Orientadores: Marcio Alberto Torsoni, Licio Augusto Velloso. / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T13:06:52Z (GMT). No. of bitstreams: 1 Roman_ErikaAnnedeFreitasRobles_M.pdf: 1187613 bytes, checksum: 8b00d8dfa387e6f44b19ac7220351d8e (MD5) Previous issue date: 2006 / Resumo: A exposição de animais homeotérmicos ao frio leva a uma poderosa ativação da sinalização anorexigênica, acompanhada por resistência molecular e funcional à inibição da alimentação induzida pela insulina. Evidências recentes sugerem que a AMPK participa do controle da saciedade e da adiposidade, dependente de nutriente. O objetivo do presente estudo foi avaliar o efeito da exposição ao frio sobre a ativação molecular da sinalização da AMPK em hipotálamo de ratos. Immunoblotting demonstrou que a exposição ao frio por si é suficiente para induzir, em um modelo tempo dependente, a ativação molecular da serina/treonina quinase, proteína quinase ativada por AMP (AMPK) e a inativação da acetil-CoA carboxilase (ACC). Estes fenômenos moleculares foram acompanhados pela resistência à inativação da AMPK e pela ativação da ACC, dependentes de nutrientes. Além disso, a exposição ao frio levou a uma inibição parcial da resposta anorexigênica induzida pela alimentação, a qual foi acompanhada pela resistência à supressão da alimentação induzida pela insulina. Finalmente, a exposição ao frio prejudicou significativamente a inibição da AMPK, induzida pela insulina, através de um mecanismo dependente do ¿cross-talk¿ molecular entre fosfatidilinositol-3(PI3)-quinase/Akt e AMPK. Como conclusão, a hiperfagia durante a exposição ao frio resulta, pelo menos em parte, da resistência hipotalâmica à sinalização anorexigênica dependente de nutrientes e insulina / Abstract: The exposure of homeothermic animals to a cold environment leads to a powerful activation of orexigenic signalling which is accompanied by molecular and functional resistance to insulin-induced inhibition of feeding. Recent evidence suggests that AMPK participates in nutrient-dependent control of satiety and adiposity. The objective of the present study was to evaluate the effect of cold exposure upon the molecular activation of AMPK signalling in the hypothalamus of rats. Immunoblotting demonstrated that cold exposure per se is sufficient for inducing, on a time-dependent basis, the molecular activation of the serine/threonine kinase AMP-activated protein kinase (AMPK) and inactivation of the acetyl-CoA carboxylase (ACC). These molecular phenomena were accompanied by resistance to nutrient-induced inactivation of AMPK and activation of ACC. Moreover, cold-exposure led to a partial inhibition of a feeding-induced anorexigenic response, which was paralleled by resistance to insulin-induced suppression of feeding. Finally, cold exposure significantly impaired insulin-induced inhibition of AMPK through a mechanism dependent on the molecular cross-talk between phosphatidylinositol-3(PI3)-kinase/Akt and AMPK. In conclusion, increased feeding during cold exposure results, at least in part, from resistance to insulin¿ and nutrient-dependent anorexigenic signalling in the hypothalamus / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

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

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Student: Monika Dobrovodová Supervisor of master thesis: PharmDr. Miroslav Kovařík, Ph.D. Advisor of master thesis: prof. MUDr. Karel Martiník, DrSc. Title of master thesis: Relation among BMI, hyperinsulinemia and selected biochemical indicators This thesis is focussed on specification of relations among BMI, insulinemia, age of the patients, C-peptid blood levels and glycemia and also searching relations among selected parameters of lipid spectrum in group of selected patients. Measuring of body height and weight and investigation of fasting glycemia, insulinemia, total cholesterolemia, blood levels of HDL and LDL and also C-peptid were done at 3472 patients. Afterwards few basic indexes of insulin resistance and sensitivity were counted. In this group was proven, that fasting insulinemia and C-peptid levels are increasing in according to increasing BMI. Also fasting glycemia is increasing modestly. Insulin resistance and sensitivity indexes used in this theses depends on BMI. Although statistically significant differences between age groups were proven according to insulin resistance and sensitivity indexes, we can't see clearly increasing or decreasing tendency in according to...

