Dissertations / Theses on the topic 'Diabetic angiopathies'

Diabetic cardiomyopathy (DCM), a disorder of the heart muscle, is one of the major and most rampant culprits claiming thousands and thousands of lives around the globe every year by interfering with the blood circulation and causing the development of heart failure eventually. The progression of the disease is asymptomatic and having a long latent period, and it is characterized functionally by ventricular dilation, diastolic dysfunction, interstitial fibrosis and cardiomyocytes hypertrophy. It was suggested the pathogenesis of the disease and the related complications are related to the effects of hyperglycemia on cardiomyocytes. So understanding the physiology of both the normal and pathological conditions, and the underlying mechanisms involved are of paramount importance to derive therapies to cope with this disease. However, it is difficult, if not impossible, to study the physiology in vivo using a live sample or to build a cellular model with adult cardiomyocytes due to the insufficient number of the cells harvested. This is not until the emergence of Embryonic Stem Cells (ESCs) that a cellular model with clinical sufficient number of cardiomyocytes could be built for investigation and drug screening. With a view to mimicking the situation of the Diabetic cardiomyopathy of the Type II Diabetes mellitus (DM) patients, mouse ESCs are used to differentiate into cardiomyocytes using the traditional hanging drop method to produce Embryoid body (EB). The cardiomyocytes were then enriched and plated so that different testing conditions could be applied. The effect of high glucose (HG), Insulin and the combination of high glucose and insulin were then analyzed. This was to show the significance of hyperglycemia, hyperinsulinemia due to insulin resistance and the role of insulin in hyperglycemia on cardiomyocytes respectively. The results agreed with previous findings that high glucose and insulin alone do induce cells apoptosis while the combination of insulin and glucose did decrease the number of apoptosis and while the co-culture of insulin with High dosage of glucose has shown to reduce the effect of hypertrophy.
published_or_final_version
Medicine
Master
Master of Medical Sciences

