Dissertations / Theses on the topic 'Insulin; Diabetes; Hypertension'

A series of studies is described in which specific and conventional insulin immunoassays, the hyperinsulinaemic clamp technique and forearm venous occlusion plethysmography with local intra-arterial infusions have been used to investigate: the effect of insulin assay specificity on the relationships among serum insulin concentrations, insulin sensitivity, and blood pressure in diabetic and non-diabetic subjects with and without essential hypertension (Chapter 5) the effect of sustained physiological activation of the renin-angiotensin system induced by moderate dietary sodium restriction on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (Chapter 6) the relationship between endothelial function and insulin sensitivity in healthy subjects (Chapter 7) Prior to these investigations, preliminary studies (Chapters 3 and 4) were performed in order to validate aspects of the clinical physiological techniques required for the measurement of blood flow and insulin sensitivity. The reproducibility of bilateral forearm venous occlusion plethysmography Studies using this technique to measure changes in forearm blood flow (FBF) during intra-arterial infusions of vasoactive substances often report changes in blood flow ratio (expressing responses in the intervention arm as a ratio of responses in the control arm) rather than absolute values for flow. However, unilateral measurements are reported by other investigators, and the possibility was considered that the method used for expressing responses might influence the conclusions reached. A reproducibility study was performed (Chapter 3) which demonstrated that the between-day intra-subject variability of bilateral forearm venous occlusion plethysmography (FBF ratios) was less than that of unilateral FBF measurements. The bilateral technique was used thereafter where possible.

Currently, it is reported that ~65% and 34% of the U.S. population is overweight and obese, respectively. Obesity is a major risk factor for cardiovascular disease. Overweight and obese individuals are also at an increased risk of developing hypertension. Whole-body insulin sensitivity is reduced in obesity, resulting in insulin resistance and increased risk of type 2 diabetes. One possible mechanism contributing to insulin resistance in obesity hypertension is renin-angiotensin system (RAS) overactivation. The RAS exhibits vasocontricting and sodium-retaining properties, yet in vivo and in vitro animal experiments suggest impairment of whole-body insulin sensitivity with increased angiotensin II (Ang II) exposure. Furthermore, evidence from clinical studies indicates Ang II receptor blockers (ARBs) may reduce the incidence of new-onset diabetes compared to other antihypertensive agents in at-risk hypertensive patients. However, it is unclear if whole-body insulin sensitivity is improved with Ang II receptor blockade in humans. Thus, we tested the hypothesis that 8-week Ang II receptor blockade with olmesartan would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Olmesartan was selected for the present study because it is devoid of partial PPARγ agonist activity. To test our hypothesis, intravenous glucose tolerance tests were performed to measure insulin sensitivity before and after control and ARB treatment in a randomized crossover manner. Because skeletal muscle tissue accounts for ~75-90% of insulin-stimulated glucose uptake, a secondary exploratory aim was to examine skeletal muscle inflammatory and collagen response in relation to insulin sensitivity during ARB treatment. No baseline differences were observed between treatments (P>0.05). Both systolic (-11.7 mmHg; P=0.008) and diastolic (-12.1 mmHg; P=0.000) BP were reduced with ARB treatment. Insulin sensitivity was not different between treatments (P>0.05). No correlates of insulin sensitivity were identified. In addition, skeletal muscle inflammatory and collagen gene expression did not change from pre- to post-ARB treatment (P>0.05). Our findings suggest that short-term RAS blockade in overweight and obese adults with elevated BP does not improve whole-body insulin sensitivity, despite a significant BP reduction. Further studies are needed to clarify the role of individual RAS blockers on insulin sensitivity during RAS inhibition in obesity hypertension.<br>Ph. D.

