<p>Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry.</p><p>Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years.</p><p>In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.</p>

Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry. Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years. In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.

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 increased prevalence of obesity amongst adolescents is considered a worldwide epidemic. Within the black population of South Africa, obesity is significantly more prevalent amongst black girls than black boys. The high prevalence of obesity amongst children can be attributed to a combination of various lifestyle factors, namely a decrease in physical activity, an increase in television viewing, Westernization and increased food supply. The decrease in physical activity amongst adolescents over the last few decades has led to an increase in the number adolescents diagnosed with type 2 diabetes mellitus. Research has indicated that insulin sensitivity improves with regular physical endurance activity, irrespective of change in bodyweight. Regular physical exercise also lowers the risk of type 2 diabetes mellitus, and prevents the development of coronary heart diseases, hypertension and obesity. The primary goals of this study were two-fold: Firstly, to determine the relationship between BMI, percentage body fat and insulin sensitivity amongst black adolescents, and, secondly, to determine whether there exists a positive correlation between current cardiovascular fitness (V02-maximum),together with everyday physical activity status, and insulin sensitivity amongst black adolescents. One hundred and twenty-four (124) black boys and 148 black girls between the ages of 14 and 17 participated in the study. The BOD-POD was used to calculate percentage body fat, and blood analysis for fasting glucose and insulin were completed. Insulin sensitivity (QUIKI-index) and resistance (HOMA) were also calculated, and habitual physical activity was measured using the "Previous Day Physical Activity Recall" (pDPAR) questionnaire. Physical development was determined with the Tanner questionnaire, cardiovascular fitness (VO2-maximum) was determined using the "Bleep" test and anthropometry (mass, length, skin folds, waist and hip circumference) was measured to determine body composition. The results of this study found a statistically significant negative correlation between skin fold thickness, percentage body fat, BMI and insulin sensitivity in girls. A significant negative correlation between percentage body fat and V02-maximum was found in boys, while their self-reported activity (PDPAR) did not correlate with percentage body fat. Current cardiovascular fitness and habitual physical activity status (PDPAR) showed no significant relationship with insulin sensitivity. Amongst the girls there was however a tendency towards a positive correlation between insulin sensitivity and V02-maximum. / Thesis (M.Sc. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

The increased prevalence of obesity amongst adolescents is considered a worldwide epidemic. Within the black population of South Africa, obesity is significantly more prevalent amongst black girls than black boys. The high prevalence of obesity amongst children can be attributed to a combination of various lifestyle factors, namely a decrease in physical activity, an increase in television viewing, Westernization and increased food supply. The decrease in physical activity amongst adolescents over the last few decades has led to an increase in the number adolescents diagnosed with type 2 diabetes mellitus. Research has indicated that insulin sensitivity improves with regular physical endurance activity, irrespective of change in bodyweight. Regular physical exercise also lowers the risk of type 2 diabetes mellitus, and prevents the development of coronary heart diseases, hypertension and obesity. The primary goals of this study were two-fold: Firstly, to determine the relationship between BMI, percentage body fat and insulin sensitivity amongst black adolescents, and, secondly, to determine whether there exists a positive correlation between current cardiovascular fitness (V02-maximum),together with everyday physical activity status, and insulin sensitivity amongst black adolescents. One hundred and twenty-four (124) black boys and 148 black girls between the ages of 14 and 17 participated in the study. The BOD-POD was used to calculate percentage body fat, and blood analysis for fasting glucose and insulin were completed. Insulin sensitivity (QUIKI-index) and resistance (HOMA) were also calculated, and habitual physical activity was measured using the "Previous Day Physical Activity Recall" (pDPAR) questionnaire. Physical development was determined with the Tanner questionnaire, cardiovascular fitness (VO2-maximum) was determined using the "Bleep" test and anthropometry (mass, length, skin folds, waist and hip circumference) was measured to determine body composition. The results of this study found a statistically significant negative correlation between skin fold thickness, percentage body fat, BMI and insulin sensitivity in girls. A significant negative correlation between percentage body fat and V02-maximum was found in boys, while their self-reported activity (PDPAR) did not correlate with percentage body fat. Current cardiovascular fitness and habitual physical activity status (PDPAR) showed no significant relationship with insulin sensitivity. Amongst the girls there was however a tendency towards a positive correlation between insulin sensitivity and V02-maximum. / Thesis (M.Sc. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