Diabetes mellitus represents a state of insulin insufficiency with elevated glucose levels. Previous studies have shown that patients with diabetes not only have an increased risk for cardiovascular disease, but they are also more likely to suffer adverse outcomes following acute myocardial infarction (AMI). Even in people without known diabetes, stress-induced hyperglycaemia at the time of AMI has been associated with poor outcomes. It is uncertain if hyperglycaemia causes direct myocardial injury following acute ischaemia and reperfusion, and if short term insulin therapy protects the ischaemic myocardium. A number of clinical trials, however, suggest that insulin therapy is beneficial. In this thesis, through a number of experimental studies, the effe􀀓ts of glucose and insulin on the myocardium were assessed. After studying these effects in animal models, the impact of an insulin-dextrose infusion regimen aimed at maintaining norrnoglycaemia during the peri-infarct period was also evaluated in a clinical trial. In the first part of the thesis, a retrospective review of patients admitted to Westmead Hospital with AMI over a 12-month period was conducted. Clinical, historical and biochemical parameters were correlated against adverse cardiac outcomes (mortality, cardiac failure, re-infarction etc). From multi-variate logistic regression analysis, admission glucose level was a consistent predictor of mortality and morbidity in all AMIpatients as well as in those who received reperfusion therapy for up to 6 months following index AMI admission. The study confirmed that hyperglycaemia remains a significant predictor of cardiac mortality and morbidity in the reperfusion era. To evaluate whether elevated glucose levels have a direct pathological role on the ischaemic myocardium, an adult rat cardiomyocyte culture model was adopted to assess the impact of glucose and insulin on cardiomyocyte viability. Rat cardiomyocytes from primary culture were incubated in media containing different levels of glucose as well as insulin under a normoxic environment. Exposure of cardiomyocytes to higher concentration of glucose (without insulin) resulted in significantly greater cytotoxicity, while cells incubated in media containing the highest insulin concentration (at normal glucose levels) had the lowest cytotoxicity. When the high glucose media was supplemented with insulin, the cytotoxic effect of high glucose was negated. To study the effects of glucose and insulin on the ischaemic myocardium, an isolated rabbit heart model of regional ischaemia and reperfusion was also developed. The hearts were perfused with buffers containing varying levels of glucose and insulin, and the infarct size for each heart was assessed. In the high-glucose protocol, the infarct size was significantly greater than that when hearts were exposed to normal glucose levels. On the other hand, insulin, when given just before reperfusion, reduced infarct size in a dose­dependent manner. Furthermore, insulin attenuated the extent of infarction in hearts that were exposed to high glucose levels. Therefore, from these 2 different animal models, elevated glucose levels were found to be harmful to the myocardium by increasingcardiomyocyte death (in the culture model) and inducing greater infarct size (in the ischaemic model). Conversely, insulin preserved cardiomyocyte viability and reduced infarct size following an ischaemic insult. The cellular mechanism for the action of insulin on the myocardium was beyond the scope of this thesis, and it is difficult to speculate whether insulin confers protection through insulin receptor or other pathways such as the insulin-like growth factor receptor. Extending these findings to clinical practice, a randomized controlled trial was conducted to evaluate the effects of maintaining normoglycaemia by an insulin infusion regimen at the time of AMI. Patients presenting with AMI who either had known diabetes or were hyperglycemic on admission were recruited into the Hyperglycemia: Intensive Insulin Infusion !n !nfarction (HI-5) Study. Subjects were randomized to receive either intensive therapy (insulin/dextrose infusion for 24 hours to keep glucose level 4 - lOmmol/1) or conventional therapy. Intensive insulin therapy did not confer survival advantage for patients following AMI up to 6 months following admission, but it resulted in a lower incidence of in-hospital cardiac failure. Insulin therapy also reduced the incidence of composite endpoints for subjects with antero-lateral AMI or those who received reperfusion therapy. Patients with pre-existing diabetes did not derive clinical benefit from insulin therapy, but as a group, they did not have greater adverse outcomes compared to those without diabetes. Unfortunately, due to the suboptimal patient recruitment as well as the better than expected overall survival for AMI patients, the power of the study was substantially reduced. Elevated inflammatory markers have been associated with worse outcomes in myocardial infarction. In the HI-5 Study, insulin therapy reduced free fatty acid (FFA) levels and attenuated the rise of C-reactive protein (CRP) levels. Day 2 CRP levels also correlated with the mean glucose levels of subjects during the first 24 hours of treatment. Suppression of FFA and the attenuation of the rise of CRP may have theoretical benefits for the preservation of ischaemic myocardium, but it has not translated into improved clinical outcomes in the HI-5 study. In summary, from experimental studies conducted in this thesis, elevated glucose levels were found to be detrimental to the myocardium during normoxia or following ischaemia, while insulin confers cardio-protection in both conditions. However, despite the reduction of FFA levels and markers of inflammation, clinical benefits were not clearly evident in the HI-5 study. The findings of other very recent clinical studies also did not support the use of insulin-based therapy following AMI, but it is possible that a higher dose of insulin maintaining tighter glycaemic control may still improve outcomes for patients following AMI. For the time being, in the absence of consistent clinical trial evidence, one cannot justify the routine use of intensive insulin-based treatment to control glucose levels during AMI. However, optimization of the management of coronary artery disease for patients with hyperglycaemia remains an important research priority of this era.

Diabetics often have elevated levels of serum lipids and cholesterol and increased risk of cardiovascular disease. Streptozotocin-induced diabetes was used to determine whether elevated serum cholesterol levels in diabetics are due to loss of control of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the committed step in cholesterol synthesis. Strain A/ST female mice were fed 10% corn oil diets, half with 2% cholesterol. Experimental groups were injected with 9.0 mg streptozotocin / 100g body weight. Diabetes was confirmed by weight loss, elevated blood sugars, and enlarged spleens. Reductase activity was assayed spectrophotometrically. Serum cholesterol levels were determined by gas liquid chromatography. Both diabetic and control mice fed cholesterol had elevated serum cholesterol levels and decreased reductase activities. These observations suggest that HMG CoA reductase is not the primary control point in the control of serum cholesterol levels in diabetic mice. The increase in serum cholesterol in the SI mice was not more than in the control group, suggesting that increased serum cholesterol is not a key factor in the control of coronary heart disease and related diseases in diabetics. The HMG CoA reductase activity was reduced in both SI and control mice fed 2% cholesterol, but not significantly, possibly due to a small sample size. Other substances that control serum cholesterol are all density classes of lipoproteins (high, intermediate, low, and very low) as well as the chylomicrons.
Department of Biology

[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.