[Formulae and special characters can only be approximated here. Please see the pdf version of the Abtract for an accurate reproduction.] Type 2 diabetes at least doubles the risk of cardiovascular disease. This can partly be explained by the increased prevalence of risk factors such as hypertension, dyslipidaemia and obesity. However, the underlying abnormality of insulin resistance and the presence of more recently identified risk factors including endothelial dysfunction, increased inflammation, and increased oxidative stress might also contribute towards the heightened cardiovascular risk. Fish oil, which contains eicosapentaenoic acid (EPA, 20:5 n-3), has wide-ranging beneficial effects on these and other abnormalities, and has reduced cardiovascular mortality in secondary prevention studies. Animal and human studies have recently established that in addition to EPA, docosahexaenoic acid (DHA, 22:6 n-3) also has beneficial effects, and furthermore, may have less detrimental effects than EPA on glycaemic control which has worsened in some fish and fish oil studies involving Type 2 diabetic subjects. Study 1 : This intervention study aimed to determine the independent effects of EPA and DHA on cardiovascular risk factors and glycaemic control in individuals with Type 2 diabetes receiving treatment for hypertension. In a double-blind placebo-controlled trial of parallel design, 59 subjects in good to moderate glycaemic control (HbA1c < 9%) were recruited from media advertising and randomised to 4 g/day of EPA, DHA or olive oil (placebo) for 6 weeks. Thirty-nine men and 12 post-menopausal women aged 61.2±1.2 yrs completed the study. Relative to placebo, and with Bonferroni adjustments for multiple comparisons, serum triglycerides fell by 19% (p=0.022) and 15% (p=0.022) in the EPA and DHA groups respectively. There were no changes in serum total cholesterol, or LDL- and HDL-cholesterol, although HDL2-cholesterol increased 16% with EPA (p=0.026) and 12% with DHA (p=0.05). HDL3-cholesterol fell by 11% (p=0.026) with EPA supplementation and LDL particle size increased by 0.26±0.10 nm (p=0.02) with DHA. Urinary F2-isoprostanes, an in-vivo marker of oxidative stress was reduced by 19% following EPA (p=0.034) and by 20% following DHA. DHA but not EPA supplementation reduced collagen-stimulated platelet aggregation (16.9%, p=0.05) and thromboxane release (18.8%, p=0.03), but there were no significant changes in PAF-stimulated platelet aggregation. Fasting glucose rose by 1.40±0.29 mmol/l (p=0.002) following EPA and 0.98±0.29 mmol/l (p=0.002) following DHA. Neither EPA nor DHA had any significant effect on HbA1c, fasting serum insulin or C-peptide, insulin sensitivity, stimulated insulin secretion, 24-hr ambulatory blood pressure and heart rate, markers of inflammation, and fibrinolytic or vascular function. Study 2 : This study aimed to examine the influence and causes of increased inflammation on vascular function in subjects recruited for Study 1. Compared with healthy controls (n=17), the diabetic subjects (n=29) had impaired flow-mediated dilatation (FMD) (3.9±3.0% vs 5.5±2.4%, p=0.07) and glyceryl-trinitrate mediated dilatation (GTNMD) (11.4±4.8% vs 15.4±7.1%, p=0.04) of the brachial artery. They also had higher levels of the inflammatory markers C-reactive protein (2.7±2.6 mg/l vs 1.4±1.1 mg/l, p=0.03), fibrinogen (3.4±0.7 g/l vs 2.7±0.3 g/l, p<0.001) and tumor necrosis factor-alpha (20.9±13.4 pg/l vs 2.5±1.7 pg/l, p<0.001). In diabetic subjects, after adjustment for age and gender, leukocyte count was an independent predictor of FMD (p=0.02), accounting for 17% of total variance. Similarly, leukocyte count accounted for 23% (p<0.001) and IL-6 for 12% (p=0.03) of variance in GTNMD. Von Willebrand factor, a marker of endothelial cell activation was correlated with leukocyte count (r=0.38, p=0.04), FMD (r=-0.35, p=0.06) and GTNMD (r=-0.47, p=0.009), whilst P-selectin, a marker of platelet activation was correlated with fibrinogen (r=0.58, p=0.001). Conclusion : EPA and DHA have similar beneficial effects on triglycerides, HDL2 cholesterol and oxidative stress in individuals with Type 2 diabetes and hypertension. However, DHA also increases LDL particle size and reduces collagen-stimulated platelet aggregation and thromboxane release, thus offering more potential than EPA as an anti-thrombotic agent. The beneficial effects of both oils were potentially offset by deterioration in glycaemic control. Neither oil affected blood pressure or vascular function. Longer-term studies with major morbidity and mortality as the primary outcome measures are required to assess the overall benefits and risks of EPA and DHA. The cross-sectional observations from Study 2 are consistent with the hypothesis that impaired vascular function in individuals with Type 2 diabetes and hypertension is at least in part secondary to increased inflammation, with associated endothelial and platelet activation.