Periodontal inflammation is a hallmark of periodontitis and a primary driver of progressive periodontal tissue destruction. In addition, inflammation is hypothesized as a critical mechanistic intermediate linking periodontal disease to systemic inflammation and extra-oral disease outcomes. However, most of the commonly used measures of periodontitis, for research and/or surveillance purposes, focus on quantifying the periodontal tissue loss (i.e., gingival recession (GR) and clinical attachment loss (CAL)). There are few indices that focus on quantifying periodontal inflammation in the periodontal literature, and there are inherent limitations in the way they are calculated. The Periodontal Inflamed Surface Area (PISA) is a composite measure that incorporates bleeding on probing (BOP) and other measures of periodontal disease to quantify the amount of periodontal inflamed surfaces. This dissertation examined PISA as a useful measure that attempted to quantify periodontal inflammation, and it is divided into three parts. The first paper is a scoping review focused on reviewing the relevant literature around PISA since its introduction to the literature in 2008. The second paper is an empirical paper that examined the psychometric properties of PISA compared to other measures of periodontitis. The third paper is another empirical study that explored how PISA correlated with some biological features of periodontitis, including the subgingival microbial profile, systemic immune response, and selected dysbiosis indices. The empirical papers utilized data from two population-based cohorts: the Oral Infections, Glucose Intolerance, and Insulin Resistance Study (ORIGINS) and the Washington Heights Inwood Community Aging Project's Ancillary Study of Oral Health (WHICAP-OH). The review found that PISA was primarily utilized in studies that looked at oral-systemic health connections, with results that mostly confirmed the associations between periodontal disease and systemic health. However, most evidence suffered from methodological concerns that could limit the validity and generalizability of results. The psychometrics analyses showed that PISA had good sensitivity, specificity, and accuracy in identifying patients with periodontitis. The latent factor analyses suggested a multi-level three-factor model showing PISA to cluster with bleeding on probing in the same factor that indicates an inflammation component of the unobserved periodontal disease status. The third paper showed that PISA was significantly associated with alpha diversity indices (Shannon's, Simpson's, and Faith's phylogenetic diversity) and two of the dysbiosis indices in both cohorts. The strength of associations and amount of variance explained in some of the biological features were higher for PISA than other measures of periodontitis. The evidence from this dissertation suggests that PISA is a valuable index that describes periodontal inflammation and has good psychometric properties. Future research can explore the replication of our methods in other cohorts to expand the validity and utility of PISA in periodontal literature.

Aim: To evaluate the association between elevated serum transaminase levels and insulin resistance (IR) in a population of healthy individuals. Methods: We define IR with a cut-off point of homeostatic model assessment (HOMA-IR) ≥ 3.8. For aspartate aminotransferase (AST), we consider elevated values >30 U/L in women and values >36 U/L in men. For alanine aminotransferase (ALT), we consider elevated values >30 U/L in women and values >40 U/L in men. We performed a crude and adjusted generalized linear model from Poisson family with robust variance, in order to evaluate the association between elevated serum transaminase levels and IR. The associations were presented as prevalence ratio (PR) with their respective 95% confidence intervals (95% CI). Results: We included 261 participants in the study. The median age was 39 years (31–45) and 23.7% of the participants were men. The prevalence of elevated serum transaminase for AST and ALT were, 13.8% and 26.1%, respectively. The prevalence of IR was 34.1%. In the crude analysis we found statistical significance between elevated AST and ALT with IR (PR = 3.18; 95% CI: 2.33–4.34 and PR = 2.44; 95% CI: 1.88–3.30; respectively). However, in the multivariate analysis, the association only remained statistically significance with ALT, but lost its significance with AST, PR = 1.90; CI 95%: 1.31–2.77 and a PR = 1.23; CI 95%: 0.93–1.61; respectively. Conclusion: Elevated serum levels of ALT were associated with insulin resistance. ALT could be used in clinical practice as an additional tool to assess IR in apparently healthy people. / Dirección de Gestión de la Investigación, Universidad de Antofagasta / Revisión por pares

