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Made available in DSpace on 2017-07-10T14:57:33Z (GMT). No. of bitstreams: 1 claudia_ lopes.pdf: 1090267 bytes, checksum: 0046c70242b43bfef4a590933029e9c2 (MD5) Previous issue date: 2016-04-06 / Periodontitis is often associated with diabetes mellitus (DM) and can be considered a chronic complications. Growing evidences suggests that periodontal disease has an adverse effect on glycemic control and an active role in the pathophysiology of complications related to DM, as in type 1 diabetes mellitus as in type 2 diabetes mellitus. Objective: Compare the response of basic periodontal therapy in diabetes patients with diabetes type 1 and type 2. Methodology: We selected 70 patients with periodontitis, these were divided into three groups: Control group (systemically healthy patients); Group test 1 (patients with type 1 diabetes mellitus); Group test 2 (patients with type 2 diabetes mellitus). The groups received basic periodontal treatment after clinical examination. The analyzis were performed at 0, 3 and 6 months, clinical parameters including periodontal and gingival crevicular amount of fluid. They were measured glycated hemoglobin (HbA1c) and prostaglandin E2 concentration. Results: There was an improvement in all clinical periodontal parameters evaluated in both groups as well as the amount of gingival crevicular fluid. It occurred more significant decrease (p<0,05) in HbA1c and PGE2 expression in group test 1, after 6 months. Conclusion: The basic periodontal treatment was more effective for glycemic control in patients with type 1 diabetes mellitus / A periodontite é frequentemente associada com diabetes mellitus (DM) e pode ser considerada uma das complicações crônicas da doença. Crescentes evidências apontam que a doença periodontal (DP) tem um efeito adverso sobre o controle glicêmico e uma participação ativa na fisiopatologia das complicações relacionadas ao DM, tanto no diabetes mellitus tipo 1(DM1) quanto no diabetes mellitus tipo 2 (DM2). Objetivo: Comparar a resposta do tratamento periodontal básico em pacientes portadores de diabetes mellitus tipo 1 e tipo 2. Metodologia: Foram selecionados 70 pacientes com periodontite, estes foram divididos em três grupos: Grupo controle (pacientes sistemicamente saudáveis); Grupo teste 1 (pacientes portadores de diabetes mellitus tipo 1); Grupo teste 2 (pacientes portadores de diabetes mellitus tipo 2). Os grupos receberam tratamento periodontal básico, após exame clínico. As análises foram realizadas aos 0, 3 e 6 meses, incluindo parâmetros clínicos periodontais e a quantidade de fluido crevicular gengival (GCF). Foram dosadas a hemoglobina glicada (HbA1c) e a concentração de prostaglandina E2 (PGE2) no GCF. Resultados: Houve melhora de todos os parâmetros clínicos periodontais avaliados em todos os grupos, bem como na quantidade de fluido crevicular gengival. Ocorreu diminuição mais expressiva (p<0,05) da HbA1c e da expressão de PGE2 no grupo teste 1, após 6 meses. Conclusão: O tratamento periodontal básico mostrou-se mais eficaz para o controle glicêmico dos pacientes portadores de diabetes mellitus tipo 1.

INTRODUÇÃO: Diabetes mellitus tipo 2 (DM2) é um fator de risco isolado para coronariopatia, principalmente quando associado à microalbuminúria (MA). Alterações estruturais e funcionais das lipoproteínas não são totalmente esclarecidas nesse contexto. OBJETIVO: Avaliar, em pacientes DM2, a influência da presença da MA e do tratamento com estatina ou insulina nas transferências para HDL (T) de lípides e no tamanho desta lipoproteína. MÉTODOS: Estudamos 33 pacientes DM2 e 34 controles pareados para idade. Uma nanoemulsão lipídica artificial radiomarcada com 3H-Triglicéride (TG) e 14C-Colesterol Livre (CL) ou 3H-Colesterol Éster (CE) e 14C-Fosfolípide (FL) foi incubada com plasma. A