Glycemic intake influences the rise in blood glucose concentration following consumption of a carbohydrate containing meal, known as the postprandial glycemic response. The glycemic response is a result of both the type and amount of carbohydrate foods consumed and is commonly measured as the glycemic index (GI) or glycemic load (GL), where the GI is a ranking in comparison to glucose and the GL is an absolute value encompassing both the GI and amount of carbohydrate consumed. Evidence from controlled trials in rat models suggests that glycemic intake has a role in development of insulin resistance, however trials and observational studies of humans have produced conflicting results. As insulin resistance is a precursor to type 2 diabetes mellitus, lifestyle factors that could prevent development of this condition have important public health implications. Previous observational studies have used food frequency questionnaires to assess usual diet, which could have resulted in a lack of precision in assessment of individual serve sizes, and have been limited to daily measures of glycemic intake. Daily measures do not take fluctuations in glycemic intake on a per meal basis into account, which may be a more relevant measure for investigation in relation to disease outcomes. This PhD research was conducted in a group of Brisbane women aged 42 to 81 years participating in the multidisciplinary Brisbane Longitudinal Assessment of Ageing in Women (LAW study). Older women may be at particular risk of insulin resistance due to age, hormonal changes, and increases in abdominal obesity associated with menopause, and the LAW study provided an ideal opportunity to study the relationship between diet and insulin resistance. Using the diet history tool, we aimed to assess the glycemic intake of the population and hypothesised that daily GI and daily GL would be significantly positively associated with increased odds of insulin resistant status. We also hypothesised that a new glycemic measure representing peaks in GL at different meals would be a stronger predictor of insulin resistant status than daily measures, and that a specially designed questionnaire would be an accurate and repeatable dietary tool for assessment of glycemic intake. To address these hypotheses, we conducted a series of studies. To assess glycemic intake, information on usual diet was obtained by detailed diet history interview and analysed using Foodworks and the Australian Food and Nutrient (AUSNUT) database, combined with a customised GI database. Mean ± SD intakes were 55.6 ± 4.4% for daily GI and 115 ± 25 for daily GL (n=470), with intake higher amoung younger participants. Bread was the largest contributor to intakes of daily GI and GL (17.1% and 20.8%, respectively), followed by fruit (15.5% and 14.2%, respectively). To determine whether daily GI and GL were significantly associated with insulin resistance, the homeostasis model assessment of insulin resistance (HOMA) was used to assess insulin resistant status. Daily GL was significantly higher in subjects who were insulin resistant compared to those who were not (134 ± 33 versus 114 ± 24 respectively, P<0.001) (n=329); the odds of subjects in the highest tertile of GL intake being insulin resistant were 12.7 times higher when compared with the lowest tertile of GL (95% CI 1.6-100.1, P=0.02). Daily GI was not significantly different in subjects who were insulin resistant compared to those who were not (56.0 ± 3.3% versus 55.7 ± 4.5%, P=0.69). To evaluate whether a new glycemic measure representing fluctuations in daily glycemic intake would be a stronger predictor of insulin resistant status than other glycemic intake measures, the GL peak score was developed to express in a single value the magnitude of GL peaks during an average day. Although a significant relationship was seen between insulin resistant status and GL peak score (Nagelkerke’s R2=0.568, P=0.039), other glycemic intake measures of daily GL (R2=0.671, P<0.001) and daily GL per megajoule (R2=0.674, P<0.001) were stronger predictors of insulin resistant status. To develop an accurate and repeatable self-administered tool for assessment of glycemic intake, two sub-samples of women (n=44 for the validation study and n=52 for the reproducibility study) completed a semi-quantitative questionnaire that contained 23 food groupings selected to include the top 100 carbohydrate foods consumed by the study population. While there were significant correlations between the glycemic intake questionnaire and the diet history for GL (r=0.54, P<0.01), carbohydrate (r=0.57, P<0.01) and GI (r=0.40, P<0.01), Bland-Altman plots showed an unacceptable difference between individual intakes in 34% of subjects for daily GL and carbohydrate, and 41% for daily GI. Reproducibility results showed significant correlations for daily GL (r=0.73, P<0.001), carbohydrate (r=0.76, P<0.001) and daily GI (r=0.64, P<0.001), but an unacceptable difference between individual intakes in 25% of subjects for daily GL and carbohydrate, and 27% for daily GI. In summary, our findings show that a significant association was observed between daily glycemic load and insulin resistant status in a group of older women, using a diet history interview to obtain precise estimation of individual carbohydrate intake. Both the type and quantity of carbohydrate are important to consider when investigating relationships between diet and insulin resistance, although our results suggest the association is more closely related to overall daily glycemic intake than individual meal intake variations. A dietary tool that permits precise estimation of carbohydrate intake is essential when evaluating possible associations between glycemic intake and individual risk of chronic diseases such as insulin resistance. Our results also suggest that studies using questionnaires to estimate glycemic intake should state degree of agreement as well as correlation coefficients when evaluating validity, as imprecise estimates of carbohydrate at an individual level may have contributed to the conflicting findings reported in previous studies.