Les diabètes de type 1 et de type 2 sont caractérisés par une sécrétion insuffisante d’insuline et une diminution de la masse des cellules bêta. Pouvoir régénérer une masse de cellules bêta fonctionnelle est donc un enjeu thérapeutique dans le traitement du diabète. Dans cet optique, nous cherchons à identifier des facteurs et mécanismes permettant d’augmenter la masse de cellules bêta. Nous nous sommes intéressés aux mécanismes de plasticité des cellules bêta dans un contexte d’insulino résistance.Dans un modèle murin d’insulino-résistance provoquée par administration chronique de glucocorticoïdes, nous avons mis en évidence une adaptation de fonction des cellules bêta par hypersécrétion d’insuline. De manière intéressante une augmentation continue et progressive de la masse des cellules bêta par prolifération mais surtout par néogénèse de cellules bêta a pu être observée. Bien que la néogénèse de cellules bêta ait été décrite dans d’autres modèles murins comme un processus récapitulant le programme de différenciation fœtale c’est à dire dérivant de cellules canalaires marquées par l’expression de Sox9 et re-exprimant Ngn3, nos expériences de lignage endocrine ont révélé que les cellules bêta néoformées ne dérivent pas des cellules Sox9 ou Ngn3. L’invalidation du récepteur aux glucocorticoïdes (GR) dans le pancréas n’altère pas l’adaptation pancréatique par néogénèse dans notre modèle d’hypercorticisme, suggérant un effet indirect des GC sur la néogénèse de cellules bêta. Cette hypothèse a pu être confirmée par la mise en évidence de la présence dans le sérum des souris CORT d’un facteur capable de stimuler la néogénèse des cellules bêta in vitro. Enfin après déplétion totale des cellules bêta, l’administration de GC permet une restauration partielle de la masse de cellules béta par néogénèse.Nos résultats apportent la preuve d’une néogénèse active et induite de cellules bêta dans le pancréas adulte de souris insulino-résistantes. Cette adaptation pancréatique résulte d’une communication inter organe adaptative et l’identification du facteur pro-néogénique représente une piste thérapeutique pour les pathologies liées aux déficiences du pancréas endocrine. / Type 1 and type 2 diabetes are characterized by an insufficient insulin secretion and a decrease of beta cell mass. Regenerate a functional beta cell mass is a therapeutic issue in the treatment of diabetes. In this context we search to identify factors and mechanisms for increasing beta cell mass. We investigated mechanisms of beta cell plasticity in a context of insulin resistance.In a mouse model of insulin resistance caused by chronic administration of glucocorticoids, we demonstrated an adaptation of beta cell function by an important increase of insulin secretion. Interestingly, a continuous and progressive increase in the mass of beta cells by proliferation but especially by neogenesis of beta cells was observed.Although beta cell neogenesis has been described in other mouse models as a process recapitulating the fetal differentiation program deriving from ductal cells labeled with Sox9 expression and re-expressing Ngn3, our endocrine lineage model revealed that neoformed beta cells do not derive from Sox9 or Ngn3 cells. Inactivation of the glucocorticoid (GR) receptor in the pancreas does not alter pancreatic adaptation by neogenesis in our model of hypercorticism, suggesting an indirect effect of GCs on beta cell neogenesis. This hypothesis could be confirmed by demonstrating the presence in the serum of CORT mice of a factor able to stimulate neogenesis of beta cells in vitro. Finally, after complete depletion of beta cells, GC administration allows a partial restoration of the beta cells mass by neogenesis.Our results provide evidence of an active and induced beta-cell neogenesis in the adult pancreas of insulin-resistant mice. This pancreatic adaptation results from an inter-organ adaptive communication and the identification of the pro-neogenic factor represents a therapeutic track for pathologies related to endocrine pancreas deficiencies.

Insulin resistance is an increasing public health issue with the current literature, suggesting reduced sensitivity of insulin leads to adult onset diabetes and associated downstream pathologies that reduce life expectancy. The main objectives of this study were to evaluate the ability of the Oral Glucose Insulin Secretion Test (OGIST) to identify insulin resistance and examine differences in the insulin sensitivity based on gender, age, and ethnicity. This study was supported by the insulin resistance theory which focuses on the reduced ability of insulin to bind to the cellular insulin receptor, reducing the sensitivity of insulin. The OGIST lab results of a total of 250 patients, aged 18-65, were included in this study from a major city in the midwestern United States. Binomial logistic regression was used to evaluate the relationship between the dependent variables and the validation independent variables and analyze the possible differences seen in insulin, proinsulin, C-peptide, and HbA1c with age. The OGIST demonstrated the ability to identify elevated levels of insulin, proinsulin, and C-peptide at the end of the first phase insulin secretion to glucose. The results of this study demonstrated patients with insulin resistance exhibited a greater reduction in insulin production with age compared to those without insulin resistance. There were no changes observed between gender or ethnicity. The OGIST was the only test that demonstrated the ability to identify the individual's insulin sensitivity, β-cell function, and progression to diabetes. The ability of the OGIST to identify both insulin resistance and β-cell function can contribute to positive social change by encouraging further research for the early diagnosis and treatment of insulin resistance and the reduction in adult onset diabetes.

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

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18501号 / 医博第3921号 / 新制||医||1005(附属図書館) / 31387 / 京都大学大学院医学研究科医学専攻 / (主査)教授 千葉 勉, 教授 横出 正之, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20615号 / 医博第4264号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 浅野 雅秀, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM