Thesis (M.S.)--University of Michigan, 1994.

Thesis (M.S.)--University of Michigan, 1994.

In Africa, use of medicinal plants for the treatment of diabetes is very common. However, efficacy on co-administering of medicinal plants with therapeutic drugs hasn't been fully determined, especially for African medicinal plants. The current study focused on assessing the in vitro modulation effects of three popular African medicinal plants, namely: Aloe ferox, Sutherlandia frutescens and Prunus africana (including five commercial preparations containing these medicinal plants) on two of the most important anti-diabetic drug metabolising enzymes, Cytochrome P450 (CYP450) 2C9 and CYP3A4 and a key drug efflux transporter, P-glycoprotein (P-gp). Vivid® microsome-based screening kits were used to assess inhibitory potency of plants preparations on CYP2C9 and CYP3A4 enzymes activities. The study showed that P. africana was a more potent inhibitor of CYP2C9 and CYP3A4 activity than the corresponding positive controls Ginkgo biloba and St. John's wort, which are known to cause clinically significant drug-herb interactions. S. frutescens leaf extract demonstrated potent to moderate inhibition on both the tested CYP activities, while its commercial products (Promune® and Probetix®) possessed moderate to mild inhibitory effects on the activities of both CYPs. Potent inhibitory effect on CYP2C9 and CYP3A4 was seen with Aloe Ferox®. Prosit® and Aloes powder® showed potent to moderate inhibition on CYP2C9 activity and moderate to mild inhibition on CYP3A4 activity. In addition to CYP450 activity, the present study also investigated the effects of the selected medicinal plant products on the activity of the main drug efflux protein, P-gp. A screening assay was specifically developed to assess the potential for herbal remedies to interact with P-gp mediated drug absorption. The assay is based on the principle of the reversal of drug resistance in modified Caco-2 cells specifically altered to express high iv efflux protein activity. These cells display a multidrug resistance phenotype and the addition of a plant extract containing a P-gp inhibitor or substrate will inhibit or compete with any cytotoxic drug and consequently reverse the drug resistance. The suitability of the assay was confirmed using a known P-gp inhibitor. The study observed that the anti-proliferation effect of vinblastine was significantly enhanced in vinblastine-resistant Caco-2 cells, which have high P-gp expression, when they were exposed to the selected African herbal preparations. This observation indicates that the studied plant preparations may alter P-gp functionality and therefore lead to interference with the absorption of co-administered drugs. The outcomes of this study provide useful information on whether there are any potential drug-herb interactions between the commonly used African medicinal plants and oral anti-diabetic drugs, at the level of CYP and P-gp drug metabolism and could contribute to better therapeutic management of Type II diabetics. However these predicted interactions will need to be verified in a clinical setting.

Mini-dissertation was submitted in partial compliance with the requirements for the Master’s Degree in Technology: Homoeopathy, Durban University of Technology, 2012. / It was reported by the International Diabetes Federation (IDF) Diabetes Atlas, in 2003, that a prevalence figure of 3.4% exists for the 24 million South Africans between the ages of 20 and 79, with an expected increase to 3.9% by 2025. Considering that patients with diabetes are at increased risk of cardiovascular disease, blindness, amputation and renal failure it is therefore not surprising that the costs associated with diabetes are estimated to increase worldwide. It is clear that according to the current trends in dietary and exercise practices, South Africa will be affected by the rise in obesity and subsequent diabetes mellitus. It is critical that a concerted effort involving all parties concerned be made to combat this rapidly increasing problem (Rheeder, 2006:20). AIM The purpose of this double-blind, randomized clinical trial was to compare the effectiveness of