Background Hypovitaminosis D is becoming recognised as an emerging threat to health, even in countries like New Zealand which enjoy plentiful sunshine. The evidence for a role for vitamin D deficiency in the aetiology of a plethora of diseases continues to accumulate, including type 2 diabetes, and the preceding insulin resistance. Objectives The primary objective of the Surya Study was to investigate the effect of improved vitamin D status (through supplementation) on insulin resistance. The secondary objectives were to investigate the vitamin D status and bone mineral density of South Asian women living in New Zealand, and to investigate the effect of vitamin D supplementation on bone turnover as measured by biochemical markers of bone resorption and formation. Method Women of South Asian origin, ≥20 years old, living in Auckland (n = 235) were recruited for the study. All were asked to complete a 4-day food diary, invited to have a bone scan, and were screened for entry into the intervention phase which required insulin resistance (HOMA-IR >1.93) and serum 25(OH)D < 50 nmol/L. Eighty-one completed a 6-month randomised controlled trial with 4000 IU vitamin D3 (n = 42) or placebo (n = 39). Primary endpoint measures included insulin resistance, insulin sensitivity (HOMA2%S), fasting C-peptide and markers of bone turnover, osteocalcin (OC) and collagen C-telopeptide (CTX). Ninety-one of the 239 had a bone scan and bone mineral density (BMD) was measured in the proximal femur and lumbar spine. Results Adequate serum 25(OH)D concentrations (>50 nmol/L) were observed in only 16% of subjects screened. Median (25th, 75th percentile) serum 25(OH)D increased significantly from 21 (11,40) to 75 (55,84) nmol/L with supplementation. Significant improvements were seen in insulin sensitivity and insulin resistance (P = 0·003, P = 0·02 respectively), and circulating serum insulin decreased (P = 0·02) with supplementation compared to placebo. There was no change in C-peptide with supplementation. Insulin resistance was most improved when endpoint serum 25(OH)D =80 nmol/L. In post-menopausal women OC and CTX levels increased in the placebo arm but CTX decreased from 0.39±0.15 to 0.36±0.17 (P = 0.012) with supplementation. Osteoporosis (T score <-2.5) was present in 32% of postmenopausal, and 3% of premenopausal women. Women 20 – 29 years (n=10) had very low BMD, calcium intake and serum 25(OH)D Conclusions Improving vitamin D status in insulin resistant women resulted in improved insulin resistance and sensitivity but no change in insulin secretion. Optimal 25(OH)D concentrations for reducing insulin resistance were shown to be ≥80 nmol/L. The prevalence of low 25(OH)D concentrations in this population was alarmingly high, especially in younger women. In post-menopausal women, vitamin D supplementation appeared to ameliorate increased bone turnover attributed to oestrogen deficiency.