[Truncated abstract] Cardiovascular reflex control of the vasculature is important in maintaining adequate tissue oxygenation in the face of disturbances in physiological homeostasis. Alterations in blood oxygen levels and blood distribution evoke integrated neural, mechanical and humoral responses which modulate peripheral vasomotor tone to maintain systemic cardiovascular integrity. The balance between the local effects of hypoxia and changes in chemoreflex control of vascular tone during hypoxia determine whether net vasoconstriction or vasodilatation is evident in the peripheral vasculature. The mechanisms contributing to hypoxic vasodilatation per se have not previously been defined in healthy humans. Study 1 of this thesis (Chapter 3) investigated the mechanisms contributing to vasomotor responses to chemoreflex activation in the human forearm ... Study 2 (Chapter 4a) investigated the mechanisms controlling vasomotor responses to isocapnic hypoxia in subjects with type 2 diabetes ... Study 3 (Chapter 5) compared the vascular responses to decreased venous return in individuals with and without right atrial afferent innervation ... The results of this thesis indicate that in healthy humans isocapnic hypoxia induces sympathetic vasoconstriction, which masks underlying β-adrenoceptor mediated vasodilatation. The normal vasomotor response to isocapnic hypoxia is impaired in subjects with type 2 diabetes. Despite intact vasoconstrictor responses, subjects with type 2 diabetes exhibited attenuated adrenaline-mediated vasodilatation compared to healthy control subjects, suggesting that the chemoreflex in these subjects is ill-equipped to respond to hypoxic stress. In clinical terms, impaired reflex vasomotor

Thesis (M.D.)--University of Adelaide, Dept. of General Practice, 2005.
Includes publications published as a result of ideas developed in this thesis, inserted at end. "April 2005" Includes bibliographical references (leaves 210-242).

Thesis (Ph.D. in Epidemiology) -- University of Colorado Denver, 2007.
Typescript. Includes bibliographical references (leaves 100-117). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