nanoemulsão e as lipoproteínas foram precipitadas, exceto a HDL, que teve sua radioatividade contada. O diâmetro da HDL foi mensurado por método de dispersão da luz. RESULTADOS: A TFL (%) foi maior no grupo com DM2 que no grupo controle (25,2±3,2 e 19,7±3,2 respectivamente; p<0,001), assim como a TCL (%): 9,1±2,7 e 6,3±1,5 respectivamente; p<0,001. O diagnóstico de MA não se associou às mudanças da propriedade de transferência. O uso da insulina associou-se à menor TFL(%): 23,5±2,1 contra 26,1±3,3; p=0,018. Já o uso da estatina associou-se à queda de todas: TCE(%): 3,5±0,9; TFL(%):23,8±2,0; TTG(%): 3,9±0,8; TCL(%):7,4±1,3 quando comparado ao grupo que não usava estatina (TCE(%):5,9±2,4; TFL(%):26,9±3,6; TTG(%):6,4±2,2; TCL(%):11,1±2,6). O tamanho de HDL foi semelhante em qualquer condição analisada. CONCLUSÕES: DM2 aumenta a transferência de lípides de superfície para HDL, enquanto o uso de estatina diminuiu todas as transferências. A presença de MA não se associou às alterações das transferências de lípides / INTRODUCTION: Type 2 diabetes mellitus (DM2) is an isolated risk factor for coronary artery disease, especially when associated to microalbuminuria (MA). Structural and functional alterations of lipoproteins are not well known in this context. OBJECTIVE: To evaluate, in DM2 patients, the influence both of MA and the treatment with statins or insulin on the lipids transfer to HDL (T) and on the size of this lipoprotein. METHODS: We studied 33 DM2 patients and 34 controls paired for age. An artificial lipidic nanoemulsion radio labeled with 3H-Triglyceride (TG) and 14C-Free Cholesterol (FC) or 3H-Cholesterol Ester (CE) and 14C-Phospholipid (PL) was incubated with plasma. The nanoemulsion and the lipoproteins were precipitated, except for HDL, that had its radioactivity measured. The HDL diameter was measured by laser light scattering method. RESULTS: The TPL (%) was greater in the DM2 group then in the control group (25,2±3,2 and 19,7±3,2 respectively; p<0,001), as well as TFC (%): 9,1±2,7 and 6,3±1,5 respectively; p<0,001. The MA did not affect the transfer. Insulinotherapy was associated with less TPL(%): 23,5±2,1 against 26,1±3,3; p=0,018, and the statin therapy with less transfer of all lipids: TCE(%): 3,5±0,9; TPL(%):23,8±2,0; TTG(%): 3,9±0,8; TFC(%):7,4±1,3 when compared to the group that did not use statin: TCE(%):5,9±2,4; TPL(%):26,9±3,6; TTG(%):6,4±2,2; TFC(%):11,1±2,6. The HDL size was about the same under all the circumstances analyzed. CONCLUSIONS: DM2 is associated with greater transfer of superficial lipids to HDL, while the statin usage was associated with a smaller transfer of all lipids. The MA diagnosis was not associated with any change in lipids transfer

This research explored health decision-making processes among people recently diagnosed with type 2 diabetes. Our analysis suggested that diagnosis with type 2 was followed by a period of intense emotional and cognitive disequilibrium. Subsequently, the informants were observed to proceed to health decision-making which was affected by three separate and interrelated factors: knowledge, self-efficacy, and purpose. Knowledge included cognitive or factual components and emotional elements. Knowledge influenced the degree of upset or disequilibrium the patient experienced, and affected a second category, agency: the informants’ confidence in their ability to enact lifestyle changes. The third factor, purpose, summarized the personal and deeply held reasons people gave as they made decisions concerning their health, eating and exercising. We propose this model, grounded in informant stories, as a heuristic, to guide further inquiry. From these stories, the patient is seen as more active and the interrelated influences of knowledge, agency, and purpose, synergistically interact to explain changes in health behaviors.