Adiponectin is an adipose-derived protein (adipocytokine) that is secreted by adipose tissue. It has insulin-sensitizing, anti-inflammatory and cardio-protective properties, and is thought to be protective against obesity-related diseases such as type 2 diabetes. Humans and cats are two species that commonly develop type 2 diabetes associated with insulin resistance, impaired beta cell function and spontaneous islet amyloid deposition. The domestic cat (Felis catus) has recently been proposed as an animal model for human type 2 diabetes. However, little is known about the physiology of adiponectin in cats. Therefore, we set out to investigate the association of adiponectin profiles with dietary carbohydrate intake, feeding, body weight, fat mass, and insulin sensitivity in healthy young adult cats (n=32; 2-4 years old; gender ratio 1:1; body condition 4-5/9). Cats were fed a moderate carbohydrate diet (37% ME) at maintenance energy requirements for four weeks. Cats were then assigned to either receive a low (19% ME) or high (52% ME) carbohydrate diet and fed at maintenance energy requirements for another four weeks, followed by ad-libitum feeding for eight weeks to facilitate weight gain. Adiponectin profiles including total circulating adiponectin and its distribution [low molecular weight (LMW) and high molecular weight (HMW) adiponectin], and proportion of adiponectin that is HMW (SA) were measured by ELISA and velocity sedimentation using sucrose gradients, followed by Western blotting, respectively. We demonstrated inter-animal variation in total adiponectin concentration at baseline (0.6 to 15.0 g/mL), with the adiponectin present in both LMW and HMW forms. Feeding with a high carbohydrate diet for four weeks at maintenance energy requirements resulted in increased total adiponectin concentration, which was associated with an increased concentration of LMW adiponectin. In contrast, feeding with a low carbohydrate diet for four weeks at maintenance energy requirements resulted in increased concentration of HMW adiponectin, decreased LMW adiponectin concentration, and increased SA, without a change in total adiponectin concentration. In cats fed the high carbohydrate diet, total adiponectin and HMW adiponectin concentrations become lower at six hours after feeding, as compared to the fasting concentrations. This phenomenon was not observed in cats fed a low carbohydrate diet, indicating a diet-dependent postprandial effect. There was no effect of gender on any of the adiponectin profiles in cats. Unlike other studies in humans and mice in which adiponectin concentrations decreased as fat mass increased, our data indicate that a moderate weight gain achieved by ad libitum feeding of a low carbohydrate diet for eight weeks correlated with increased adiponectin concentrations. Total adiponectin concentration (mirrored by HMW adiponectin) was positively correlated with body weight gain and fat mass gain (but not absolute fat mass) in our overweight cats. Furthermore, the fat mass-related increases in plasma adiponectin over eight weeks correlated with insulin sensitivity (higher adiponectin concentration corresponded to greater insulin sensitivity in overweight cats). These data hint at the possibility that in overweight animals, adiponectin is similar to other adipokines that rise concomitantly with increased of moderate fat mass gain and thus increases insulin sensitivity. Overall, the knowledge in this study therefore provides useful information to veterinarians and cat food manufacturers, and forms a foundation for future studies to extend our knowledge of adiponectin in cats. Data gathered in cats may also be applicable to humans and could therefore inform research using cats as an animal model of human obesity and type 2 diabetes.

Submitted by Simone Souza (simonecgsouza@hotmail.com) on 2017-09-15T15:03:15Z No. of bitstreams: 1 DISS_2014_Larissa Finger.pdf: 952368 bytes, checksum: ce15137e3eda929260a105c871adbf0a (MD5) / Approved for entry into archive by Jordan (jordanbiblio@gmail.com) on 2017-09-19T13:39:00Z (GMT) No. of bitstreams: 1 DISS_2014_Larissa Finger.pdf: 952368 bytes, checksum: ce15137e3eda929260a105c871adbf0a (MD5) / Made available in DSpace on 2017-09-19T13:39:00Z (GMT). No. of bitstreams: 1 DISS_2014_Larissa Finger.pdf: 952368 bytes, checksum: ce15137e3eda929260a105c871adbf0a (MD5) Previous issue date: 2014-08-29 / CAPES / A redução na ingestão de proteínas e aumento na ingestão de carboidratos perfaz um padrão alimentar muito presente no estilo de vida