Made available in DSpace on 2014-06-11T19:29:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-10Bitstream added on 2014-06-13T20:20:18Z : No. of bitstreams: 1 neves_hm_me_botfm.pdf: 1895405 bytes, checksum: d93ed4db6e670953f5e8d484e472c07b (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A exposição do feto à hiperglicemia materna leva à hiperinsulinemia fetal, podendo causar aumento de células adiposas com posterior obesidade e resistência insulínica infantil. O resultado pode ser o aparecimento do diabete na vida adulta. O excessivo crescimento fetal visto em mães hiperglicêmicas é mediado pela hiperinsulinemia fetal provocada pelo excesso de glicose ou nutrientes que atravessam ou são secretados pela placenta e potencialmente modificado por fatores genéticos. A maioria dos órgãos fetais é afetada pela macrossomia que comumente caracteriza o feto de mulheres hiperglicêmicas, com exceção do cérebro. Esta pesquisa foi planejada para medir o volume renal fetal em gestantes com taxas de glicemia normal e em gestantes com glicemia alterada e verificar se o crescimento renal é afetado pela hiperglicemia materna, através de um estudo longitudinal que realizou e comparou curvas de volume renal, estimados pela equação da elipse, em fetos de 339 gestantes consideradas como normoglicêmicas e de 92 gestantes hiperglicêmicas atendidas no ambulatório de pré-natal do Hospital Geral de Nova Iguaçu. Também teve por objetivo obter equações de referência que pudessem predizer a idade gestacional em função dos volumes renais em gestações normais e sob efeito dos distúrbios hiperglicêmicos. O volume renal dos fetos de gestantes hiperglicêmicas se mostrou estatisticamente maior que o volume renal dos fetos de gestantes normoglicêmicas. O percentil 50 da curva de volume renal fetal das gestantes hiperglicêmicas está acima do percentil 75 da curva de volume renal fetal das gestantes normoglicêmicas, caracterizando organomegalia fetal. Dessa forma, foi possível estabelecer um padrão de crescimento renal para gestantes hiperglicêmicas de acordo com a idade gestacional que pode ser incorporada como modelo para datar idade gestacional após 22 semanas na prática da ultrassonografia. / The exposure of the fetus to maternal hyperglycemia leads to fetal hyperinsulinemia, that could cause adipose cells to increase with later childhood obesity and insulin resistance. The result can be the onset of diabetes in adulthood. The excessive fetal growth seen in mothers with hyperglycemia is mediated by fetal hyperinsulinemia caused by excess of glucose or nutrients that traverse or are secreted by placenta and potentially modified by genetic factors. Most fetal organs are affected by macrosomia which commonly characterizes the fetus of maternal hyperglycemia, with the exception of the brain. This research was designed to measure the fetal renal volume in pregnant women with normal levels of blood glucose and in pregnant women with altered glucose and verify whether renal growth is affected by maternal hyperglycaemia, through a longitudinal study that conducted and compared curves of renal volume, estimated by the equation of the ellipse, in fetuses of 339 pregnant women considered normoglycemic and 92 hyperglycemic pregnant women seen at prenatal clinic of the Hospital Geral de Nova Iguaçu (General Hospital of Nova Iguaçu). It also had the objective of obtaining reference equations that could predict gestational age in terms of renal volumes in normal pregnancies and under the effects of hyperglycemic disturbances. The renal volume of fetuses of hyperglycemic pregnant women was statistically greater than the renal volume of the fetuses of normoglycemic pregnant women. The 50th percentile curve of fetal renal volume of hyperglycemic pregnant women is above the 75th percentile curve of fetal renal volume of the pregnant normoglycemic, characterizing fetal organomegaly. Thus, it was possible to establish a pattern of renal growth in hyperglycemic pregnant women according to gestational age that may be incorporated in the practice of ultrasound as a model for dating gestational age after 22 weeks.

