Orientador: Arlete Maria dos Santos Fernandes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T08:29:22Z (GMT). No. of bitstreams: 1 Kimura_VaneskadeCarvalhoMelhado_M.pdf: 1746047 bytes, checksum: 4c3f59da8a72a362f8d251faab5d3939 (MD5) Previous issue date: 2014 / Resumo: A resistência insulínica (RI) é um estado no qual há diminuição da resposta dos tecidos-alvo à ação da insulina. A prevalência da RI na população adulta jovem não obesa e com resposta normal ao teste de tolerância oral à glicose (TTOG) é estimada em 25%. Estudos sugerem que vários fatores poderiam contribuir com a deterioração da tolerância à glicose em mulheres jovens, entre eles a elevação do peso corporal e o uso de métodos contraceptivos (MAC) hormonais. Objetivos: avaliar uma coorte de mulheres saudáveis em período reprodutivo e sem antecedentes que pudessem interferir no metabolismo de carboidratos, para determinar a prevalência e os fatores associados à RI. Sujeitos e Método: para o diagnóstico de RI foi utilizada a técnica do clamp euglicêmico hiperinsulinêmico (CEH). As variáveis estudadas foram sociodemográficas, uso atual de MAC combinado ou não hormonal, tempo de uso do MAC, composição corporal avaliada pela técnica de absortimetria de duplo feixe de raios-X (DXA), valores de perfis lipídico e glicêmico, medidas de pressão arterial e da ingestão calórica. Foi realizada análise das médias e desvio padrão (DP) das variáveis relacionadas à RI e ao uso de MAC e regressão linear múltipla para avaliar fatores que pudessem influenciar a tendência à RI. Participaram deste estudo 47 mulheres saudáveis, que responderam à veiculação da pesquisa, com idade de 18 a 40 anos, IMC<30kg/m2 e todas realizaram CEH com 40mU de insulina. Resultados: do total das mulheres, 16 usavam algum tipo de método contraceptivo hormonal combinado (34%) e 31 usavam método não hormonal (66%). A prevalência de RI foi de 19,1% e significativamente maior entre as que utilizavam método hormonal (6/16) combinado em relação às que utilizavam método não hormonal (3/31). Mulheres com RI tiveram valores médios significativamente maiores de peso, IMC, massa e percentual de massa gorda, razão androide/ginecoide, e dos valores de triglicérides, insulina de jejum, HOMA IR e HOMA Bc. Após análise linear múltipla, as variáveis associadas à tendência à RI foram não ter gestação anterior, tempo de uso de MAC >1 ano e maiores valores de triglicérides. Conclusões: Uma de cada 5 mulheres em idade reprodutiva e saudável apresentou RI e mostrou elevação de peso corporal e de cintura. É importante iniciar medidas de prevenção precoces, estimulando hábitos saudáveis de alimentação e exercícios físicos nas mulheres observadas com elevação de peso e medida de cintura durante o acompanhamento de planejamento familiar / Abstract: Insulin resistance (IR) is a condition in which there is decreased response of target tissues to the effects of insulin. The prevalence of IR in the young non obese adult population with normal response to the oral glucose tolerance test (OGTT) is estimated to be 25%. Studies suggest that several factors might contribute to the deterioration of glucose tolerance in young women, among them increased body weight and the use of hormonal contraceptive methods. Objectives: evaluate a cohort of healthy women of childbearing age, without antecedents that might interfere in carbohydrate metabolism, to determine the prevalence and the factors associated with IR. Subjects and Method: the hyperinsulinemic-euglycemic clamp technique was used for the IR diagnosis. The variables studied were: sociodemographic, current use of hormonal, combined or non hormonal contraceptive methods, how long hormonal contraceptive methods have been used, body composition evaluated by the dual-energy X-ray absorptiometry (DXA) technique, values of lipid and glucose profiles, blood pressure and caloric intake measures. The means and standard deviation (SD) of variables related with IR; use of hormonal contraceptive methods and multiple linear regression were analyzed to evaluate factors that might influence tendency to IR. Forty-seven healthy women who answered research recruiting advertisement participated in this study; their ages ranged between 18 and 40 years, presented BMI<30kg/m2 and all of them were examined by the hyperinsulinemic-euglycemic clamp technique with 40mU of insulin. Results: of the total of 47 women, 16 used some type of combined hormonal contraceptive method (34%) and 31 used a non hormonal contraceptive method (66%). The prevalence of IR was 19.1% and significantly higher among those who used a combined hormonal contraceptive method (6/16) compared with those who used a non hormonal contraceptive method (3/31). Women with IR presented significantly higher mean values of weight, BMI, mass and percentage of fat body mass, android/gynecoid ratio, and values of triglycerides, fasting insulin, HOMA IR and HOMA Bc. After multiple linear analysis, the variables associated with tendency to IR were not having been pregnant before, having used hormonal contraceptive method >1 year and higher triglycerides values. Conclusions: One in every 5 healthy women of childbearing age presented IR and increased body weight and waist circumference. It is important to adopt early prevention measures, stimulating healthy eating habits and physical exercises for women with weight and waist measure increase during the family planning follow-up period / Mestrado / Fisiopatologia Ginecológica / Mestra em Ciências da Saúde

Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum. The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death. This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress. In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease. Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum. The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death. This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress. In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease. Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

The obesity epidemic is an important global health concern. Obesity is associated with a number of diseases including type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and some cancers. Insulin resistance, a precursor to type 2 diabetes, is defined as an unresponsiveness of metabolic tissues to insulin, leading to long-term hyperglycemia and hyperinsulinemia. The fatty acid-induced model of insulin resistance indicates that an accumulation of lipid intermediates interferes with insulin signal transduction leading to insulin resistance. It is, therefore, important to examine means by which these lipid intermediates can be reduced to alleviate interferences in insulin signaling in the treatment of insulin resistance and type 2 diabetes. Exercise and metformin are two common interventions in patients with type 2 diabetes and obesity. They both commonly activate AMP-activated protein kinase (AMPK). AMPK contributes to a number of metabolic processes including increased glucose and fatty acid oxidation. However, the effects of AMPK activation on insulin sensitivity are currently not fully understood. This compilation of studies examined the insulin sensitizing effects of AMPK activation via metformin, exercise, and novel AMPK activator R419 in obese mice. In Chapter 2 we show that metformin increases AMPK phosphorylation of acetyl-CoA carboxylase (ACC) 1 Ser79 and ACC2 Ser212, resulting in increased fatty acid oxidation, decreased lipid content and improvements in hepatic insulin sensitivity. In Chapter 3 we show that exercise-induced improvements in insulin sensitivity occur independent of AMPK phosphorylation of ACC phosphorylation sites and independent of lipid content in the liver. Finally, in Chapter 4 we show that R419 improves skeletal muscle insulin sensitivity independent of AMPK and lipid content but improves exercise capacity via a skeletal muscle AMPK-dependent pathway in obese mice. These findings suggest that future studies examining the effects of AMPK activation in obesity will aid in our understanding of the mechanisms of insulin resistance and introduce methods of prevention and treatment of obesity and type 2 diabetes. / Thesis / Doctor of Philosophy (PhD)