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Mon travail de thèse a été axé sur l'étude du rôle des lipides musculaires dans la régulation du métabolisme énergétique et la sensibilité à l'insuline. Les lipides sont présents sous deux formes au sein du muscle squelettique : soit sous forme d'adipocytes insérés entre les fibres/faisceaux musculaires, soit sous forme de gouttelettes lipidiques à l'intérieur des fibres musculaires (i.e. triglycérides intramyocellulaires ou IMTG). Ces deux dépôts de lipides, lorsqu'ils sont présents en excès, sont associés à la mise en place de l'insulino-résistance musculaire chez l'homme, via l'accumulation intracellulaire d'espèces lipidiques lipotoxiques altérant la signalisation insulinique pour les IMTG, et par un mécanisme inconnu pour les adipocytes. Dans un premier temps, nous avons isolé et mieux caractérisé, à partir de biopsies musculaires humaines, deux populations de cellules progénitrices. La première population présente un potentiel de différenciation myogénique en culture, il s'agit des cellules satellites (cellules progénitrices musculaires). La deuxième population est composée de cellules capables d'acquérir les propriétés phénotypiques et métaboliques d'adipocytes blancs matures, il s'agit des progéniteurs fibro/adipocytaires (FAPs). Grace à ces modèles d'étude, nous avons mis en évidence que les sécrétions des adipocytes dérivés des FAPs sont capables d'altérer la voie de signalisation et les effets de l'insuline sur des fibres musculaires humaines in vitro. Cet effet paracrine pourrait en partie expliquer la corrélation négative observée entre le contenu en adipocytes intramusculaires et la sensibilité à l'insuline chez l'homme. Dans un second temps, nous avons étudié le rôle de deux protéines, G0/G1 Switch Gene 2 (G0S2) et la périlipine 5 (PLIN5), dans la dynamique des gouttelettes lipidiques ainsi que leur impact sur le métabolisme des lipides et la sensibilité à l'insuline. Nous avons montré in vitro que ces deux protéines jouent un rôle clé dans le contrôle de la lipolyse musculaire (i.e. hydrolyse des IMTG) via l'adipose triglyceride lipase (ATGL, enzyme limitante de la lipolyse musculaire), et que G0S2 et PLIN5 inhibent l'activité de l'ATGL par des mécanismes directs et indirects, respectivement. Par ailleurs, nos données ont montré que l'invalidation de G0S2 et PLIN5 dans le muscle squelettique active la lipolyse, augmente la lipotoxicité et diminue la sensibilité à l'insuline in vivo chez la souris. Nous avons également démontré un rôle important de PLIN5 dans la régulation de l'oxydation des acides gras en ajustant finement leur disponibilité aux besoins énergétiques des cellules. En résumé, ces travaux démontrent d'une part qu'une communication entre adipocytes et fibres au sein du muscle peut entraîner une altération de la sensibilité à l'insuline musculaire chez l'homme, et d'autre part que G0S2 et PLIN5, deux protéines de la gouttelette lipidique, sont au centre du contrôle de l'homéostasie lipidique et du maintien de l'insulino-sensibilité musculaire. Ces données permettent ainsi d'élargir les connaissances existantes sur le lien entre les lipides musculaires et la sensibilité à l'insuline chez l'homme. / My PhD research work was focused on the role of muscle lipids in the regulation of energy metabolism and insulin sensitivity. Lipids can be found under two different forms in skeletal muscle: adipocytes located between muscle fibers/bundles and lipid droplets inside muscle fibers (i.e. intramyocellular triacylglycerols or IMTG). These depots, when present in excess, have both been associated with insulin-resistance in humans, mainly because of intracellular lipotoxic lipid accumulation known to impair insulin signaling for IMTG, and through a yet unknown mechanism for adipocytes. First, we isolated and characterized two distinct populations of progenitor cells from human muscle biopsies. The first population is composed of satellite cells (muscle progenitor cells) and display a myogenic differentiation potential in vitro. The second population is composed of cells that acquire the phenotypic and metabolic properties of functional white adipocytes, called fibro/adipogenic progenitors (FAPs). By using these cell models, we showed that FAPs-derived adipocytes secretions are able to impair insulin signaling and action in human skeletal muscle fibers in vitro. This paracrine effect could explain, at least partly, the inverse relationship observed between intramuscular adipocyte content and insulin sensitivity in humans. Secondly, we studied the role of two proteins, G0/G1 Switch Gene 2 (G0S2) and perilipin 5 (PLIN5), in lipid droplets dynamics as well as their impact on lipid metabolism and insulin sensitivity. We showed in vitro that these two proteins play a key role in the control of muscle lipolysis (i.e. IMTG hydrolysis) via the adipose triglyceride lipase (ATGL, catalyzing the limiting step of muscle lipolysis), and that G0S2 and PLIN5 inhibit ATGL activity through direct and indirect mechanisms, respectively. Furthermore, our data showed that G0S2 and PLIN5 invalidation in vivo in mouse skeletal muscle activates lipolysis, increases lipotoxicity and impairs insulin sensitivity. We have also highlighted an important role for PLIN5 in the regulation of fatty acids oxidation, by finely adjusting their availability to energy demand. Overall, these results clearly show on one hand that a crosstalk between adipocytes and fibers within skeletal muscle can lead to an alteration of insulin sensitivity in humans, and on the other hand that G0S2 and PLIN5, two lipid droplet proteins, play a central role in the control of muscle lipid homeostasis and insulin sensitivity. These data help to develop our current understanding of the link between muscle lipids and insulin sensitivity in humans.