atual da população mundial e está associado à incidência de patologias tais como diabetes mellitus, obesidade, hipertensão, entre outras. A ingestão de quantidades insuficientes de proteínas também está associada ao desenvolvimento de estresse oxidativo, o que contribui para o estabelecimento de lesões teciduais que podem culminar em prejuízo funcional de diversos órgãos. Diante destes fatos, o nosso objetivo foi investigar os possíveis danos renais decorrentes da administração da dieta hipoproteica-hiperglicídica a ratos no início da fase de crescimento. Ratos Wistar machos (~30 dias e 100g) foram divididos nos grupos: 1) Controle, alimentado com uma dieta com 17% de proteína e 63% de carboidrato por 15 (C15) ou 45 dias (C45); 2) LPHC, ratos alimentados com uma dieta contendo 6% de proteína e 74% de carboidrato por 15 (LPHC15) ou 45 dias (LPHC45) e 3) reversão, alimentados por 15 dias com a dieta LPHC e por mais 30 dias com a dieta controle (R45). A tolerância à glicose (GTT) foi avaliada pelas áreas sob as curvas (AUC) glicêmicas obtidas pelo método trapezoidal e a tolerância à insulina (ITT) pela constante de decaimento da glicose sérica (Kitt). O estresse oxidativo foi avaliado pela da quantificação do nível de lipoperoxidação através da dosagem do MDA (malondialdeído) nos rins, níveis de GSH (glutationa reduzida) e determinação da atividade das enzimas GPx (glutationa peroxidase), GR (glutationa redutase), catalase e SOD (superóxido dismutase) nos rins, além da quantificação da capacidade antioxidante total (CAT) no plasma. Analisou-se também. A função renal foi avaliada pela da quantificação da creatinina plasmática e análise histológica. Os resultados foram expressos como a média ± E.P.M. e as comparações estatísticas realizadas através do Teste t de Student ou ANOVA uma via, seguida de pós-teste de Tukey (p < 0,05). Os animais LPHC15, apresentaram valores similares ao grupo C15 para GSH, GPx, GR, SOD e catalase. No entanto, o peso dos rins (C15: 5,59 ± 0,21; LPHC15: 4,60 ± 0,08 mg / g de peso corporal) e a CAT (C15: 0,486 ± 0,059; LPHC5: 0,252 ± 0,059 mmol/L) foram menores e a creatinina plasmática (C45: 0,672 ± 0,028; LPHC45: 1,003 ± 0,039 mg/dL) e o nível de MDA (C15: 0,0195 ± 0,001; LPHC15: 0,033 ± 0,001 mmol/g de tecido) foram maiores no grupo LPHC15 em relação ao C15. Após a administração da dieta LPHC por 45 dias, os valores da glicemia de jejum dos animais C45 e LPHC45 foram similares. No entanto, a glicemia dos animais do grupo R45 foi 11% (p0,05) maior que nos demais grupos. No GTT não houve diferença na AUC entre os grupos analisados. O mesmo ocorreu na análise do decaimento da glicose plasmática após administração de insulina entre os diferentes grupos. A atividade das enzimas SOD e catalase também foi similar nos três grupos avaliados, já a atividade das enzimas GPx (C45: 2,730 ± 0,732; LPHC45: 0,928 ± 0,176; R45: 3,290 ± 0,304 U/mg de proteína) e GR (C45: 4,701 ± 0,320; LPHC45: 2,840 ± 0,151; R45: 6,308 ± 1,087 U/mg de proteína) foram menores no grupo LPHC45. A concentração de GSH foi menor no grupo R45 (C45: 0,785 ± 0,034; LPHC45: 0,760 ± 0,047; R45: 0,510 ± 0,024 mmol/g de tecido). O nível de MDA foi maior nos grupos LPHC45 e R45 (C45: 11,170 ± 2,020; LPHC45: 31,030 ± 3,060; R45: 31,540 ± 4,460 mmol/g de tecido). O peso dos rins (C45: 3,72 ± 0,03; LPHC45: 3,17 ± 0,05; R45: 3,66 ± 0,09) e a CAT (C45: 0,583 ± 0,059; LPHC45: 0,135 ± 0,050; R45= 0,407 ± 0,108 mmol/L) foram menores no grupo LPHC45. O nível plasmático de creatinina foi maior nos grupos LPHC45 e R45 (C45: 0,556 ± 0,020; LPHC45: 0,640 ± 0,021; R45: 0,678 ± 0,023 mg/dL). Análise histológica mostrou deposição de lipídeos no interstício dos rins nos grupos LPHC45 e R45, classificada como leve a acentuada. Estes dados permitem concluir que a dieta LPHC introduzida logo após o desmame e administrada por 45 dias não altera a tolerância à glicose nem a sensibilidade à insulina, diferente do que já foi demonstrado em estudo prévio, quando a mesma é administrada por 15 dias, resultando em maior sensibilidade à insulina. No entanto, restrição protéica introduzida logo após o desmame levou a um prejuízo no desenvolvimento dos rins, com possível prejuízo na função renal, associada a acúmulo de lipídeos e ao stresse oxidativo. Embora a reversão da dieta recupere o peso dos rins, os níveis elevados de creatinina sérica e o maior conteúdo de MDA no órgão sugerem que os danos funcionais decorrentes do stress oxidativo são irreversíveis. / The reduction in protein intake and the increase in carbohydrate intake