Diabetes has afflicted 8.3%, approximately 25.8 million, of the United States population and is the seventh leading cause of death [1]. Type I diabetes (T1D) accounts for 5 to 10% of all diagnosed cases of diabetes in the United States [2]. If present trends continue, the rate of T1D incidence among children under the age of 14 will increase by 3% globally [3]. T1D is an autoimmune disorder in which the β-cells of the pancreatic islets are destroyed, leading to high blood sugar. Hyperglycemia and loss of immunological tolerance to self-antigens are common associations of T1D [4]. Periodontal disease impacts as much as 47% of the U.S. population and is a significant cause for tooth loss in adults [5]. Chronic infections from bacterial populations that colonize the tooth root surface result in the activation of immunological mediators and various metabolic byproducts, such as cytokines, chemokines, and tissue-destructive enzymes [6, 7]. Studies have demonstrated that the increased systemic inflammation associated with periodontal disease appears to contribute to several systemic diseases, particularly diabetes [8, 9], with a strong, bi-directional, relationship between diabetes and periodontal disease in which glycemic control is a major determinant. Improved biomarkers for T1D prediction are needed. Cytokines serve an important part in the onset of T1D and strongly determine the ultimate fate of β cell destruction [10]. Such cytokines include interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Th1 cytokines such as IL-1β, IFN-γ, and TNF-α have been demonstrated to induce pancreatic β-cell apoptosis. Matrix metalloproteinases (MMPs) have been demonstrated to participate in the pathogenesis of periodontitis. Hence, the measurement of these inflammatory cytokines and MMPs may serve as a marker for the onset or progression of T1D and glycemic control. There have been no previous studies describing the distribution of salivary biomarkers of inflammation in T1D. Saliva represents a suitable bioreservoir for cytokines and can be collected noninvasively with very little to no stress upon the donor allowing for multiple collections if needed and it is easy to collect, store, and transport [11], however there are circadian patterns that must be accounted for. Therefore, we measured the levels of cytokines and MMPs in the saliva of T1D patients, characterized diurnal patterns of salivary cytokines in healthy subjects, and explored sources of inflammation to increase our understanding of salivary biomarkers of inflammation as a prediction of the progression of T1D and gum health and glycemic control. This work demonstrated that specific salivary inflammatory markers - MMP-8, MMP-9, and TNF-α - in T1D subjects are associated with decreased glycemic control. Diurnal patterns of salivary proteins must be accounted for upon collection due to the unique rhythms of cytokine expression within each individual. Upon glucose stimulation, pro-inflammatory (Th2) cytokines, such as IFN-γ and IL-13, tend to decrease, whereas anti-inflammatory (Th1) cytokines, such as IL-10, tend to increase. Hyperglycemic conditions may promote an anti-inflammatory profile of human submandibular gland cells.

Em diferentes mopdelos, o aumento dos níveis séricos de glicose pode ativar cascatas de sinalização envolvendo receptores semelhantes a Toll, o fator de transcrição NF-kB, moléculas da familia NLRP, ASC e caspase-1, que culminam na produção, ativação e liberação de moléculas inflamatórias. Investigamos o perfil inflamatório sérico e placentário em gestantes com distúrbios glicêmicos e a possível participação da via do inflamassoma NLRP1 e NRLP3 para o estabelecimento desse perfil. Para avaliar o papel da hiperglicemia no estabelecimento desse perfil, a via do inflamassoma foi também estudada em explantes de vilos coriônicos tratados com 100, 200, 300 e 400 mg/dL de glicose. Nossos resultados mostraram aumento na ativação de NF-kB e da expressão de NLRP1, NLRP3, ASC e Caspase-1 nas placentas de gestantes hiperglicemicas e nas culturas tratadas com doses de 300 r 400 mg/dL de glicose. Esses dados sugerem que a ativação da via do inflamassoma na porção fetal da placenta contribui para o processo inflamatório nessas pacientes. / In different models, the increase in serum glucose levels can activate signaling cascades involving Toll-like receptors, the transcription factor NF-kB, NLRP proteins, ASC and caspase-1, which culminate in the production, activation and release of inflammatory molecules . We investigated the serum and placental inflammatory profile in pregnant women with glucose disorders and the possible participation of via the NLRP1 and NRLP3 inflammasome to establish this profile. To evaluate the role of hyperglycemia, molecules of the inflammasome pathway was also studied in explants of chorionic villi treated with 100, 200, 300 and 400 mg / dL glucose. Our results showed an increase in NF-kB activation and expression of NLRP1, NLRP3, ASC and Caspase-1 in placentas of pregnant hyperglycemic women and in cultures treated with 300 and 400 mg / dL glucose. These data suggest that the inflammasome activation of the fetal portion of the placenta contributes to the inflammatory process in these patients.

Pregnancies complicated with diabetes mellitus (DM) are associated with poor maternal and fetal outcomes, such as birth trauma, fetal overgrowth (macrosomia) and programming of the fetus to develop metabolic syndrome in adult life. Maternal hyperglycemia is thought to contribute to fetal macrosomia, however the role of the placenta in these pregnancies is incompletely understood, therefore we aimed to investigate the specific consequences of high glucose on placental metabolism. To achieve this aim an in vitro model of placental exposure to high glucose was developed. This model was used with the aim of analysing how high glucose alters the transcriptome and metabolome of these cells, using a systems biology approach to identify candidate functional pathways which may be altered in placenta as a result of hyperglycemia. These candidate functional pathways were validated in an ex vivo model of placenta exposed to high glucose and in placental tissue from pregnancies complicated by DM. A trophoblast cell line (BeWo) was cultured in low (5 mM) and high (12 mM or 25 mM) D-glucose conditions for 48 hours. Transcriptomic and metabolomic analysis of these cells was performed using microarrays, and gas- and liquid-chromatography-mass spectrometry, respectively. Transcript and metabolite changes were independently analysed and integrated, using network analysis. From the integrated analysis of the ‘omic datasets, β-fatty acid oxidation (β-FAO), purine metabolism, phosphatidylinositol/PI3K phosphate pathway and lipid metabolism, were identified as candidates for further study. Changes within the PI3K pathway and lipid metabolism/β-fatty acid oxidation were validated in an ex vivo placental explant model of high glucose and in placental tissue from women with DM, compared to uncomplicated pregnancies. mRNA, protein expression and protein activation of key molecules within the PI3K pathway were not significantly altered in placenta as a response of high glucose ex vivo or DM in vivo. The second candidate functional pathway, lipid metabolism, has previously been implicated in association with placental dysfunction in pregnancies complicated by DM. Placental fatty acid transporter and lipase protein expression, as well as, relative abundance of different fatty acids were unaltered in response to high glucose or DM. High glucose levels increased triglyceride levels within the placenta, indicating reduced rates of β-FAO. The effect of high glucose could be ameliorated using a PPARα agonist. This may provide a novel therapeutic intervention to prevent excess esterification of fatty acids to triglycerides in maternal diabetes, which may in turn influence fetal growth. This study illustrates how a systems biology approach can be used to identify novel candidate functional pathways that are altered within the trophoblast in response to high glucose. Thus, improving understanding of placental dysfunction in these pregnancies and providing novel candidate pathways for future study, which may represent potential therapeutic targets for intervention of fetal macrosomia in pregnancies complicated by DM.

No description available.

The occurrence of a functional intracellular renin-angiotensin system (RAS) has emerged as a new paradigm. Recently, we and others demonstrated intracellular synthesis of ANG II in cardiac myocytes and vascular smooth muscle cells that was dramatically stimulated in high glucose conditions. Cardiac fibroblasts significantly contribute to diabetes-induced diastolic dysfunction. The objective of the present study was to determine the existence of the intracellular RAS in cardiac fibroblasts and its role in extracellular matrix deposition. Neonatal rat ventricular fibroblasts were serum starved and exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent receptor-mediated uptake of ANG II. Under these conditions, an increase in ANG II levels in the cell lysate represented intracellular synthesis. Both isoproterenol and high glucose significantly increased intracellular ANG II levels. Confocal microscopy revealed perinuclear and nuclear distribution of intracellular ANG II. Consistent with intracellular synthesis, Western analysis showed increased intracellular levels of renin following stimulation with isoproterenol and high glucose. ANG II synthesis was catalyzed by renin and angiotensin-converting enzyme (ACE), but not chymase, as determined using specific inhibitors. High glucose resulted in increased transforming growth factor-β and collagen-1 synthesis by cardiac fibroblasts that was partially inhibited by candesartan but completely prevented by renin and ACE inhibitors. In conclusion, cardiac fibroblasts contain a functional intracellular RAS that participates in extracellular matrix formation in high glucose conditions, an observation that may be helpful in developing an appropriate therapeutic strategy in diabetic conditions.

Background: Caring for patients with malignancies and presenting hyperglycemia has been an ongoing problem that needed to be addressed. The Endocrinologist Society and the Joint British Diabetes Societies for Inpatient Care suggested a change in the process by which patients in this population are managed. Purpose: The purpose of this project was to implement evidence-based practice guidelines for managing steroid-induced hyperglycemia focusing on the interdisciplinary team and adaptation of nurses who care for patients with malignancies. Theoretical Framework: The theoretical framework selected for this project was Roy’s Adaptation Model. Methods: This project used a mixed method approach, with a triangulation design and incorporation of focus groups and a survey to evaluate the multidisciplinary team adaptation. Results: The results indicated that 93% of the team reported positive perceptions of adaptation to the change in blood glucose monitoring with this patient population. Dietary staff expressed some concern with their change in procedures to support the steroid-induced hyperglycemia protocol. Conclusion: This project demonstrated that the healthcare team can adapt to changes, that changes are difficult but needed to improve patients’ outcomes. The pursuit of evidence-based practice involves ongoing appraisal of current standards of care with patient outcomes for consideration of the need for change or a paradigm shift.