Diabetes has become a longstanding public health challenge around the world. Over the last 3 decades, the number of people with Type II diabetes (T2DM) has grown to an epidemic level in Canada. Prior research indicated African immigrants residing in Ontario, Canada experienced a 2-4 times higher prevalence of T2DM than Canadian-born individuals. The social determinants of health theoretical framework guided this study assessing the relationship of the risk factors with T2DM. A quantitative, cross-sectional design was employed using the 2007-2014 Canadian Community Health Survey data. The random sample included 1,526 African immigrants residing in Ontario, Canada. Descriptive, bivariate, and multivariate analyses were conducted. Study results indicated a lower income level, high acculturation index, and a country of origin significantly associated with T2DM in adjusted and unadjusted binary logistic regression models. Using the results of the study to create a valid and reliable acculturation measurement scale and a cultural-based design of public health programs, increase awareness, and change policies that consider the needs of the sample populations could lead to positive social change by curbing the prevalence of T2DM observed in African immigrants residing in Ontario and Canada at large.

研究目的：本研究使用共通信念模式，以瞭解第二型糖尿病患者持有的疾病表徵對自我照護行為的預測關係。過去的研究顯示，糖尿病患者的「控制」表徵能夠有效預測患者的自我照護行為和糖化血色素值；也就是，患者相信疾病能被控制的程度愈高，在自我照護行為的表現愈好，糖化血色素值愈低。但是，「結果」表徵與「情緒」表徵無法顯著一致的預測患者的自我照護行為。透過回顧與健康行為相關的理論發展與文獻，考量慢性疾病的自我調節歷程中，除了疾病表徵以外，還需要納入與自我意識有關的人格特質。為此，本研究目的有四:(1)先檢驗在台灣糖尿病患者的疾病表徵建構，是否與國外使用疾病共通信念模式的研究結果一致，有相同的因素結構。(2)檢定台灣第二型糖尿病患者，其持有的疾病表徵對自我照護行為與血糖控制的預測，是否與Harvey和Lawson(2009)的研究結果一致。(3)評估糖尿病患者的人格特質對自我照護行為與糖化血色素值的影響。(4)探索第二型糖尿病患者反芻反思特質，在疾病表徵影響自我照護行為上的調節效果。 研究方法：本研究以立意取樣的方式，邀請新竹某教學醫院門診的第二型糖尿病患者為受試。排除漏答與亂填者，共有142位符合資格的受試者；每位受試者皆需完成受試者同意書、背景資料、糖尿病自我照護量表、疾病表徵問卷與中文版反芻反思量表。根據研究目的，以階層回歸和羅吉斯回歸分析等統計方法進行假設考驗。 研究結果：(1)臺灣第二型糖尿病患者的疾病表徵結構與國外患者相似，共包含：「認同」、「病因」、「時間感急慢性」、「時間感循環性」、「結果」、「情緒」和「控制」表徵。(2)研究結果與Harvey和Lawson(2009)的研究結果一致，「控制」表徵可以顯著預測整體自我照護行為和糖化血色素值。(3)第二型糖尿病患者的反芻反思特質，無法單獨預測自我照護行為與糖化血色素值。(4) 第二型糖尿病患者的反芻反思特質會與病表徵產生交互作用，共同調節各種自我照護行為的表現。 結論：本研究資料與其他使用共通信念模式的研究資料一致，亦即控制表徵能預測自我照護行為和糖化血色素值。此外，本研究發現，不同自我照護行為會受到疾病表徵與反芻或反思特質的交互作用而影響。由於，增加自我照護行為的執行度，是目前糖尿病治療與衛教的首要目標。建議未來從事糖尿病照護的實務工作者，能提供疾病表徵與反芻反思特質的專業心理評估；以協助建立個別評估與個別介入的個別化治療方案，進而提高患者在自我照護行為的執行度、增加臨床治療的效果。 / Background and Aims. It is increasingly being used to understand and predict individuals' coping with and subsequent self-care of chronic illness is Leventhal and colleagues' the common sense model. This model postulates that it is the individual's illness representation is the proximal determinant of coping behavior. The role of personality in determining self-care behavior has been relatively ignored, possibly because of the lack of convergence in concepts and measures. Due to the lack of research in the area of interest, the present study attempt to resolve this issue. We investigated, (a) using subjects of Type-II diabetes in Taiwan, are the results of present study similar as others studies directed by common sense model to identify the factors of illness representation, (b) discussing the influences of illness representation to self-care behavior and glycemic control (HbA1c); like as Harvey and Lawson(2009)’s study, (c) assessing whether traits of normal personality are associated with variations in self-care behavior and glycemic control in patients with type 2 diabetes, (d) examining whether personality moderate the relationships between illness representations and self-care behavior. Methods. Patients were eligible if they had Type 2 diabetes, were aged 20 years or more at diagnosis. Before we collect data, a physician will invite patient to enter the study. Patient want to join this study, they be giving an informed consent and be asked to complete four questionnaires. A total 142 patients completed the demographic survey ( age, educational level, diabetes duration et al.), Diabetes Self-Care Scale, the Revised Illness Perception Questionnaire(IPQ-R), the Chinese version of Rumination- Reflection Questionnaire. Analysis were concluded using multiple regression analysis, logistic regression and so on. Results. The results revealed that: (1) as our hypothesis, the structures of the IPQ-R in type 2 diabetes in Taiwan were similar as other foreign studies directed by common sense model. (2) Control representation can induce main effect on self care behavior. Higher control representation was significantly positive associated with self care behavior, and it was significantly negative associated with HbA1c. (3) Self reflection and self rumination were inconsistently associated with self care behavior and HbA1c. (4) Personality moderated the relationships between illness representations and self-care behavior. Conclusions. This study supports the Common Sense Model (CSM) of illness representation when considering type 2 diabetes in Taiwan. Based on our results, we found personality traits may offer new insights in to variations in self-care in patients with type 2 diabetes undergoing standard management. Personality refers as self-reflection and self-rumination which moderated the relationships between illness representations and self-care behavior. Therefore, CSM could become the theoretical framework for psychological interventions in type 2 diabetes. Furthermore, according to the study result, we suggested the practitioners paying attention to the different interaction when representation and personality are together in diabetes’ each self-care behavior.

