Proefschrift Maastricht. / Met lit. opg. - Met een samenvatting in het Nederlands.

Proefschrift Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Rijksuniversiteit Limburg, Maastricht. / Met lit. opg. en een samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Made available in DSpace on 2013-08-07T19:05:14Z (GMT). No. of bitstreams: 1 000380711-Texto+Completo-0.pdf: 3272506 bytes, checksum: fec29259ab112a4da7e58d3b56ab863f (MD5) Previous issue date: 2006 / Type 1 diabetes is an autoimmune disease mediated by T cells. Nonobese diabetic mice (NOD) are the most important experimental model of organ specific autoimmune disease. These animals develop beta cells damage associated to insulitis and autoantibodies, and diabetes similar to the human type 1 diabetes. The incidence of diabetes in NOD mice is not constant, depending on gender and environment. Recent publications demonstrated that in germ free environment (SPF), the incidence of diabetes in females ranges from 60 to 100%, and from 20 to 60% in males. However, there are no data describing the incidence of diabetes employing this model in conventional environment. The aim of this study was to verify the incidence of diabetes in NOD mice placed in conventional environment, as well as to verify the survival of these animals. Initially, three NOD couples were bred to produce offsprings for the research. During 32 weeks, 79 males and 58 females were followed. Every 15 days, weaning, non-fasting glucose blood levels and body weight were measured and the number of deaths were registered. Diabetes was considered in those animals presenting glucose blood levels above 250 mg/dl. After 32 weeks, 38% of these animals became diabetic. The incidence was significantly higher in females (51%) when compared to males (27%, P<0,05). Moreover, diabetes diagnosis was made around the 8th week in both genders. The total NOD mice survival in eight months was 60%.Survival was significantly higher in males (85%) than in females (60%, P<0,05). In conclusion, the incidence of diabetes in females NOD mice in conventional environment is significantly higher than in males, similarly to what is observed in germ free environment. Females Survival is lower in females than males, probably related to higher incidence of diabetes. Therefore, these data demonstrate that, even in conventional environment NOD mice breed grow and develop diabetes in an acceptable rate, which allows its experimental use. / O diabetes mellitus tipo 1 é uma doença auto-imune mediada por células T. Os camundongos NOD (nonobese diabetic) são o modelo experimental de doença autoimune órgão-específica mais utilizado em todo o mundo. Apresentam destruição das células beta associada com insulite e produção de auto-anticorpos. A incidência de diabetes nestes camundongos é variável, dependendo do ambiente em que estão alocados, assim como do sexo dos mesmos. Dados na literatura demonstram que em biotério SPF (Specific Patogen Free), a incidência de diabetes em fêmeas varia de 60 a 100% e em machos de 20 a 60%. No entanto, não são descritos valores de incidência de diabetes nestes camundongos em biotério convencional. Este trabalho tem o objetivo de avaliar a incidência de diabetes mellitus insulino-dependente de camundongos NOD em biotério convencional, além de verificar a sobrevida dos animais. Três casais de camundongos NOD foram endocruzados para a obtenção dos animais desta pesquisa. Setenta e nove machos e 58 fêmeas foram acompanhados durante 32 semanas de vida em biotério convencional. Peso e glicemia foram mensurados após o desmame, a cada 15 dias, e as mortes contabilizadas. Foram considerados diabéticos, os animais que apresentavam glicemia acima de 250mg/dl. Em 32 semanas de seguimento, 38% da amostra tornou-se diabética; as fêmeas (51%) tornaram-se significativamente (P<0,001) mais diabéticas do que os machos (27%). Além disso, verificou-se que o início do diabetes, em ambos os sexos, ocorreu por volta da oitava semana de vida.A sobrevida dos camundongos NOD em biotério convencional, em 32 semanas de vida, foi de 60%, as fêmeas tiveram sobrevida de aproximadamente 40% e os machos de 85%, sendo esta diferença significativa (P<0,02). Conclui-se que, em ambiente convencional, os camundongos NOD do sexo feminino desenvolvem mais diabetes que os machos, similarmente aos camundongos NOD criados em biotério SPF. As fêmeas possuem sobrevida menor que os machos, provavelmente devido a presença do diabetes. Desta forma, verifica-se que, mesmo em ambiente convencional, é possível que camundongos NOD, apresentem diabetes em proporções que possibilitem sua utilização experimental.