Momordica charantia homoeopathic mother tincture as compared to Momordica charantia 6CH, in the treatment of type 2 diabetes mellitus in patients on Metformin. METHODOLOGY Thirty patients were recruited and were selected for the study on the basis of inclusion and exclusion criteria. These participants were then randomly and equally divided into two groups. Each participant attended a total of four consultations with the researcher, over a two month period, at the Durban University of Technology (DUT) Homoeopathic Day Clinic. At the commencement of the first consultation, each participant received the subject information letter (Appendix A) for perusal and the informed consent form (Appendix B) to sign. Following this, the researcher took a full, detailed iv case history (Appendix F) and performed a physical examination (Appendix G) of each patient. Participants were required to have a Glycosylated haemoglobin (HbA1C) test performed following the first and fourth consultations. Participants were also required to complete daily Log Sheets (comprising self administered fasting blood glucose readings using issued Bayer Ascensia Elite Glucometers) for the entire duration of the study (8 weeks). SPSS version 18 was used to analyse the data. A p value < 0.05 was considered as statistically significant. The time effect was assessed for intra-group comparison whereas the time x group treatment effect was assessed for inter-group comparison. Means were calculated for both fasting blood glucose and glycosylated haemoglobin for the two respective groups and tabulated in order to describe the data obtained (Descriptive statistics). RESULTS Both groups reflected a statistically non significant decrease in fasting blood glucose levels with no significant differences between the two groups when comparing reduction in fasting blood glucose levels. Group 1 (Momordica charantia homoeopathic mother tincture) reflected a non significant increase in glycosylated haemoglobin (HbA1C) levels while Group 2 (Momordica charantia 6CH) reflected a statistically significant increase over time in HbA1C levels. There were no significant differences between the two groups when comparing reduction in HbA1C levels. / M

This research explicated the use of exploratory data analysis in describing type II diabetes mellitus among the Navajo Indians. A sample of 98 diagnosed diabetics was obtained from a retrospective chart review and had a 1.3:1 female to male ratio, a median age of 58.6 years, and a mean duration for diabetes of 7.66 years. Other characteristics included a median age at diagnosis of 50 years, a median weight prior to diagnosis (expressed in percent desired weight) of 140%, and a median blood glucose value at time of diagnosis of 241 mg/dl. The distribution patterns for age, weight, and blood glucose revealed several asymmetry problems which had implications for the appropriateness of using parametric statistics in numerical summarizations. Bivariate analyses revealed a negative association between age at diagnosis and percent desired weight prior to diagnosis. This finding identifies the risk that obesity brings to the young and that aging brings to the non-obese, Navajo Indian.

CONTEXTO: as mulheres na pós-menopausa com diabetes mellitus não insulino-dependente (DMNID) constituem um grupo com maior risco de doença cardiovascular, visto serem muitas delas obesas, hipertensas e hiperlipidêmicas. A tibolona pode se constituir opção viável para a terapêutica de reposição hormonal nessas pacientes, no entanto são necessários estudos que avaliem as implicações clínicas, modificações metabólicas e resultados terapêuticos da tibolona nesse grupo de pacientes. OBJETIVO: determinar o perfil de segurança clínico-laboratorial da terapia com tibolona em pacientes na pós-menopausa portadoras de DMNID. TIPO DE ESTUDO: prospectivo, longitudinal, aberto e não controlado. LOCAL: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. PARTICIPANTES: 24 pacientes na pós-menopausa portadoras de DMNID, tratadas com 2,5 mg/dia de tibolona, pelo período de 6 meses. VARIÁVEIS: avaliação clínica, medidas antropométricas (IMC, RCQ e % Gordura), dosagens hormonais (FSH, LH, T4 livre, TSH), bioquímica sangüínea (uréia, creatinina, bilirrubinas, TGO, TGP, glicose e hemoglobina glicosilada) e ultra-sonografia transvaginal (espessura endometrial e volume uterino). ANÁLISE ESTATÍSTICA: teste não-paramétrico de Kolmogorov-Smirnov, análise de variância para medidas repetidas e teste “t" pareado para dois períodos, sendo adotado nível de significância de 5%. RESULTADOS: após 6 meses, todas as pacientes permaneceram em uso da medicação. Como efeitos colaterais, 8,3% apresentaram cefaléia, 8,3% mastalgia e 16,6% sangramento genital. Houve melhora na % de gordura corporal (43,15 ? 6,39 vs 41,76 ? 5,20; p=0,01) e na pressão arterial diastólica (87,29 ? 7,36 vs 78,33 ? 11,67; p=0,0005). Não houve variações significativas na pressão arterial sistólica, freqüência cardíaca, IMC e RCQ, bem como nos parâmetros bioquímicos. Houve diminuição dos sintomas climatéricos (22,17 ? 7,15 vs 3,08 ? 3,33; p=0,0001). A avaliação ultra-sonográfica não revelou variações do volume uterino e espessura endometrial. CONCLUSÃO: a utilização de tibolona durante um período de 6 meses, mostrou bom perfil de segurança clínico-laboratorial em pacientes na pós-menopausa portadoras de DMNID. / CONTEXT: Postmenopausal women with non-insulin-dependent diabetes mellitus (NIDDM) represent a high risk group since many of them are obese, hypertensive and hyperlipidemic, with a higher risk for cardiovascular disease. Tibolone may represent a viable option for the hormonal replacement therapy of these patients. There is the need for studies assessing the clinical implications, metabolic modifications and therapeutic results of tibolone in this group of patients. OBJECTIVE: To determine the clinical-laboratory safety profile of tibolone treatment in postmenopausal women with NIDDM over a period of 180 days. TYPE OF STUDY: Prospective, longitudinal, open and uncontrolled. PLACE: University Hospital, Faculty of Medicine of Ribeirão Preto. PARTICIPANTS: 24 postmenopausal women with NIDDM treated with 2.5 mg/day tibolone. VARIABLES: Clinical evaluation, anthropometric measurements (BMI, WHR and % body fat), blood determinations (FSH, LH, free T4, TSH, urea, creatinine, bilirubins, GOT and GPT, glucose, and glycosylated hemoglobin), and transvaginal ultrasonography (endometrial thickness and uterine volume). STATISTICAL ANALYSIS: Non-parametric Kolmogorov-Smirnov test, repeated measures analysis of variance and paired t-test for two periods, with the level of significance set at 5 %. RESULTS: After 6 months, all patients continued to use the medication. Side effects were headache in 8.3% of patients, mastalgia in 8.3%, and genital bleeding in 16.6%. There was an improvement in % body fat (43.15 ? 6.39 vs 41.76 ? 5.20; p=0.01) and diastolic arterial pressure (87.29 ? 7.36 vs 78.33 ? 11.67; p=0.0005). There were no significant variations in systolic arterial pressure, heart rate, BMI or WHR in the biochemical parameters. There was a reduction in the climacteric symptoms (22.17 ? 7.15 vs 3.08 ? 3.33; p=0.0001) and ultrasonography showed no changes in uterine volume or endometrial thickness. CONCLUSION: Treatment with tibolone for 180 days showed a good clinical-laboratory safety profile in postmenopausal women with NIDDM.

Este estudo, com delineamento tipo caso-controle, teve como proposta testar as hipóteses de que a amamentação ao seio é um fator de proteção para o DMID e o leite de vaca, introduzido precocemente na alimentação infantil, é um fator de risco para a doença. Os casos foram identificados na Associação de Diabetes Juvenil de São Paulo e no ambulatório de Endocrinologia da Escola Paulista de Medicina. Trezentos e quarenta e seis casos, com idade inferior a 18 anos no momento da entrevista, foram comparados com 346 controles pareados aos casos segundo sexo, idade e local de residência. Foram consideradas como variáveis de principal interesse a duração do aleitamento exclusivamente ao seio, a idade da introdução de alimentos lácteos na dieta e ter recebido leite em pó na maternidade. Foram consideradas como variáveis de controle as idades da mãe e do pai no momento do nascimento da criança, o histórico da mãe de rubéola congênita, a duração da gestação, o peso e o comprimento ao nascer, a situação de vacinação, os antecedentes relativos a doenças viróticas da criança, o histórico da criança de episódios graves de diarréia, a data da insulinoterapia, os antecedentes familiares de DMID e DMNID, a renda familiar per capita e a ordem de nascimento da criança. Utilizaram-se o teste t de Student pareado para a comparação das médias das variáveis cujos valores têm distribuição normal e o teste pareado dos sinais dos postos de Wilcoxon para as demais, a técnica de tábua de vida atuarial para se conhecer, aos 7 e aos 60 dias, a proporção de crianças ainda em aleitamento exclusivamente ao seio e sem introdução de alimentos lác- teos. O modelo de regressão logística condicional foi utilizado tanto para as análises da gradação dos odds ratios como para ajustar os efeitos sobre o DMID das três variáveis de interesse a possíveis variáveis de confusão. Os resultados encontrados neste estudo indicam que são fatores de risco para o DMID a ausência de aleitamento exclusivamente, especialmente durante a primeira semana de vida (OR = 2,13, IC: 1,28 - 3,55) e a idade da introdução de alimentos lácteos, especialmente quando esses alimentos são introduzidos durante os primeiros sete dias de vida (OR = 2,29; IC: 1,37 - 3,83). / This case-control study aimed to test the assumption that breast feeding protects against insulin-dependent diabetes mellitus, and that the early introduction of cow milk into the infant diet is a risk factor for the disease. The cases were identified in the Juvenile Diabetes Association of São Paulo, and in the Out-patients Endocrinology Department of the Escola Paulista de Medicina. Three hundred and forty-six cases among patients younger than eighteen years old at the time of the interview were compared with 346 paired control cases for sex, age and place of residence. The main variables were the duration of exclusive breast feeding , the age at which milk products were introduced into the diet, and whether powdered milk was given in the maternity unit. The ages of the parents when the child was born, history of congenital rubella in the mother, duration of gestation, weight and height at birth, vaccination status, the child\'s viral disease history, the child\'s history of severa attacks of diarrhea, the date of insulin therapy, previous familial history of insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus, the per-capita income of the family, and the order of birth of the child. Student\'s paired test was used to compare the mean values of variables with normal distribution, and Wilcoxon\'s signed ranks test was used for all other variables. The actuarial life table technique was used at 7 and 60 days in order to determine the proportion of children still being exclusively breast fed without the introduction of milk products. The conditional logistical regression method was used in dose-response analyses of the odds ratio and to adjust for the effect of the three variables of interest and possible confounding variables on insulin-dependent diabetes mellitus. The findings of this study indicate that the lack of exclusive breast feeding is a risk factor to insulin-dependent diabetes mellitus, particularly during the first week of life (OR=2.13; IC: 1.28-3.55) and that the age at introduction of milk products is a risk factor for the disease, particularly when these products are introduced during the first seven days of life (OR=2.29; IC: 1.37 -33.83).

Type 2 diabetes is a metabolic disease marked by an abnormally high level of glucose (sugar) in the blood. Type 2 diabetes is now reaching an epidemic level with more than 30 million adults in the United States afflicted and 1.5 million new cases documented every year. Type 2 diabetes is linked with obesity, heart disease, hypertension, and liver disease, and individuals with type 2 diabetes are at an increased risk for heart failure, stroke, blindness, kidney failure, and amputation. According to the Centers for Disease Control and Prevention, more than $245 billion was spent in the United States in 2012 on medical expenses related to diabetes and despite that, nearly a quarter of a million Americans are losing their lives due to this disease each year. Indeed, type 2 diabetes is one of the leading causes of death in the United States and worldwide; its prevalence has almost doubled in the last 35 years, from 4.7% of the total population in 1980 to 8.5% in 2014. Consequently, more than 400 million people are at high risk for severe health problems and complications, poor quality of life, and early death. Research such as the Diabetes Prevention Program (DPP), the Finnish Diabetes Prevention Study (DPS), the Vesterbotten Intervention Program (VIP), and the Diabetes Prevention Program Outcome Study (DPPOS) suggests that type 2 diabetes can be delayed, and even prevented, with a lifestyle behavioral modification program that includes healthy eating and/or exercise. Therefore, focus has been shifted from management to prevention. An early manifestation of dysfunction in the progression of type 2 diabetes is insulin resistance, a metabolic impairment associated with obesity. Indeed, it is estimated that ~90% of people with type 2 diabetes also are obese. The link between insulin resistance and obesity is well-established; however, the mechanistic basis(es) underpinning this link is/are still debated with multiple candidate molecules, systems, and pathways potentially involved. One theory that has gained traction in recent years suggests that type 2 diabetes, and the insulin-resistant state that predates it, are rooted in dysfunctional lipid metabolism (i.e., a reduced capacity to use lipid for energy production in circumstances where lipid would be preferred, such as in the basal fasting condition, after a high-fat meal, and during light- and moderate-intensity exercise). However, there are conflicting findings regarding the degree to which the ability to oxidize lipid during these circumstances is compromised for individuals with the overweight/obesity that is associated with the disease progression. The reason(s) for this ambiguity is/are unclear but might have to do with a number of factors that were poorly controlled when substrate selectivity (i.e., lipid vs. carbohydrate oxidation rates) were compared between normal-weight individuals and those with the overweight/obese condition. These include: (a) acute energy balance and macronutrient composition of the diet; (b) the intensity and duration of the exercise bout; and (c) subject characteristics including the amount of muscle tissue they possess, their cardiorespiratory fitness level, and, perhaps most importantly, their insulin-sensitivity state. The purpose of this dissertational work is to: (a) help to resolve this ambiguity by identifying the degree to which conflicting results that have been reported might be explained by factors that were left unaccounted for and/or inadequately controlled in previous research; and (b) compare substrate selectivity in normal-weight individuals and those with the overweight/obesity condition during a physiologically-equivalent exercise challenge with the aforementioned factors rigidly controlled.

2 型糖尿病(T2D)的發展歷史悠久，但導致T2D 患者胰島素抵抗的確切病理還沒有完全理解。骨骼肌佔大多數(70-80%)的胰島素引導的葡萄糖的吸收，所以它一直是胰島素抵抗的研究焦點。許多 T2D 患者的骨骼組織顯示線粒體功能障礙，但線粒體功能障礙和胰島素抵抗之間的關係尚不清楚還在辯論中。在這個項目中，這種關係是通過研究游離脂肪酸(FFA)( 24 小時處理)對 C2C12 小鼠骨骼肌細胞的效果來闡明。 / 免疫印記法顯示FFA 誘導胰島素抵抗，結合二維電泳和質譜分析的蛋白質組學研究發現FFA 有抑制糖酵解，增加β-氧化作用，沒有改變檸檬酸循環和抑製氧化磷酸化的作用。FFA 抑制電子傳遞鏈的幾個組成部分，揭示線粒體功能障礙，背後的原因可推測為FFA 增加令β-氧化作用增加，但沒有協調改變率檸檬酸循環，導致積累不完全β-氧化的中轉體，導致線粒體過載，最終導致胰島素抵抗。 / There is a long history of Type 2 diabetes (T2D) research development, but the exact pathology leading to insulin resistance of T2D is still not fully understood. T2D is frequently characterized by tissue insulin resistance and it is often associated with an elevated concentration of palmitic acid (PA, a major kind of dietary fatty acid) in serum. Due to this correlation, much of the effort in the field had been concentrated on the effect of PA in insulin action and glucose metabolism, and how elevated PA could possibly cause insulin resistance in specific tissues. / Skeletal muscle accounts for the majority (70-80%) of insulin-mediated glucose uptake, so it has been the focus of insulin resistance studies. Many T2D patients having elevated serum free fatty acid (FFA, where PA is a kind of FFA) also show mitochondrial dysfunction in their skeletal tissue, but the relationship between mitochondrial dysfunction and insulin resistance in skeletal muscle remains unclear and under debate. In this project, the three-party relationship was elucidated by studying the effect of 24hrs of incubation of palmitic acid (PA) on skeletal muscle using C2C12 mouse skeletal cells as model. / PA-treated C2C12 cells show reduction in insulin-stimulated Akt phosphorylation when compared with untreated C2C12 cells. Comparative proteomic study for both total proteins and mitochondrial proteins with 2D gel electrophoresis and mass spectrometry unveil, when compared with untreated cells, PA-treated C2C12 cells show down-regulation in enzymes involved in glycolysis(e.g. glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, fructose-bisphosphate aldose A), up-regulation in enzymes involved in beta-oxidation(e.g. 3-ketoacyl-CoA thiolase, 3-hydroxyacyl-CoA dehydrogenase), and down-regulation in proteins involved in oxidative phosphorylation(e.g. ATP synthase subunits, NADH-ubiquinone oxidoreductase 75kDa subunit, cytochrome b-c complex subunit 1). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Lam, Chor Kwan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 69-78). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / Thesis/Assessment Committee --- p.i / Declaration --- p.ii / Abstract (in English) --- p.iii / Abstract (in Chinese) --- p.v / Acknowledgments --- p.vi / Table of Contents --- p.vii / List of Abbreviations --- p.x / List of Figures --- p.xiii / List of Tables --- p.xiv / Chapter 1. --- Literature review --- p.1 / Chapter 1.1. --- Introduction to diabetes mellitus --- p.1 / Chapter 1.1.1. --- Definition and prevalence --- p.1 / Chapter 1.1.2. --- Diagnosis and classification --- p.2 / Chapter 1.1.3. --- Symptoms and complications --- p.4 / Chapter 1.1.4. --- Causes and risk factors --- p.5 / Chapter 1.1.5. --- Prevention and treatment --- p.6 / Chapter 1.2. --- The role of muscle tissue in pathophysiology of T2DM --- p.7 / Chapter 1.3. --- Insulin receptor substrate-1 and Fatty acids-induced insulin resistance --- p.15 / Chapter 1.4. --- Introduction of proteomics --- p.18 / Chapter 1.4.1. --- The application of proteomics in disease discovery --- p.18 / Chapter 1.4.2. --- Application of Proteomics --- p.19 / Chapter 1.4.3 --- Two-dimensional gel electrophoresis --- p.20 / Chapter 1.4.4 --- Organelles proteomics --- p.21 / Chapter 1.4.5. --- Mass spectrometry --- p.22 / Chapter 1.4.6 --- Application of proteomic technology in disease pathology --- p.24 / Chapter 1.4.7 --- Current challenges --- p.25 / Chapter 1.5 --- Objectives --- p.27 / Chapter 2 --- Materials and Methods --- p.28 / Chapter 2.1 --- Fatty acid preparation --- p.28 / Chapter 2.2 --- Cell culture --- p.28 / Chapter 2.2.1 --- Treatment of C2C12 myotubes with Palmitic acid --- p.28 / Chapter 2.2.2 --- MTT assay for viability measurement --- p.29 / Chapter 2.2.3 --- Determination of the IC₅₀ values --- p.31 / Chapter 2.3 --- Proteomic analysis of C2C12 cells with and without PA treatment --- p.32 / Chapter 2.3.1 --- Protein sample preparation from C2C12 skeletal muscle cells --- p.32 / Chapter 2.3.2 --- Protein quantitation --- p.33 / Chapter 2.3.3 --- 2D Gel electrophoresis --- p.34 / Chapter 2.3.4 --- Image analysis --- p.36 / Chapter 2.3.5 --- In gel digestion and MALDI-ToF MS --- p.37 / Chapter 2.4 --- Mitochondrial purification and protein extraction --- p.38 / Chapter 2.4.1 --- Ultracentrifugation method --- p.38 / Chapter 2.4.2 --- Mitochondrial Isolation Kit --- p.39 / Chapter 2.5 --- Western Immunoblotting --- p.40 / Chapter 2.5.1 --- Protein sample preparation --- p.40 / Chapter 2.5.2 --- SDS-PAGE --- p.40 / Chapter 2.5.3 --- Western blotting --- p.40 / Chapter 2.5.4 --- Membrane Blocking and Antibody Incubations --- p.41 / Chapter 2.5.5 --- Detection of Proteins --- p.42 / Chapter 3 --- Results --- p.43 / Chapter 3.1 --- Differentiation of C2C12 myoblast into myotubes --- p.43 / Chapter 3.2 --- The effect of Palmitic acid on C2C12 Proliferation --- p.44 / Chapter 3.3 --- Comparison of total protein profiles of palmitic acid-treated C2C12 myotubes with control myotubes --- p.45 / Chapter 3.4 --- Western blotting of Akt and Phospho-Akt in C2C12 cells treated with Palmitic acid after acute exposure to insulin --- p.50 / Chapter 3.5 --- Comparison of two mitochondria isolation methodsultracentrifugation and mitochondrial isolation kit --- p.51 / Chapter 3.5.1 --- Quantity of extracted mitochondrial protein --- p.51 / Chapter 3.5.2 --- Purity of extracted mitochondrial protein --- p.52 / Chapter 3.6 --- Comparison of mitochondrial protein profiles between palmitic acid-treated and control C2C12 myotubes --- p.53 / Chapter 3.7 --- Western blotting of insulin receptor substrate-1 and its serine phosphorylation --- p.58 / Chapter 4 --- Discussion --- p.59 / Chapter 4.1 --- Investigation of anti-proliferating effect of Palmitic acid on C2C12 using MTT assay --- p.59 / Chapter 4.2 --- Comparison of total protein profiles of palmitic C2C12 myotubes with control myotubes --- p.60 / Chapter 4.3 --- Western blotting of insulin receptor substrate-1and its serine phosphorylation --- p.62 / Chapter 4.4 --- Western blotting of Akt and Phospho-Akt in C2C12 cells treated with Palmitic acid after acute exposure to insulin --- p.63 / Chapter 4.5 --- Comparison of mitochondrial protein profiles between palmitic acid-treated and control C2C12 myotubes --- p.65 / Chapter 4.6 --- Problems faced and future prospect --- p.68 / Chapter 5 --- References --- p.69

As the prevalence of atherosclerosis has risen to an alarming level throughout the world, this thesis investigated: (1) the effects of type 2 diabetes mellitus on the risk factors for atherosclerosis and the intima-media thickness (IMT) of the common carotid arteries (a surrogate marker for atherosclerosis), (2) the contribution of various risk factors to the IMT of the common carotid arteries and (3) the interrelationship between the risk factors. / Atherosclerosis is the process by which the inner lining of a large or medium artery is deposited with lipids, cellular waste and other substances. It reduces the vessel's elasticity, lumen size and blood flow. Atherosclerosis is the primary underlying mechanism leading to cardiovascular and cerebrovascular diseases, the second and third leading causes of death in Hong Kong. / Both traditional and emerging risk factors for atherosclerosis were studied: traditional risk factors include age, blood pressure, indices of glycaemia control (fasting glucose, insulin and haemoglobin-Alc), and fasting lipids, while the emerging risk factors include, abdominal fat volume (subcutaneous and visceral), inflammatory markers (interleukin-6 (IL-6), interleukin-8 (IL-8) and high sensitivity c-reactive protein (hsCRP)), adiponectin, stress hormones (24 hr urinary noradrenaline and adrenaline, and plasma cortisol), and occupational stress (measured by a effort-reward imbalance questionnaire). / Starting with 204 subjects recruited from three different studies, data from 84 normoglycaemic subjects, 23 patients with impaired glucose tolerance (IGT) and 77 patients with diabetes mellitus (DM) were included in the analysis. When the IMT of the common carotid arteries and various risk factors were compared between normoglycaemic, IGT and DM subjects: (1) the IMT of the common carotid arteries showed an increasing trend with the worsening of glycaemia control (normal&lt;IGT&lt;DM), (2) increased prevalence of hypertension, dyslipidaemia, and obesity were observed among DM patients, and (3) increased levels of inflammatory markers, reduced concentration of adiponectin (a anti-inflammatory substance), and increased plasma cortisol concentration were also found among DM subjects. As the studies were limited by sample size, only a few risk factors were found significantly related to the carotid IMT. Age was the only common risk factor which was found to be correlated to the IMT of both the normoglycaemic and the DM/IGT subjects. (Abstract shortened by UMI.) / Fok Siu Pong. / "June 2005." / Adviser: Lester A. H. Critchley. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0173. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 200-228). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.