Doctor Educationis / Diabetes has since been a global epidemic; an estimated 5.0 million deaths of diabetes in the world have been recorded; one in 11 adults have diabetes (415 million); and by 2040, one adult in 10 (642 million) will have diabetes. In Africa, more than two thirds of people with diabetes are undiagnosed, and 42 million have diabetes in the Sub-Saharan region with 324 877 adult deaths in South Africa (IDF, 2015). The global prevalence (age-standardized) of diabetes has nearly doubled since 1980,rising from 4.7% to 8.5% in the adult population. This reflects an increase associated with risk factors such as overweight or obese (WHO, 2016). Medicinal plants on the other hand, have played a significant role in the treatment and prevention of diabetes for centuries. In South Africa, indigenous medicinal plants have increasingly been used in the treatment of diabetes. In this study, a new anti-diabetes herbal compound named Jiang Tang 2016 (JT2016), made of three well researched South African indigenous medicinal plants is investigated for its hypoglycemic effects in HFD/STZ induced diabetic SD rats. These plants have been used for centuries in the indigenous system of medicine against various ailments, they are easily accessible, they grow in abundance, and are economically sustainable. Aim The aim of this study was to investigate the hypoglycemic effects and safety of the anti- diabetes herbal compound, Jiang Tang 2016 (JT2016) in HFD/STZ induced diabetic SD rats

This study examined the rates and risks of premature neonates >2500grams developing intraoperative non-euglycemia events (IONEE). A retrospective chart review of 26 premature neonates >2500 grams who underwent surgical procedures between January 1 and December 31, 2009 was conducted. Statistical analysis was done using Chi square and t-tests. Ten of the 26 subjects (38%) experienced an IONEE. Hyperglycemia was the primary IONEE that was noted in the neonates. (Mean: 143.19; sd: 56.041) Length of surgery was significantly longer in those premature neonates with IONEE than those with euglycemia (71.7 0± 27.03 vs. 45.62 ± 17.98 minutes). All IONEE subjects received general anesthesia (n=10) while none of those with only intravenous anesthesia had an IONEE (X2 (1) = 4.875, p=.027). Subjects with IONEE had a higher mean preoperative glucose level (127.11 gm/dL ± 31.66) than those who did not experienced IONEE (86.36 gm/dL ± 29.39; t(21) = 3.151, p=.005). A higher proportion of subjects who developed IONEE had the capillary heel (60%) as opposed to an arterial (40%) site for blood collection (X2 (1) = 6.518, p =.001). Also, subjects free of preoperative pulmonary complications were more prone to develop IONEE (X2 (1)= 8.60, p = .003). The presence of IONEE was associated with development of metabolic acidosis (X2 (1)= 5.426, p=.020) and lower postoperative pH values (7.19 ± 0.20 vs. 7.35 ± 0.11). Anesthesia providers need to establish intraoperative guidelines for the monitoring and treatment of IONEE to protect these premature neonates from having complications such as developmental delay.

<p> Diabetes mellitus is a major independent risk factor for cardiovascular disease (CVD) and stroke, however the cellular mechanisms by which diabetes contributes to vascular dysfunction are not fully understood. In recent decades, multiple molecular mechanisms have been implicated in hyperglycemia-associated vascular damage and CVD [1]. It is well established that hyperglycemia promotes intracellular glucose flux through the hexosamine pathway where the rate-limiting enzyme, glutamine:fructose-6-phosphate amidotransferase (GFAT) produces glucosamine-6-phosphate [2,3]. We have shown that elevated levels of intracellular glucosamine cause ER stress and activation of the UPR in multiple cell types [4]. Additionally, we have previously shown that ER stress is associated with lipid accumulation, activation of inflammatory pathways, and is associated with atherosclerotic plaque formation in hyperglycemic mice [ 4,5]. We hypothesize that the accumulation of intracellular glucosamine, observed in conditions of hyperglycemia, promotes atherogenesis via a mechanism that involves the hexosamine pathway, protein glycosylation and ER stress.</p> <p> Using in vitro over-expression studies, we investigated the role of GFAT in hyperglycemia-associated ER stress. We developed methods to increase GFAT expression in both HepG2 cells and HASMC. However, we found that GFAT over-expression is insufficient to induce an ER stress response. Further investigation of this system suggests that the over-expressed GFAT does not increase intracellular glucosamine levels to sufficiently promote ER stress.</p> <p> We have also investigated the role of protein glycosylation in glucosamine-induced ER stress. We have shown that O-linked glycosylation plays a role in ER stress induction. We have also shown that N-linked protein glycosylation is affected by elevated cellular glucosamine levels. Thus, dysregulated glycosylation of newly synthesized proteins may contribute to the accumulation of unfolded protein in the ER and lead to the activation of the UPR.</p> / Thesis / Master of Science (MSc)