Orientador: Doris Hissako Sumida / Banca: Nancy Alfieri Nunes / Banca: Cléa Adas Saliba Garbin / Banca: Doris Hissako Sumida / Resumo: Nos últimos anos tem ocorrido uma redução acentuada nos índices de cárie dentária em diversas regiões do planeta, fato que tem se atribuído ao consumo de produtos fluoretados. Entretanto, o flúor, quando ingerido em excesso, causa intoxicação crônica ou aguda, como a fluorose dentária e distúrbios na homeostase da glicose. As crianças se tornam foco de preocupação, principalmente às portadoras de diabetes mellitus (DM), pois geralmente ingerem grandes quantidades de dentifrício fluoretado durante a escovação, ultrapassando a dose preconizada como limite de ingestão diária de flúor de 0,05 a 0,07mg/F/kg de peso corpóreo. Este trabalho, que foi dividido em duas partes, pretende realizar uma breve revisão de literatura sobre os efeitos decorrentes da ingestão de NaF no metabolismo de carboidratos e avaliar os efeitos da ingestão do fluoreto na sensibilidade à insulina e na transdução do sinal insulínico. A primeira parte, baseada em artigos científicos publicados, procura discorrer sobre os efeitos da ingestão de flúor no metabolismo de carboidratos, na tolerância à glicose e no sinal insulínico, e algumas considerações sobre o diabetes mellitus e sobre as possíveis complicações que a ingestão de NaF pode ocasionar às crianças portadoras desta doença. Estes trabalhos demonstraram que o tratamento agudo ou prolongado com altas doses de fluoreto de sódio interfere na homeostase da glicose. Convém salientar que esta alteração é similar à observada em casos de diabetes mellitus. Além do mais, o flúor quando ingerido em excesso, também ocasiona diminuição da secreção de insulina, inibição da glicólise e depleção de glicogênio. Muitas dessas respostas sugerem que o NaF pode promover resistência à insulina. Portanto, a ingestão em excesso de NaF pode prejudicar a saúde, principalmente de crianças portadora de DM. / Abstract: Over the last few years there has been a significant reduction in the incidence of dental caries in several regions of the world. This has been attributed to the consumption of fluoridated products. However, excess of fluoride intake can cause chronic or acute intoxication, such as dental fluorosis and impaired glucose homeostasis. Concern is focused on children, especially those with diabetes mellitus, because children usually swallow large amounts of fluoridated dentifrice during tooth brushing, in excess of the maximum recommended daily fluoride dose of 0.05 to 0.07 mg/F/kg of body weight. This report, divided into two parts, intends to make a brief literature review about effects of NAF intake on glucose metabolism, and to determine the effects of this intake on insulin sensitivity and insulin signal transduction. The first part, based on published scientific articles, endeavors to describe the effects of NaF intake on glucose metabolism, glucose tolerance and insulin signal, and put forward considerations concerning diabetes mellitus (DM), and the possible complications that NaF intake could cause in children with DM. These reports demonstrated that the acute or chronic treatment with high sodium fluoride dose interferes in glucose homeostasis, resulting in conditions such as hyperglycemia. This alteration is similar to that observed in DM. Furthermore, NaF ingestion in high doses can produce abnormalities in insulin secretion, glycolysis inhibition, and glycogen depletion. Many of these evidences suggest that NaF can induce insulin resistance. Thus, excessive fluoride consumption could worsen health, particularly of diabetic children. Based on that fluoride can interfere in the glucose metabolism, it is important for the second part of this report to determine the acute effect of fluoride on insulin sensitivity and pp185 (IRS-1/IRS-2) phosphorylation in insulin sensitive tissues. / Mestre

Corneal Confocal Microscopy (CCM) is a non-invasive imaging technique to quantify small nerve fibre structure in patients with diabetic somatic and autonomic neuropathy and increasingly other metabolic, hereditary, toxic and inflammatory peripheral neuropathies. This thesis establishes that CCM is indeed a powerful imaging technique which can identify early small fibre degeneration and regeneration in relation to the clinical phenotype of subjects with obesity, impaired glucose tolerance and Type1/2 diabetes. We demonstrate a precise relationship between small fibre neuropathy and erectile dysfunction in subjects with Type 1 diabetes. We also demonstrate the utility of CCM in demonstrating relative protection from small fibre damage in Type 1 patients with extreme duration diabetes (medallists) at baseline and over 3 years and repair in patients undergoing simultaneous pancreas and kidney transplantation. This thesis provides further evidence for the utility of CCM as a marker of early small fibre neuropathy by demonstrating nerve damage in subjects with morbid obesity with and without diabetes and explore the mechanisms underlying nerve damage at baseline and repair following bariatric surgery. We also show that CCM can track dynamic changes in small fibre degeneration and regeneration in subjects with impaired glucose tolerance in relation to change in glucose tolerance status and following continuous subcutaneous insulin infusion in subjects with Type 1 diabetes.

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