charles. "Analysis of the role of nuclear factor-kappa B in insulin resistance caused by antiretroviral drugs." Diss., University of Pretoria, 2020. http://hdl.handle.net/2263/79321.
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Human immunodeficiency virus still remains the leading cause of death globally
including women of child-bearing age. The rate of AIDS-related death has
significantly declined since the introduction of antiretroviral treatment and other
non-medical interventions such as the distribution and use of condoms. The
introduction of antiretroviral treatment has however led to insulin resistance amongst users. Clustered regularly interspaced short palindromic repeats (CRISPR)
CRISPR-associated nuclease 9 (Cas) has been used to knockout NFκB to
understand the pathway at which antiretroviral treatment causes insulin resistance.
Heteroduplex mobility assay has shown that CRISPR-Cas9 knock out the gene of
interest. These results have played a foundation in understanding how CRISPR-Cas9 can be integrated and utilized in medical research.Dissertation (MSc (Chemical Pathology))--University of Pretoria, 2020.
National Research Foundation (NRF)
Chemical Pathology
MSc (Chemical Pathology)
Restricted
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Landis, Justine M. "Mechanistic Analysis of Differential Signal Transduction Mediated by the Insulin Receptor Substrate Proteins IRS-1 and IRS-2: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/735.
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The Insulin Receptor Substrate (IRS) proteins IRS-1 and IRS-2 are cytoplasmic adaptor proteins that organize and propagate intracellular signaling downstream of specific growth factor receptors, including the Insulin and Insulin-Like Growth Factor-1 Receptors (IR and IGF-1R, respectively). Despite sharing a high level of homology and the ability to stimulate Phosphotidylinositol-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signaling, IRS-1 and IRS-2 play distinct roles in mammary tumor progression. Specifically, IRS-1 promotes growth and proliferation, whereas IRS- 2 promotes motility, invasion, survival, aerobic glycolyis, and metastasis. To further understand the differences between IRS-1 and IRS-2, I investigated the mechanistic basis of IRS-2-mediated PI3K activation. I identified tyrosines in IRS-2 that mediate its recruitment and activation of PI3K in response to insulin and IGF-1 stimulation. Using a PI3K-binding deficient IRS-2 mutant, I demonstrated that IRS-2-dependent PI3K signaling promotes aerobic glycolysis through its ability to selectively regulate the phosphorylation of the Akt effector Glycogen Synthase Kinase-3β (Gsk-3β). I also performed a rigorous comparison of IRS-1 and IRS-2 signal transduction and their ability to regulate functions associated with tumor progression. These studies required the generation of a novel model system where IRS-1 and IRS-2 function could be compared in a genetically identical background. Using this model, I confirmed a role for IRS-1 in growth regulation and IRS-2 in tumor cell invasion, as well as expanded the understanding of differential IRS protein function by showing that IRS-2 more vi effectively promotes Akt activation. The model system I have established can be used for further characterization of IRS-1 and IRS-2-specific functions.
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Landis, Justine M. "Mechanistic Analysis of Differential Signal Transduction Mediated by the Insulin Receptor Substrate Proteins IRS-1 and IRS-2: A Dissertation." eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/735.
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The Insulin Receptor Substrate (IRS) proteins IRS-1 and IRS-2 are cytoplasmic adaptor proteins that organize and propagate intracellular signaling downstream of specific growth factor receptors, including the Insulin and Insulin-Like Growth Factor-1 Receptors (IR and IGF-1R, respectively). Despite sharing a high level of homology and the ability to stimulate Phosphotidylinositol-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signaling, IRS-1 and IRS-2 play distinct roles in mammary tumor progression. Specifically, IRS-1 promotes growth and proliferation, whereas IRS- 2 promotes motility, invasion, survival, aerobic glycolyis, and metastasis. To further understand the differences between IRS-1 and IRS-2, I investigated the mechanistic basis of IRS-2-mediated PI3K activation. I identified tyrosines in IRS-2 that mediate its recruitment and activation of PI3K in response to insulin and IGF-1 stimulation. Using a PI3K-binding deficient IRS-2 mutant, I demonstrated that IRS-2-dependent PI3K signaling promotes aerobic glycolysis through its ability to selectively regulate the phosphorylation of the Akt effector Glycogen Synthase Kinase-3β (Gsk-3β). I also performed a rigorous comparison of IRS-1 and IRS-2 signal transduction and their ability to regulate functions associated with tumor progression. These studies required the generation of a novel model system where IRS-1 and IRS-2 function could be compared in a genetically identical background. Using this model, I confirmed a role for IRS-1 in growth regulation and IRS-2 in tumor cell invasion, as well as expanded the understanding of differential IRS protein function by showing that IRS-2 more vi effectively promotes Akt activation. The model system I have established can be used for further characterization of IRS-1 and IRS-2-specific functions.
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Baroni, Marco Giorgio. "Genetic analysis of non-insulin dependent diabetes mellitus (NIDDM) using DNA markers at candidate gene loci." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294972.
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Mikawa, Satoshi. "STRUCTURAL ANALYSIS AND EXPRESSION OF THE GENES FOR GOAT GROWTH HORMONE AND INSULIN-LIKE GROWTH FACTOR-I." Kyoto University, 1995. http://hdl.handle.net/2433/160854.
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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものであるKyoto University (京都大学)
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新制・課程博士
博士(農学)
甲第6065号
農博第835号
新制||農||696(附属図書館)
学位論文||H7||N2788(農学部図書室)
UT51-95-D384
京都大学大学院農学研究科農芸化学専攻
(主査)教授 駒野 徹, 教授 佐々木 隆造, 教授 内海 恭三
学位規則第4条第1項該当
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Renner, Benjamin Johannes [Verfasser]. "Detailed analysis of modulating effects of Clusterin in insulin and IGF-1 signal transduction / Benjamin Johannes Renner." Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1148989269/34.
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Spaeth, Brianne, and Barbara Fontana. "A Cost-Effectiveness Analysis Comparing Glargine Versus Rosiglitazone or Pioglitazone for Patients Failing Metformin Plus a Sulfonylurea." The University of Arizona, 2008. http://hdl.handle.net/10150/624269.
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Class of 2008 AbstractObjectives: To determine the cost-effectiveness of adding a thiazolidinedione (TZD) versus insulin glargine (glargine) as a triple regimen for treatment of Type 2 diabetes mellitus for patients not controlled with metformin and a sulfonylurea. Methods: A decision analytic model was developed to compare the clinical outcomes and costs of triple therapy with either a TZD or glargine. Published literature was used to determine treatment efficacy and the frequency of clinically important adverse effects. Cost data were obtained from the 2007 Physician Fee Reference and North Carolina Industrial Commission website. The decision tree was built using TreeAge software. Clinical outcome measures included HgA1c (A1C) control, hypoglycemia frequency, and the development of edema associated with the use of these medications. A Monte Carlo probabilistic sensitivity analysis was conducted to determine the mean and 95% CIs for both treatment efficacy and costs. Results: There was no statistically significant difference in the efficacy of adding either a TZD or glargine in achieving a goal A1C ≤ 7%. However, glargine triple therapy was estimated to be significantly less costly than TZD triple therapy ($3,161/yr; 95% CI $3,116 to $3,356 versus $3,769/yr; 95% CI $3,667 to $3,902, respectively). Conclusions: Most patients requiring triple therapy for the management of T2DM should receive glargine rather than a TZD due to the significantly lower cost producing similar clinical efficacy.
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Evaneshko, Veronica. "Exploratory data analysis of type II diabetes among Navajo Indians." Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276762.
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This research explicated the use of exploratory data analysis in describing type II diabetes mellitus among the Navajo Indians. A sample of 98 diagnosed diabetics was obtained from a retrospective chart review and had a 1.3:1 female to male ratio, a median age of 58.6 years, and a mean duration for diabetes of 7.66 years. Other characteristics included a median age at diagnosis of 50 years, a median weight prior to diagnosis (expressed in percent desired weight) of 140%, and a median blood glucose value at time of diagnosis of 241 mg/dl. The distribution patterns for age, weight, and blood glucose revealed several asymmetry problems which had implications for the appropriateness of using parametric statistics in numerical summarizations. Bivariate analyses revealed a negative association between age at diagnosis and percent desired weight prior to diagnosis. This finding identifies the risk that obesity brings to the young and that aging brings to the non-obese, Navajo Indian.
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Gautam, Dinesh Chandra. "Analysis of insulin receptor function in the central nervous system by conditional inactivation of its gene in mice." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=96492353X.
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Pirog, Antoine. "An embedded system for the multiparametric analysis of biological signals : application to the pancreatic biosensor of insulin demand." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0836/document.
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L'enregistrement extracellulaire d'activité électrique est une technique très répandue en neurosciences, mais son application aux îlots pancréatiques et cellules bêta n'est que très récente. La facilité d'utilisation des MEAs (Microelectrode Arrays, Matrices de Microélectrodes) a ouvert de nouvelles perspectives à l'électrophysiologie des cellules bêta, dont des méthodes de criblage en clinique ou des approches biocapteur pour le pancréas artificiel. Cette thèse contribue à la conception et la caractérisation d'un biocapteur hybride composé de cellules pancréatiques cultivées sur un MEA et d'un système électronique de traitement du signal. Le système ainsi réalisé est le fruit de collaborations et projets pluridisciplinaires menés à l'IMS (groupe bioélectronique), en partenariat avec le CBMN (biologie cellulaire et biocapteurs), tous deux au sein de l'Université de Bordeaux. Les projets faisaient également appel au service d'endocrinologie des Hôpitaux Universitaires de Bordeaux, Montpellier, Grenoble et Genève.Les projets en question incluent:- ISLET-CHIP (ANR 2013-PRTS-0017), qui explore une méthode pour évaluer la qualité d'un greffon pancréatique destiné à des patients diabétiques de type I.- BIODIA (EU FEDER), qui caractérise la réponse électrique d'îlots à des stimuli de glucose, hormones et médicaments pour des applications de criblage, différentiation cellulaire, et en boucle-fermée.- DIAGLYC (Bourse régionale 2017 1R30 226), qui étudie l'utilisation du biocapteur hybride comme un capteur pour le pancréas artificiel.La thèse aborde le biocapteur dans ses aspects à la fois électronique et biologique, son intégration dans des expériences appliquées, et ses résultats expérimentaux. Elle s'intéresse également à la modélisation d'une boucle de régulation chez le patient diabétique de type I.D'abord, le système d'analyse électronique est décrit. Issue de l'équipe Elibio, elle réalise acquisition multicanaux et traitement du signal numérique. Elle est construite autour d'un FPGA (Field Programmable Gate Array) qui rend son architecture de calcul polyvalente et évolutive. Elle est capable de mesurer, afficher, et enregistrer des données multicanaux. Le calcul embarqué est optimisé pour de faibles latences de calcul, compatibles avec des applications en boucle fermée. La thèse décrit ses algorithmes de traitement et son architecture.Des résultats expérimentaux utilisant le système et ses algorithmes sont ensuite montrés pour illustrer la réponse des îlots à des stimuli de glucose, médicaments et hormones. L'activité des îlots est quantifiée en analysant leurs APs (Action Potentials, Potentiels d'Action), et plus notoirement leurs SPs (Slow Potentials, Potentiels Lents), une nouvelle signature électrique exclusivement mesurée sur les îlots pancréatiques. Ces mesures, en régimes statique et dynamique, contribuent non seulement à caractériser la réponse du biocapteur, mais aussi à mettre en évidence les algorithmes internes des îlots de Langerhans.Enfin, des approches pour l'intégration du biocapteur dans un pancréas artificiel sont étudiées. Les réponses au glucose et aux hormones sont modélisées et simulées dans un modèle des interactions glucose-insuline dans le corps entier. Ce concept est novateur dans le sens où le capteur en charge de mesurer le besoin d'insuline n'est pas seulement sensible au glucose, mais aussi aux hormones présentes dans le sangExtracellular recording of electrical activity is a widespread technique in neurosciences, but only recently has it been applied to pancreatic islets and beta cells. The ease of use of Microelectrode Arrays (MEAs) has opened new perspectives for the electrophysiology of pancreatic cells, including screening methods for clinics and biosensor approaches for the artificial pancreas. This thesis is a contribution to the design and characterization of a hybrid biosensor composed of pancreatic cells cultured on an MEA and dedicated processing electronics. This device is the product of multi-disciplinary projects conducted at IMS (Bioelectronics group), partnered with CBMN (Cell biology and Biosensors team), both at the University of Bordeaux. Projects also involved the endocrinology service of university hospitals in Bordeaux, Montpellier, Grenoble, and Geneva.The covered projects include:- ISLET-CHIP (French ANR 2013-PRTS-0017), investigating a method of evaluating the quality of a preparation prior to its transplantation in type-I diabetic patients.- BIODIA (EU FEDER), characterizing islet electrical response to glucose, hormone, and drug stimuli for screening, cell differentiation, and closed-loop approaches.- DIAGLYC (French regional grant 2017 1R30 226), investigating the use of the hybrid biosensor as an artificial pancreas front-end sensor.The thesis tackles the biosensor in both its electronic and biological aspects, its integration in applicative experimental setups, and experimental results. It also addresses the modeling of a closed regulation loop for type-I diabetic patients.First, the electronic processing platform is described. It is a custom board performing multichannel acquisition and digital signal processing. It is built around an FPGA (Field Programmable Gate Array) that makes its processing architecture versatile and evolutive. It is capable of measuring, displaying and storing multichannel data. Computation was optimized for low-processing latencies compatible with closed-loop configurations. Both its processing algorithms and architecture are detailed.Then, experimental results using this system and its algorithms are shown to illustrate islet response to glucose, drug, and hormone stimuli. Islet activity is quantified by analyzing Action Potentials (APs), and more importantly Slow Potentials (SPs), a novel electrical signature exclusively measured on pancreatic islets. These measurements in both steady state and dynamic regime help characterize the biosensor response, but also shed light on the endogenous algorithms of islets of Langerhans.Finally, approaches for integrating the biosensor in an artificial pancreas are investigated. The measured glucose and hormone responses are modeled and simulated in a full-body glucose-insulin system. This concept is novel in that the sensor in charge of measuring insulin demand in the body is not only sensitive to glucose, but also to blood hormones
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Martí, Aluja Idoia. "Analysis of polymerisation / aggregation processes by nir chemical imaging and ftir spectroscopy." Doctoral thesis, Universitat Rovira i Virgili, 2013. http://hdl.handle.net/10803/125668.
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El principal objectiu d’aquesta tesi és desenvolupar mètodes analítics basats en la combinació entre l’espectroscòpia d’infraroig i tècniques quimiomètriques per analitzar in situ un procés de polimerització i l’agregació de la insulina. El procés de polimerització es va monitoritzar mitjançant la tècnica de near-infraredchemicalimaging (NIR-CI). L’anàlisi quimiomètric de les dades obtingudes ha permès evidenciar la presència d’un equilibri tautomèric d’un dels reactius. El segon procés estudiat ha estat l’agregació de la insulina, establint diverses metodologies basades en l’espectroscòpia d’infraroig (IR). Aquestes metodologies han permès, per una banda, avaluar l’efecte de fàrmacs antiretrovirals en el procés; i per altra banda, la influència de les tres variables bioquímiques més importants (temperatura, pH i força iònica) en el procés.The overall objective of this thesis is to develop analytical methods based on infrared spectroscopy and chemometric techniques to analyse two different processes that involve a state change from a liquid to a solid. The first studied process is a polymerisation process and it was followed by near-infrared chemical imaging (NIR-CI). The chemometric treatment of the images acquired allowed evidencing a tautomer’s equilibrium of one of the reagents. The second studied process was insulin aggregation. Aggregation process was monitored infrared spectroscopy (IR), and different methods were established which allowed on the one hand the assessment of the effect of antiretroviral drugs on the process; and on the other hand, the influence of biochemical variables on the process.
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Morrice, Nicola. "Endocrine and genomic analysis of Fenretinide-mediated retinoic acid receptor signalling in models of obesity and type-2 diabetes." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=232274.
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Obesity and type-2 diabetes are major global health crises. The synthetic retinoid compound 4-hydroxy(phenyl)retinamide (Fenretinide, FEN), has been shown to inhibit adiposity and reverse insulin resistance in pre-clinical studies. Fenretinide acts via several different mechanisms, including induction of retinoid signalling and increased hepatic lipid oxidation to exert its metabolic effects. However, the signalling mechanisms behind these effects have yet to be fully elucidated. A number of approaches were taken in this thesis to investigate the signalling mechanisms of Fenretinide. To characterise the relationship between Fenretinide and leptin signalling, Fenretinide treatment was administered in two different leptin-deficient mouse models. Fenretinide effects on hepatic signalling mechanisms were further characterised by performing global transcriptomics analysis in liver from mice receiving HFD ± Fenretinide. In this analysis, the important metabolic hormone fibroblast growth factor (FGF) 21 was identified as a novel retinoid-dependent target of Fenretinide signalling, which was further characterised in multiple mouse models. Retinoic-acid receptor-specific ChIP-sequencing was performed in order to identify other liver genes that are regulated by Fenretinide via retinoid-dependent signalling mechanisms. This work has shown that the beneficial effects of Fenretinide on adiposity occur via a mechanism independent of that through which Fenretinide mediates effects on glucose homeostasis. Fenretinide effects on insulin sensitivity and glucose homeostasis are most likely mediated via the inhibition of ceramide synthesis in the liver and other metabolically active tissues. This work also shows that Fenretinide can normalise the effects of chronic HFD-feeding by targeting the expression of a set of PPARα-target genes in the liver via a retinoid-dependent signalling mechanism. Overall, the work described in this thesis both uncovers more detail about the signalling mechanisms of Fenretinide and identifies novel target genes that may be exploited for the development of new therapeutics to treat obesity and type 2 diabetes.
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Inteeworn, Natalie. "The Effect of Hypothyroidism on Glucose Tolerance in Dogs." Thesis, Virginia Tech, 2008. http://hdl.handle.net/10919/32030.
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Background: Canine hypothyroidism is thought to cause abnormalities in glucose homeostasis, but the effect on glucose tolerance and insulin sensitivity has not been determined to date.
Hypothesis/Objectives: The purpose of the study was to investigate whether hypothyroidism has an effect on glucose tolerance and insulin sensitivity in dogs. We hypothesized that hypothyroidism causes insulin resistance.
Animals: Sixteen euthyroid bitches were randomly selected and allocated into two groups. In 8 dogs, hypothyroidism was induced by administration of 1 mCi/kg I-131. Experiments were performed on non-anesthetized, fasted dogs in anestrous approximately 12 months after hypothyroidism was induced.
Methods: The insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and minimal model analysis were used to determine basal insulin and glucose concentrations, acute insulin response to glucose (AIRg), insulin sensitivity (SI), glucose effectiveness (SG) and the disposition index (DI).
Results: In the hypothyroid group, basal glucose concentrations were mildly decreased (P = 0.0079), whereas basal insulin was increased (P = 0.019). Insulin sensitivity was reduced in the hypothyroid group (P<0.001), whereas AIRg was higher (P=0.01). Other parameters were not different between groups.
Conclusions/Clinical Importance: Hypothyroidism negatively affects glucose homeostasis by inducing insulin resistance. In hypothyroid dogs, the disposition index (insulin sensitivity x insulin secretion) remained unchanged due to a compensatory increase in insulin secretion, thereby maintaining glucose tolerance. In cases with impaired insulin secretion, such as canine diabetes mellitus, concurrent hypothyroidism can have important clinical implications in the successful management of the disease.Master of Science
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Sah, Pri Azurahisham. "Analysis, development and management of glucose-insulin regulatory system for out of hospital cardiac arrest (ohca) patients, treated with hypothermia." Thesis, University of Canterbury. Mechanical Engineering, 2015. http://hdl.handle.net/10092/10498.
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Hyperglycaemia is prevalent in critical care and increases the risks of further complications and mortality. Glycaemic control has shown benefits in reducing mortality. However, due in parts to excessive metabolic variability, many studies have found it difficult to reproduce these results. Out-of-Hospital Cardiac Arrest (OHCA) patients have low survival rates and often experience hyperglycaemia. However, these patients belongs to one group who has shown benefit from accurate glycaemic control (AGC), but can be highly insulin resistant and variable, particularly on the first two days of stay.
Hypothermia is often used to treat post-cardiac arrest patients or out of hospital cardiac arrest (OHCA) and these same patients often simultaneously receive insulin. In general, it leads to a lowering of metabolic rate that induces changes in energy metabolism. However, its impact on metabolism and insulin resistance in critical illness is unknown, although one of the adverse events associated with hypothermic therapy is a decrease in insulin sensitivity and insulin secretion. However, this decrease may not be notable in the cohort that is already highly resistant and variable. Hence, understanding metabolic evolution and variability would enable safer and more accurate glycaemic control using insulin in this cohort.
OHCA patients were undergone preliminary analysis during cool and warm, which includes insulin sensitivity (SI), blood glucose (BG), and exogenous insulin and dextrose. Patients were analysed based on overall cohort, sub-cohorts, and 6 and 12 hour time block. Generally, the results show that OHCA patients had very low metabolic activity during cool period but significantly increased over time. In contrast, BG is higher during cool period and decreased over time. The analysis is equally important as the controller development since it provides scientific evidence and understanding of patients’ physiology and metabolic evolution especially during cool and warm.
Model-based methods can deliver control that is patient-specific and adaptive to handle highly dynamic patients. A physiological ICING-2 model of the glucose-insulin regulatory system is presented in this thesis. This model has three compartments for glucose utilisation, effective interstitial insulin and its transport, and insulin kinetics in blood plasma, with emphasis on clinical applicability. The predictive control for the model is driven by the patient-specific and time-varying insulin sensitivity parameter. A novel integral-based parameter identification enables fast and accurate real-time model adaptation to individual patients and patient condition.
Stochastic models and time-series methods for forecasting future insulin sensitivity are presented in this thesis. These methods can deliver probability intervals to support clinical control interventions. The risk of adverse glycaemic outcomes given observed variability from cohort-specific and patient-specific forecasting methods can be quantified to inform clinical staff. Hypoglycaemia can thus be further avoided with the probability interval guided intervention assessments.
Simulation studies of STAR-OHCA control trials on ‘virtual patients’ derived from retrospective clinical data provided a framework to optimise control protocol design in-silico. Comparisons with retrospective control showed substantial improvements in glycaemia within the target 4 - 7 mmol/L range by optimising the infusions of insulin. The simulation environment allowed experimentation with controller parameters to arrive at a protocol that operates within the constraints found earlier during patient analysis.
Overall, the research presented takes model-based OHCA glycaemic control from concept to proof-of-concept virtual trials. The thesis employs the full range of models, tools and methods to optimise the protocol design and problem solution.