Abstract The increasing prevalence of metabolic syndrome and the consequent cardiovascular diseases, including atherosclerotic diseases and type 2 diabetes, are a cause of public concern worldwide. This development has stimulated an active search for novel risk factors and new candidate genes. The hormones regulating energy balance and the polymorphisms associated with them are of special interest as potential risk factors for metabolic syndrome. Ghrelin is a novel peptide hormone from stomach with strong growth hormone releasing activity. It is also able to modify glucose and insulin metabolism, blood pressure levels, cardiac function, adipogenesis and inflammatory processes in experimental conditions. Whether ghrelin and ghrelin gene variations have a role in the development of metabolic syndrome and the associated diseases, is not known. In the present study, the associations between fasting plasma ghrelin concentrations, ghrelin gene mutations (Arg51Gln and Leu72Met), features of metabolic syndrome, type 2 diabetes and carotid artery atherosclerosis were analysed. In addition, the relationship between ghrelin and insulin-like growth factor I (IGF-I) concentrations was studied. The study population consisted of 1045 middle-aged subjects of the hypertensive and the control cohorts of the OPERA project from the City of Oulu, Finland. Low ghrelin concentrations were found to be associated with several components of metabolic syndrome: adiposity, low HDL cholesterol levels, high insulin concentrations and high blood pressure levels. The prevalence of insulin resistance and type 2 diabetes was increased amongst the subjects with low ghrelin concentrations. Out of the individual factors tested, IGF-I concentration was the most significant predictor of ghrelin concentrations. This negative association was strongest in the subjects with insulin resistance and type 2 diabetes, which suggests that changes in ghrelin/IGF-I interactions might be involved in the development of these conditions. The subjects with the Gln51 allele of the ghrelin gene had lower ghrelin concentrations and, consistent with the findings mentioned above, higher prevalence of type 2 diabetes and hypertension compared with the subjects homozygous for the Arg51 allele. No correlation between ghrelin and C-reactive protein concentrations was seen. However, there was a positive association between ghrelin concentrations and carotid artery intima-media thickness. This association was independent of the commonly recognised risk factors of atherosclerosis and was only seen in men, who also had more advanced atherosclerosis than women. These observations call for further studies to clarify the potential causative role of ghrelin in the etiology of metabolic syndrome, type 2 diabetes and atherosclerotic cardiovascular diseases<br>Tiivistelmä Metaboliseen oireyhtymään liittyy kohonnut riski sairastua sydän- ja verisuonisairauksiin kuten tyypin 2 diabetekseen ja sepelvaltimotautiin. Metabolisen oireyhtymän nopea esiintyvyyden kasvu on johtanut aktiiviseen uusien riskitekijöiden etsintään. Erityisen kiinnostuksen kohteena ovat olleet energia-aineenvaihduntaa säätelevät hormonit ja niihin liittyvät polymorfiat. Greliini on ensisijaisesti vatsalaukusta erittyvä hormoni, joka lisää voimakkaasti kasvuhormonin eritystä. Koeolosuhteissa sillä on myös vaikutuksia sokeriaineenvaihduntaan, verenpaineeseen, sydämen toimintaan, rasvakudoksen kehittymiseen ja tulehduksellisiin tapahtumiin, minkä perusteella on syytä epäillä greliinillä olevan osuutta metabolisen oireyhtymän ja siihen liittyvien sairauksien synnyssä. Tässä tutkimuksessa selviteltiin greliinin paastoplasmapitoisuuksien ja greliinipolymorfioiden (Arg51Gln ja Leu72Met) yhteyksiä metabolisen oireyhtymän piirteisiin, tyypin 2 diabetekseen ja kaulavaltimoiden ateroskleroosiin. Lisäksi tutkittiin greliinin ja insuliinin kaltaisen kasvutekijän (IGF-I) pitoisuuksien yhteyksiä. Tutkimusväestö koostui 1045 oululaisesta keski-ikäisestä OPERA tutkimukseen kuuluvasta henkilöstä. Tutkimuksessa matalien greliinipitoisuuksien havaittiin olevan yhteydessä useisiin metabolisen oireyhtymän piirteisiin: lihavuuteen, alhaisiin HDL kolesterolin pitoisuuksiin, korkeisiin insuliinipitoisuuksiin ja kohonneeseen verenpaineeseen. Matala greliinipitoisuus yhdistyi myös tyypin 2 diabeteksen ja verenpainetaudin esiintyvyyteen. Tutkituista tekijöistä IGF-I -pitoisuudet selittivät parhaiten greliinipitoisuuksia. Tämä käänteinen yhteys oli erityisen vahva tyypin 2 diabeetikoilla ja insuliiniresistenteillä henkilöillä viitaten greliinin ja IGF-I:n mahdollisen vuorovaikutukseen liittyvän näiden tilojen kehittymiseen. Lisäksi havaittiin, että greliinigeenin Gln51-alleelia kantavien henkilöiden greliinipitoisuudet olivat alhaiset, ja että he sairastivat enemmän diabetesta ja verenpainetautia kuin henkilöt jotka olivat homotsygootteja Arg51-alleelin suhteen. Greliinipitoisuudet ja C-reaktiivisen proteiinin pitoisuudet eivät korreloineet keskenään. Kaulavaltimon seinämäpaksuus korreloi positiivisesti greliinipitoisuuksien kanssa miehillä riippumatta perinteisistä ateroskleroosin riskitekijöistä. Tutkimustulokset tukevat olettamusta, että greliinillä saattaa olla merkitystä metabolisen oireyhtymän, tyypin 2 diabeteksen ja ateroskleroosin kehittymisessä. Jatkotutkimukset ovat tarpeen tämän yhteyden osoittamiseksi

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas<br>A Síndrome metabólica consiste num conjunto de fatores de risco (obesidade abdominal, hipertriglicemia, diminuição do colesterol de alta densidade, hipertensão e hiperglicemia) que predispõem o indivíduo para doenças do foro cardiovascular. O facto da literatura frequentemente associar os indivíduos infetados com o vírus da imunodeficiência humana a um risco aumentado de hipertensão, hiperlipidemia e diabetes, torna importante investigar, se existe efetivamente uma maior prevalência de síndrome metabólica neste grupo de indivíduos e, se sim, quais as causas possíveis (infeção viral e o processo inflamatório e ou/ a terapia tripla de alta atividade). Durante o processo inflamatório, causado pela infeção, está descrito um aumento plasmático de adipocinas (proteína C reativa, interleucina 6, fator de necrose tumoral α, leptina). Estas promovem a hiperglicemia e diminuição da sensibilidade da insulina, contribuindo assim para um aumento da resistência à ação da insulina. A presença de resistência à insulina promove a dislipidemia. Em relação à terapia tripla de alta atividade, os inibidores da protéase exercem alguma toxicidade na mitocôndria, promovem dislipidemia (hipertriglicemia, aumento do colesterol de baixa densidade e do colesterol total e diminuição do colesterol de alta densidade), lipohipertrofia e resistência à insulina. Os inibidores da transcriptase reversa nucleotídea exercem também toxicidade na mitocôndia, promovem resistência à insulina, dislipidemia (hipertriglicemia, aumento do colesterol de baixa densidade e do colesterol total e diminuição do colesterol de alta densidade) e lipoatrofia. Assim, os estudos realizados parecem apontar como causa principal dessas alterações metabólicas, efetivamente a inflamação e/ou a terapia tripla de alta atividade. Metabolic syndrome is a cluster of conditions (abdominal obesity, high serum triglycerides, low high-density lipoprotein levels, elevated blood pressure and elevated plasma glucose) that increase the risk of cardiovascular disease. Scientific literature often correlates HIV infection with a raised risk of hypertension, hyperlipidemia and diabetes. Thereafter, it becomes relevant to study if there is a larger prevalence of metabolic syndrome in HIV-infected patients, and if it does, which are the possible causes (viral infection, inflammation and/or highly active antiretroviral therapy). During HIV infection-associated inflammation, there is evidence of an increase in plasmatic adipokines (C-reactive protein, Interleukin-6, Tumor necrosis factor alpha, Leptin).These proteins promote hyperglicemia and decreased insulin sensitivity, leading this way to insulin resistance. On the other hand, insulin resistance promotes dyslipidemia. In regard to highly active antiretroviral therapy, protease inhibitors induce to some extent mitochondrial toxicity, promoting dyslipidemia (high serum triglycerides, high low-density lipoprotein and total cholesterol levels, low high-density lipoprotein levels), lipohypertrophy and insulin resistance. Nucleoside reverse transcriptase inhibitors also exert mithocondrial toxicity, leading to insulin resistance, dyslipidemia (high serum triglycerides, high low-density lipoprotein and total cholesterol levels, low high-density lipoprotein levels) and lipoatrophy. In sum, up-to-date literature points out the relevance of inflammation and highly active antiretroviral therapy as the main causes of metabolic disorders seen in HIV-infected patients.

by Mui Kin Tung.<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 1993.<br>Includes bibliographical references (leaves 97-113).<br>Chapter CHAPTER 1: --- INTRODUCTION --- p.1<br>Chapter CHAPTER 2: --- LITERATURE REVIEW --- p.5<br>Chapter 2.1 --- ION TRANSPORT SYSTEMS IN HUMAN ERYTHROCYTES --- p.6<br>Chapter 2.1.1 --- "Sodium Pump (Na+,K+-ATPase)" --- p.6<br>Chapter 2.1.2 --- Passive Sodium Transport Systems --- p.9<br>Chapter 2.1.2.1 --- Sodium-potassium-chloride cotransport system --- p.9<br>Chapter 2.1.2.2 --- Sodium-lithium Countertransport --- p.13<br>Chapter 2.1.3 --- Ouabain- and Frusemide-Resistant Passive Effluxes --- p.17<br>Chapter 2.2 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN ESSENTIAL HYPERTENSION --- p.17<br>Chapter 2.2.1 --- "Sodium Pump (Na+, K+-ATPase) in Essential Hypertension" --- p.18<br>Chapter 2.2.2 --- Sodium-Potassium-Chloride Cotransport in Essential Hypertension --- p.20<br>Chapter 2.2.3 --- Sodium-Lithium Countertransport in Essential Hypertension --- p.23<br>Chapter 2.2.4 --- Passive Ion Fluxes in Essential Hypertension --- p.26<br>Chapter 2.2.5 --- Intracellular Sodium Concentration in Essential Hypertension --- p.26<br>Chapter 2.3 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN DIABETES MELLITUS --- p.27<br>Chapter CHAPTER 3: --- MATERIALS & METHODS --- p.29<br>Chapter 3.1 --- MATERIALS --- p.30<br>Chapter 3.1.1 --- Choline Wash Solution (CWS) --- p.30<br>Chapter 3.1.2 --- Lithium Loading Solution --- p.31<br>Chapter 3.1.3 --- Choline Wash Solution with Ouabain (CWS-O) --- p.31<br>Chapter 3.1.4 --- Sodium Containing Medium (SCM) --- p.31<br>Chapter 3.1.5 --- Sodium Free Medium (SFM) --- p.31<br>Chapter 3.1.6 --- Sodium Free Medium with Bumetanide (SFM-B) --- p.32<br>Chapter 3.1.7 --- Preservation Solution --- p.32<br>Chapter 3.2 --- STUDY POPULATION --- p.32<br>Chapter 3.2.1 --- Control Subjects --- p.35<br>Chapter 3.2.2 --- Patients with Essential Hypertension --- p.35<br>Chapter 3.2.3 --- Diabetic Patients --- p.35<br>Chapter 3.3 --- DETERMINATION OF ERYTHROCYTE INTRACELLULAR SODIUM AND POTASSIUM CONCENTRATIONS (Naic/Kic --- p.36<br>Chapter 3.3.1 --- Preparation of Erythrocytes --- p.36<br>Chapter 3.3.2 --- Preparation of Haemolysates --- p.38<br>Chapter 3.3.3 --- Determination of Sodium and Potassium Concentrations in Haemolysates --- p.38<br>Chapter 3.3.4 --- Determination of Haemoglobin Concentration in Haemolysates --- p.38<br>Chapter 3.3.5 --- Evaluation of Erythrocyte Intracellular Sodium and Potassium Concentrations --- p.39<br>Chapter 3.4 --- DETERMINATION OF ERYTHROCYTE PASSIVE POTASSIUM EFFLUX --- p.39<br>Chapter 3.4.1 --- Determination of Potassium Concentrations in Supernatant --- p.40<br>Chapter 3.4.2 --- Evaluation of Passive Potassium Efflux --- p.40<br>Chapter 3.5 --- DETERMINATION OF ERYTHROCYTE SODIUM-LITHIUM COUNTERTRANSPORT (SLC) AND LITHIUM-POTASSIUM COTRANSPORT (LPC) --- p.41<br>Chapter 3.5.1 --- Lithium Loading --- p.42<br>Chapter 3.5.2 --- Determination of Haematocrit --- p.42<br>Chapter 3.5.3 --- Preparation of Haemolysates --- p.42<br>Chapter 3.5.4 --- Determination of the Lithium Concentration in Haemolysates --- p.43<br>Chapter 3.5.5 --- Determination of Lithium Efflux --- p.43<br>Chapter 3.5.6 --- Evaluation of Lithium Efflux Rate --- p.43<br>Chapter 3.5.7 --- Evaluation of Intracellular Lithium Concentration --- p.44<br>Chapter 3.6 --- VALIDATION OF METHODOLOGY FOR DETERMINATION OF ERYTHROCYTE SODIUM TRANSPORT SYSTEMS --- p.45<br>Chapter 3.6.1 --- Effect of Time Course of Lithium Efflux --- p.45<br>Chapter 3.6.2 --- Intracellular Potassium Concentration and Its Effect on Ouabain- and Frusemide-Resistant Passive Potassium Efflux --- p.45<br>Chapter 3.7 --- PRESERVATION OF ERYTHROCYTES FOR DETERMINATION OF SODIUM TRANSPORT SYSTEMS --- p.51<br>Chapter 3.8 --- PRECISION OF THE METHOD --- p.51<br>Chapter 3.9 --- STATISTICS --- p.52<br>Chapter CHAPTER 4: --- RESULTS --- p.56<br>Chapter 4.1 --- POPULATION CHARACTERISTICS --- p.57<br>Chapter 4.2 --- ERYTHROCYTE INTRACELLULAR LITHIUM CONCENTRATIONS AFTER LITHIUM LOADING --- p.57<br>Chapter 4.3 --- RELATIONSHIP BETWEEN ERYTHROCYTE ION TRANSPORT PARAMETERS AND OTHER VARIABLES --- p.58<br>Chapter 4.4 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN ESSENTIAL HYPERTENSION --- p.64<br>Chapter 4.5 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN PATIENTS WITH DIABETES MELLITUS --- p.64<br>Chapter 4.5.1 --- NIDDM Patients without Hypertension --- p.64<br>Chapter 4.5.2 --- NIDDM Patients with Hypertension --- p.65<br>Chapter 4.5.3 --- NIDDM Patients with and without Hypertension --- p.65<br>Chapter 4.6 --- ERYTHROCYTE SODIUM TRANSPORT SYSTEMS IN DIABETES MELLITUS PATIENTS WITH PROTEINURIA --- p.65<br>Chapter 4.6.1 --- Clinical Features and Biochemistry Indices --- p.69<br>Chapter 4.6.2 --- Ion Transport Systems and NIDDM Patients with Proteinuria --- p.69<br>Chapter 4.7 --- EFFECTS OF TREATMENTS ON ERYTHROCYTE ION TRANSPORT SYSTEMS IN DIABETIC HYPERTENSIVE PATIENTS --- p.70<br>Chapter 4.7.1 --- Effects of Diuretic Therapy --- p.70<br>Chapter 4.7.2 --- Effects of Enalapril and Nifedipine Therapy --- p.74<br>Chapter 4.7.3 --- Effects of Enalapril Therapy --- p.74<br>Chapter 4.7.4 --- Effects of Nifedipine Therapy --- p.75<br>Chapter 4.7.5 --- Comparison of the Effects of Enalapril and Nifedipine Therapy --- p.75<br>Chapter CHAPTER 5: --- DISCUSSION --- p.81<br>Chapter 5.1 --- SODIUM TRANSPORT IN ESSENTIAL HYPERTENSION --- p.82<br>Chapter 5.1.1 --- Erythrocyte Sodium-Lithium Countertransport in Essential Hypertension --- p.82<br>Chapter 5.1.2 --- Erythrocyte Sodium-Potassium Cotransport in Essential Hypertension --- p.86<br>Chapter 5.1.3 --- Erythrocyte Intracellular Concentration of Sodiumin Essential Hypertension --- p.87<br>Chapter 5.1.4 --- Erythrocyte Passive Potassium Efflux in Essential Hypertension --- p.90<br>Chapter 5.2 --- SODIUM TRANSPORT SYSTEMS IN NON-INSULIN- DEPENDENT DIABETES MELLITUS (NIDDM) --- p.91<br>Chapter 5.2.1 --- Sodium-Lithium Countertransport in Non-Insulin-Dependent Diabetes Mellitus --- p.91<br>Chapter 5.2.2 --- Erythrocyte Lithium-Potassium Cotransport and Intracellular Sodium Concentration in Non-Insulin-Dependent Diabetes Mellitus --- p.93<br>Chapter 5.3 --- EFFECT OF ANTIHYPERTENSIVE AGENTS ON ERYTHROCYTE SODIUM TRANSPORT SYSTEMS --- p.95<br>REFERENCES --- p.98

Thesis (M.A.)--York University, 2007. Graduate Programme in Psychology.<br>Typescript. Includes bibliographical references (leaves 91-106). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR32021

Orientação : Liliana Mendes<br>A Diabetes Mellitus tipo 2 está muitas vezes associada a Hipertensão Arterial ou Pressão Arterial normal alta e está frequentemente presente nos doentes com Síndrome Metabólica. Os fármacos Anti-Hipertensores têm diferentes efeitos a nível metabólico, existindo evidência científica de que o Sistema Renina-Angiotensina-Aldosterona é fundamental para os mecanismos de Resistência à insulina. O objetivo deste trabalho é compreender os mecanismos dos vários Anti- Hipertensores, e de que forma eles contribuem para o aumento da concentração de insulina e para a resistência por parte dos tecidos à hormona.<br>Diabetes mellitus type 2 is associated in many times to Hypertension or High-Normal Blood Pressure and occurred frequently in metabolic syndrome patients. Antihypertensive agents have different effects in metabolism. There is evidence that Renin-Angiotensin-Aldosterone System is important for the mechanism of insulin Resistance. The purpose of this work is understand the mechanisms of Antihypertensive agents and how they contribute to the insulin increase tissues resistance to the hormone.

Lee Kwing Chin, Kenneth.<br>Thesis (Ph.D.)--Chinese University of Hong Kong, 1999.<br>Includes bibliographical references (p. 298-357).<br>Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Mode of access: World Wide Web.<br>Abstracts in English and Chinese.

Magnetic resonance spectroscopy (MRS) is a noninvasive technique that enables to follow metabolic processes in selected tissues in vivo. Recently the attention has been focused on metabolic mapping in target organs of insulin action to describe the pathophysiology of insulin resistance. The aim of our study was to present the practical application of ³¹P (phosphorus) MRS and ¹H (proton) MRS in metabolic studies of skeletal muscle in insulin resistant subjects and in subjects with impaired fasting glucose. The third study was aimed to evaluate the brain metabolism with ¹H MRS in healthy controls and subjects with type 1 diabetes during hyperinsulinemia. ¹H and ³¹P MRS were performed using a MR Scanner Siemens Vision operating at 1,5 Tesla. To assess the parameters of glucose metabolism and insulin action oral glucose tolerance test and hyperinsulinemic euglycemic clamp were performed. The study 1 was aimed to evaluate the skeletal muscle (m. soleus) energetic metabolism in the offspring of hypertensive parents (OH) with a higher level of insulin resistance. The concentrations of selected high energy phosphates (phosphocreatine, inorganic phosphate, adenosintriphosphate, phosphomonoesters, phosphodiesters) were evaluated with ³¹P MRS. Their amount in OH was comparable to healthy controls. However we...

Les kinines agissent sur deux types de récepteurs couplés aux protéines G, nommés B1 et B2, lesquels jouent un rôle important dans le contrôle cardiovasculaire, la nociception et l’inflammation. Nous considérons l’hypothèse que le récepteur B1 des kinines est induit et contribue aux complications diabétiques, incluant l’hypertension artérielle, les polyneuropathies sensorielles, l’augmentation du stress oxydatif vasculaire, l’inflammation vasculaire et l’obésité chez le rat traité au D-glucose (10% dans l’eau de boisson) pendant 8 ou 12 semaines. Dans ce modèle de résistance à l’insuline, nous avons évalué les effets d’un traitement pharmacologique d’une semaine avec un antagoniste du récepteur B1 des kinines, le SSR240612 (10 mg/kg/jr). Les résultats montrent que le SSR240612 renverse l’hypertension, l’allodynie tactile et au froid, la production de l’anion superoxyde et la surexpression de plusieurs marqueurs inflammatoires dans l’aorte (iNOS, IL-1β, macrophage (CD68, CD11), ICAM-1, E-selectine, MIF ainsi que le B1R) et dans les adipocytes (iNOS, IL-1β, TNF-α et macrophage CD68). De plus, le SSR240612 corrige la résistance à l’insuline, les anomalies du profil lipidique plasmatique et le gain de poids et de masse adipeuse. Ces données supportent l’implication des kinines dans les complications diabétiques dans un modèle animal de résistance à l’insuline et suggèrent que le récepteur B1 est une cible thérapeutique potentielle dans le diabète et l’obésité.<br>Kinins act on two G-protein-coupled receptors, denoted as B1 and B2, and play an important role in cardiovascular regulation, nociception and inflammation. We have considered the hypothesis that kinin B1 receptor is upregulated and involved in diabetic complications, notably hypertension, pain sensory neuropathy, the oxidative stress in the vasculature, vascular inflammation, insulin resistance and obesity in rats treated for 8 or 12 weeks with D-glucose (10% of glucose in their drinking water). In this model of insulin resistance, we assessed the effects of one-week treatment with SSR240612 (10 mg/kg/day), a selective kinin B1 receptor antagonist. Data show that SSR240612 reverses high blood pressure, tactile and cold allodynia, the production of oxidative stress (superoxyde anion) in the aorta, the overexpression of iNOS, IL-1β, macrophage (CD68, CD11), ICAM-1, E-selectine, MIF and B1R in the aorta and iNOS, IL-1β, TNF-α and macrophage (CD68) in adipocytes. Moreover, SSR240612 reverses insulin resistance, plasma fatty acids composition changes and body and tissue fat gain. These data support a key role for kinins in diabetic complications in a rat model of insulin resistance and suggest that kinin B1 receptor is a promising therapeutic target in diabetes and obesity.

Indiana University-Purdue University Indianapolis (IUPUI)<br>Obesity increases cardiovascular disease risk and is associated with factors of the “metabolic syndrome” (MetS), a disorder including hypertension, hypercholesterolemia and/or impaired glucose tolerance. Expanding adipose and subsequent inflammation is implicated in vascular dysfunction in MetS. Perivascular adipose tissue (PVAT) surrounds virtually every artery and is capable of releasing factors that influence vascular reactivity, but the effects of PVAT in the coronary circulation are unknown. Accordingly, the goal of this investigation was to delineate mechanisms by which lean vs. MetS coronary PVAT influences vasomotor tone and the coronary PVAT proteome. We tested the hypothesis that MetS alters the functional expression and vascular contractile effects of coronary PVAT in an Ossabaw swine model of the MetS. Utilizing isometric tension measurements of coronary arteries in the absence and presence of PVAT, we revealed the vascular effects of PVAT vary according to anatomical location as coronary and mesenteric, but not subcutaneous adipose tissue augmented coronary artery contractions to KCl. Factors released from coronary PVAT increase baseline tension and potentiate constriction of isolated coronary arteries relative to the amount of adipose tissue present. The effects of coronary PVAT are elevated in the setting of MetS and occur independent of endothelial function. MetS is also associated with substantial alterations in the coronary PVAT proteome and underlying increases in vascular smooth muscle Ca2+ handling via CaV1.2 channels, H2O2-sensitive K+ channels and/or upstream mediators of these ion channels. Rho-kinase signaling participates in the increase in coronary artery contractions to PVAT in lean, but not MetS swine. These data provide novel evidence that the vascular effects of PVAT vary according to anatomic location and are influenced by the MetS phenotype.