<p>During development of type 1 and type 2 diabetes plasma insulin patterns are altered. Since the islet insulin release pattern has been implicated in this development, insulin secretion from single islets was studied and linked to the islet protein levels of uncoupling protein-2 (UCP2). Islets were isolated from NOD- and KKA^y- mice, GK- and GK-derived congenic rats, which are animal models of diabetes, and three human subjects with type 2 diabetes. At basal glucose (3 mM), insulin release from such islets was pulsatile and the amount released was comparable to that of control islets. When the glucose concentration was raised to 11 mM insulin release was essentially unchanged in islets isolated from older NOD- and KKA^y- mice, GK- and Niddm1i congenic rats, and NIDDM persons. In islets from Niddm1f congenic rats, younger NOD- and KKA^y-mice, control animals and normal human donors the secretion rate increased 2-9 fold when the glucose concentration was raised. This rise in secretion was manifested as increase of the amplitude of the insulin oscillations without affecting their frequency. Impaired glucose-induced insulin release was associated with reduction in glucose oxidation measured in NOD-islets, unaffected respiration measured in GK-islets and higher protein level of UCP2 measured in KKA^y-islets. When the UCP2 amounts in KKA^y-islets were reduced by culture to those of control islets, glucose-induced insulin secretion was essentially normalized. Our studies suggest that the deranged plasma insulin patterns observed in diabetes are related to decrease in the amplitude of insulin oscillations from the islets rather than loss of the oscillatory activity. This reduction of pulse amplitude may be related to impaired glucose metabolism and/or increased mitochondrial uncoupling. </p>

<p>Population pharmacokinetic-pharmacodynamic (PK-PD) models can be fitted using nonlinear mixed effects modelling (NONMEM). This is an efficient way of learning about drugs and diseases from data collected in clinical trials. Identifying covariates which explain differences between patients is important to discover patient subpopulations at risk of sub-therapeutic or toxic effects and for treatment individualization. Stepwise covariate modelling (SCM) is commonly used to this end. The aim of the current thesis work was to evaluate SCM and to develop alternative approaches. A further aim was to develop a mechanistic PK-PD model describing fasting plasma glucose, fasting insulin, insulin sensitivity and beta-cell mass.</p><p>The lasso is a penalized estimation method performing covariate selection simultaneously to shrinkage estimation. The lasso was implemented within NONMEM as an alternative to SCM and is discussed in comparison with that method. Further, various ways of incorporating information and propagating knowledge from previous studies into an analysis were investigated. In order to compare the different approaches, investigations were made under varying, replicated conditions. In the course of the investigations, more than one million NONMEM analyses were performed on simulated data. Due to selection bias the use of SCM performed poorly when analysing small datasets or rare subgroups. In these situations, the lasso method in NONMEM performed better, was faster, and additionally validated the covariate model. Alternatively, the performance of SCM can be improved by propagating knowledge or incorporating information from previously analysed studies and by population optimal design.</p><p>A model was also developed on a physiological/mechanistic basis to fit data from three phase II/III studies on the investigational drug, tesaglitazar. This model described fasting glucose and insulin levels well, despite heterogeneous patient groups ranging from non-diabetic insulin resistant subjects to patients with advanced diabetes. The model predictions of beta-cell mass and insulin sensitivity were well in agreement with values in the literature.</p>