feature a dietary pattern present in the current lifestyle of the population worldwide, and it is associated with the incidence of pathologies such as diabetes mellitus, obesity and high blood pressure among others. Low protein intake is also associated with the development of oxidative stress, which contributes to the establishment of tissue lesions that may result in functional impairment of various organs. In view of these facts, this study aimed to investigate the possible renal damages caused by the administration of a hypoproteic-hyperglycemic diet to rats in the early growth stages. Male Wistar rats (~30 days and 100g) were divided into the following groups: 1) Control, fed on a diet containing 17% protein and 63% carbohydrates for 15 (C15) or 45 (C45) days; 2) LPHC, fed on a diet containing 6% protein and 74% carbohydrates for 15 (LPHC15) or 45 (LPHC45) days, and 3) reversal group, fed on a LPHC diet during 15 days and then fed on a control diet for the following 30 days (R45). Glucose tolerance (GTT) was assessed by the areas under glycemic curves (AUC) obtained by the Trapezoidal Rule and insulin tolerance (ITT) was calculated according to the serum glucose decline rate constant (Kitt). Oxidative stress was evaluated by quantifying the lipid peroxidation level through the dosage of MDA (malondialdehyde) in kidneys, levels of GSH (reduced glutathione) and by determining the activity of the enzymes GPx (glutathione peroxidase), GR (glutathione reductase), catalase and SOD (superoxide dismutase) in the kidneys as well as quantifying the total antioxidant capacity (TAC) in plasma. The renal function was evaluated by the quantification of plasma creatinine and histological analysis. Results were expressed as the mean ± SEM, and statistical comparisons were carried out by means of the Student t Test or one-way ANOVA, followed by Tukey’s post-test (p < 0,05). LPHC15 animals presented similar values to those of the C15 group in reference to GSH, GPx, GR, SOD and catalase. However, the weight of kidneys (C15: 5,59 ± 0,21; LPHC15: 4,60 ± 0,08 mg / g body weight) and TAC values (C15: 0,486 ± 0,059; LPHC5: 0,252 ± 0,059 mmol/L) were lower, while plasma creatinine (C45: 0,672 ± 0,028; LPHC45: 1,003 ± 0,039 mg/dL) and MDA level (C15: 0,0195 ± 0,001; LPHC15: 0,033 ± 0,001 mmol/g tissue) were higher for the LPHC15 group compared with C15. After administering the LPHC diet for 45 days, the values for fasting glycemia in C45 and LPHC45 animals were similar. However, the glycemia level of R45 animals was 11% (p < 0,05) higher than in the other groups. There were no differences in the AUC between groups analyzed for GTT. The same happened when plasma glucose decline was analyzed following insulin administration. The activity of SOD and catalase enzymes was similar in the three groups under evaluation, whereas the activity of GPx (C45: 2,730 ± 0,732; LPHC45: 0,928 ± 0,176; R45: 3,290 ± 0,304 U/mg protein) and GR (C45: 2,730 ± 0,732; LPHC45: 0,928 ± 0,176; R45: 3,290 ± 0,304 U/mg protein) was lower in the LPHC45 group. GSH concentration was lower in the R45 group (C45: 0,785 ± 0,034; LPHC45: 0,760 ± 0,047; R45: 0,510 ± 0,024 mmol/g of tissue). The level of MDA was higher in the LPHC45 and R45 groups (C45: 11,170 ± 2,020; LPHC45: 31,030 ± 3,060; R45: 31,540 ± 4,460 mmol/g of tissue). The weight of kidneys (C45: 3,72 ± 0,03; LPHC45: 3,17 ± 0,05; R45: 3,66 ± 0,09) and TAC (C45: 0,583 ± 0,059; LPHC45: 0,135 ± 0,050; R45= 0,407 ± 0,108 mmol/L) showed lower values in the LPHC45 group. LPHC45 and R45 groups presented higher levels of plasma creatinine (C45: 0,556 ± 0,020; LPHC45: 0,640 ± 0,021; R45: 0,678 ± 0,023 mg/dL). Histological analysis showed interstitial lipid deposition in kidneys for LPHC45 and R45 groups, graded from mild to marked. These data lead to the conclusion that the LPHC diet, when introduced immediately after weaning and administered along 45 days, does not alter either glucose tolerance or insulin sensitivity. This conclusion is different from what was concluded in a previous study where LPHC diet administered during 15 days resulted in greater insulin sensitivity. Yet protein restriction, introduced soon after weaning, has led to damage in kidney development, which may result in impaired renal function associated to increased fat deposition and oxidative stress. Even though the diet reversal may recover kidney weight, the increased levels of serum creatinine and higher content of MDA in the organ suggest that functional damages resulting from oxidative stress are irreversible.

Esta tese avaliou as respostas fisiológicas à hiperinsulinemia aguda em mulheres na pós-menopausa, verificando os efeitos isolados e associados da terapia hormonal (TH) e do treinamento aeróbico (TF) sobre estas respostas. Assim, 31 mulheres histerectomizadas, saudáveis e na pós-menopausa foram divididas, aleatoriamente e de forma duplo cega, nos grupos: PLA-CO(n=7), TH-CO(n=6), PLA-TF(n=10), TH-TF(n=8). Os grupos TH receberam valerato estradiol (1 mg/dia) e os PLA, placebo. Os grupos TF treinaram em cicloergômetro, 3x/sem em intensidade moderada e os CO permaneceram sedentários. Antes e após 6 meses, foi realizado um clampeamento euglicêmico/hiperinsulinêmico. Em resposta à hiperinsulinemia, houve aumento das catecolaminas plasmáticas, da modulação simpática cardíaca, da pressão arterial sistólica, da frequência cardíaca e do fluxo sanguíneo. Após 6 meses, o TF aumentou a sensibilidade à insulina e reduziu o aumento da noradrenalina durante a hiperinsulinemia. Tanto isoladamente quanto em associação, o TF e a TH impediram a redução do aumento do fluxo sanguíneo durante a hiperinsulinemia, o que foi observado no grupo PLA-CO. Além disso, quando associadas, estas condutas reduziram o aumento da adrenalina durante a hiperinsulinemia. Concluindo: em mulheres pós-menopausadas saudáveis, a hiperinsulinemia aguda aumentou a atividade simpática e promoveu vasodilatação, levando ao aumento da pressão arterial sistólica e da frequência cardíaca, sem alterar a pressão diastólica, respectivamente. O TF aumentou a sensibilidade à insulina, diminuindo a ativação simpática e mantendo a vasodilatação induzida pela hiperinsulinemia, enquanto que a TH teve o mesmo efeito sobre a vasodilatação, sem alterar a sensibilidade à insulina. A associação das duas condutas teve pouco efeito aditivo / This thesis evaluated the physiological responses to acute hyperinsulinemia in post-menopausal women, analyzing the isolated and combines effects of hormone therapy (HT) and aerobic training (AT) on these responses. Thus, 31 healthy, hysterectomized postmenopausal women were randomly divided (in a double-blinded manner) into groups: PLA-CO(n=7), HT-CO(n=6), PLA-AT(n=10), HT-AT(n=8). HT groups received valerato estradiol (1 mg/day) while PLA groups received placebo. AT groups trained on cycle ergometer, 3x/week at moderate intensity, while CO groups stayed sedentary. Before and after 6 months, an euglycemic hyperinsulinemic clamp were performed. Hyperinsulinemia increased plasma catecholamines, sympathetic cardiac modulation, systolic blood pressure, heart rate, and blood flow. After 6 months, AT increased insulin sensitivity and reduced insulin induced increase in norepinephrine. AT and HT, applied alone or together, abolished the decline in insulin induced increase in blood flow that was observed in PLA-CO. Besides, the association of both interventions decreased insulin induced increase in epinephrine. In conclusion: in healthy postmenopausal women, acute hyperinsulinemia increased sympathetic activity but produced vasodilation, which resulted in an increase in systolic blood pressure and heart rate, with no change in diastolic blood pressure, respectively. AT increased insulin sensitivity, decreasing sympathetic activation and maintaining vasodilatory response during hyperinsulinemia, while HT had the same effect on vasodilation without changing insulin sensitivity. The association of both interventions had minor addictive effects