УВОД: Diabetes mellitus (DM) је водећа глобална епидемија 21. века, сложена болест коју карактерише поремећај метаболизма и хронична хипергликемија, која доводи до развоја микроваскуларних и макроваскуларних компликација. Повишене вредности гликемије у ДМT2 доводе до поремећаја ћелија крви и њихових параметара. Истраживања су показала да хема-толошки параметри имају допринос у настанку оштећења васкуларног ендотела и учествују у развоју дегенеративних промена и путем других механизама код пацијената са дијабетесом. Циљ истраживања је да се утврде могуће промене параметара комплетне крвне слике (ККС) у зависности од гликорегулације, дужине трајања болести и њихова повезаност са микро и макро ангиопатским комликацијама код пацијената са шећерном болести тип 2 (ДМT2). МЕТОДЕ: Студија је била проспективна у трајању од једне године, од 2016. до 2017. године. Истраживањем је обухваћено укупно 137 испитаника, од којих 90 болује од ДМТ2, а 47 је здравих, оба пола, старијих од 40 година, спроведена у Дому здравља “Др Милорад Мика Павловић”, Инђија, Србија. Да би се утврдила могућа корелација између параметара ККС, гликорегулације у ДМT2 и дегенеративних компликација, испитаници су подељени на више начина: на групу оболелих од ДМT2 и групу здравих; групе оболелих са вредностима HbA1c≤7% и оне са вредностима HbA1c >7%, као и на групе са и без дегенеративних компликација. Коришћењем стандардних биохемијских поступака анализирани су параметри ККС, параметри гликорегулације, липидни статус, а вршена су и антропометријска мерења. Подаци од пацијената прикупљени су путем упитника и електронског картона пацијента. РЕЗУЛТАТИ: Утврђена је статистички значајна разлика између група са и без шећерне болести за WBC, еозинофилне гранулоците, хемоглобин, MCH, MCHC, SE у 2016. год, неутрофилне гранулоците, моноците, RDW, PDW, SE у 2017. год. У групи чија је дужина трајања ДМT2 већа од 6 година утврђене су повишене вредности MCHC и PDW. У односу на гликорегулацију уочене су значајне разлике у PMDW, великим тромбоцитима и RDW у групи са HbA1c>7%. У односу на дегенеративне микроваскуларне компликације постоје значајне разлике у броју лимфоцита и неутрофилних гранулоцита, а за макроваскуларне компликације у вредностима PDW-а. ЗАКЉУЧАК: На основу добијених резултата нашег истраживања може се закључити да постоји повезаност између појединих хематолошких параметара и гликорегулације, обољевања од шећерне болести као и повезаност са компликацијама код пацијената са ДМТ2.
UVOD: Diabetes mellitus (DM) je vodeća globalna epidemija 21. veka, složena bolest koju karakteriše poremećaj metabolizma i hronična hiperglikemija, koja dovodi do razvoja mikrovaskularnih i makrovaskularnih komplikacija. Povišene vrednosti glikemije u DMT2 dovode do poremećaja ćelija krvi i njihovih parametara. Istraživanja su pokazala da hema-tološki parametri imaju doprinos u nastanku oštećenja vaskularnog endotela i učestvuju u razvoju degenerativnih promena i putem drugih mehanizama kod pacijenata sa dijabetesom. Cilj istraživanja je da se utvrde moguće promene parametara kompletne krvne slike (KKS) u zavisnosti od glikoregulacije, dužine trajanja bolesti i njihova povezanost sa mikro i makro angiopatskim komlikacijama kod pacijenata sa šećernom bolesti tip 2 (DMT2). METODE: Studija je bila prospektivna u trajanju od jedne godine, od 2016. do 2017. godine. Istraživanjem je obuhvaćeno ukupno 137 ispitanika, od kojih 90 boluje od DMT2, a 47 je zdravih, oba pola, starijih od 40 godina, sprovedena u Domu zdravlja “Dr Milorad Mika Pavlović”, Inđija, Srbija. Da bi se utvrdila moguća korelacija između parametara KKS, glikoregulacije u DMT2 i degenerativnih komplikacija, ispitanici su podeljeni na više načina: na grupu obolelih od DMT2 i grupu zdravih; grupe obolelih sa vrednostima HbA1c≤7% i one sa vrednostima HbA1c >7%, kao i na grupe sa i bez degenerativnih komplikacija. Korišćenjem standardnih biohemijskih postupaka analizirani su parametri KKS, parametri glikoregulacije, lipidni status, a vršena su i antropometrijska merenja. Podaci od pacijenata prikupljeni su putem upitnika i elektronskog kartona pacijenta. REZULTATI: Utvrđena je statistički značajna razlika između grupa sa i bez šećerne bolesti za WBC, eozinofilne granulocite, hemoglobin, MCH, MCHC, SE u 2016. god, neutrofilne granulocite, monocite, RDW, PDW, SE u 2017. god. U grupi čija je dužina trajanja DMT2 veća od 6 godina utvrđene su povišene vrednosti MCHC i PDW. U odnosu na glikoregulaciju uočene su značajne razlike u PMDW, velikim trombocitima i RDW u grupi sa HbA1c>7%. U odnosu na degenerativne mikrovaskularne komplikacije postoje značajne razlike u broju limfocita i neutrofilnih granulocita, a za makrovaskularne komplikacije u vrednostima PDW-a. ZAKLJUČAK: Na osnovu dobijenih rezultata našeg istraživanja može se zaključiti da postoji povezanost između pojedinih hematoloških parametara i glikoregulacije, oboljevanja od šećerne bolesti kao i povezanost sa komplikacijama kod pacijenata sa DMT2.
BACKGROUND: Diabetes mellitus (DM) is the leading global epidemic of the 21st century,a complex disease characterized by metabolism disorders and chronic hyperglycaemia, that leads to the development of microvascular and macrovascular complications. Elevated blood glucose level in T2DM lead to disturbance of blood cells and its parameters. Previous studies have reported that haematological parameters have contributed to the development of vascular endothelial damage and are involved in the development of degenerative changes through other mechanisms in patients with diabetes. The aim of the research is to determine possible changes in the complete blood count (CBC) parameters depending on glycemic control, the duration of the disease and their association with micro and macroangiopathic complications in patients with Type 2 diabetes mellitus (T2DM). METHODS: The study was prospective from 2016. to 2017. year. The study included a total of 137 subjects, 90 with T2DM and 47 healthy, of both gender over the age of 40 years, from the Health Care Center "Dr Milorad Mika Pavlović" Indjija, Serbia. The subjects were divided into several ways, in order to notice the possible correlation between the CBC parameters and glucose control in T2DM, with and without T2DM, two groups with HbA1c≤7% and with HbA1c>7%, and with and without complications. We analysed CBC parameters, parameters of glycoregulation, lipid status using standard biochemical methods, performed anthropometric measurements and collected patients data by questionnaire and electronic patient card. RESULTS: There were statistical difference between group with T2DM and healthy subjects for WBC, eos, Hgb, MCH, MCHC, ESR in 2016. and neutro, mono, RDW, PDW, ESR in 2017. In the group of T2DM patients with duration of disease longer than 6 years we found elevated value of MCHC, PDW. In relationship to glycoregulation, significant differences in PMDW, large platelets and RDW were found in the group HbA1c>7%. According to degenerative complications significant differences were revealed in lympho, neutro in the group with microvascular complication, and PDW in the group with macrovascular complications. CONCLUSION: Based on the resuluts of our research, it can be concluded that there is an association between particular haematological parameters and glycoregulation, diabetes mellitus, as well as relationship with degenerative complications in patients with T2DM.

Le diabète, caractérisé notamment par une atteinte neuro-vasculaire, représente aujourd’hui un réel problème de santé publique. Cependant plus de 30% des patients, ne peuvent bénéficier des traitements actuels (chirurgie et pharmacothérapie) d’où, la nécessité de développer de nouvelles approches thérapeutiques innovantes. L’objectif de ce travail a été de caractériser un modèle murin de neuro-angiopathie diabétique, représentatif de la pathologie humaine puis, d’évaluer les effets des molécules guidance neuronale dans la récupération de la fonction neuro-vasculaire. Dans un premier temps, nous avons mis en place un modèle et des techniques exploratoires de l’étude de la fonction neuro-vasculaire chez les souris diabétiques. Nous avons observé que suite à l’ischémie du membre inférieur, la revascularisation est altérée chez les animaux diabétiques par comparaison aux animaux non-diabétiques. A ce défaut de la fonction vasculaire, s’ajoute également un défaut de la fonction nerveuse. En effet, les paramètres électrophysiologiques, le flux sanguin nerveux, le nombre de capillaires dans le nerf sciatique et la régénération nerveuse sont fortement impactés chez les animaux diabétiques. Afin de palier au défaut de revascularisation et/ou de régénération nerveuse, nous avons proposé que le ciblage thérapeutique des molécules de guidance neuronale, éphrine-B2 et Sémaphorine-3A (Séma-3A) améliorerait la fonction neuro-vasculaire. Après ischémie, les cellules mononuclées du sang périphérique (CM-SP) provenant de patients diabétiques ou de sujets contrôles, traitées préalablement avec l’éphrine-B2/Fc, ont été ensuite injectées aux animaux diabétiques. Une nette amélioration de la revascularisation a été observée dans les groupes d’animaux traités avec l’éphrine-B2/Fc par rapport aux animaux non-traités ou traités avec des CM-SP non stimulées. Enfin, nous avons administré un inhibiteur de Séma-3A, SM-345431 (Vinaxanthone) à des animaux contrôles et diabétiques après ischémie du membre inférieur. Ce qui nous a permis de montrer que cette inhibition améliore significativement la revascularisation et régule notamment la voie de signalisation des MAPK, Erk1/2 et p38 ainsi que, les niveaux de VEGF et de TGF-β1. Dans l’ensemble, l’effet sur la fonction nerveuse périphérique n’a pas montré de différences majeures entre les groupes traités et non-traités. En somme, nos travaux ont permis de montrer que la thérapie cellulaire utilisant les CM-SP stimulées avec l’éphrine-B2/Fc, ou bien l’injection intramusculaire d’un inhibiteur de Séma-3A, à visée pro-angiogénique et/ou pro-neurorégénérative, apparaît comme une stratégie prometteuse et susceptible d’améliorer la qualité de vie des malades atteints de diabète
Diabetes, characterized by neuro-vascular damages, is a real public health problem. More than 30% of diabetic patients can benefit from existing therapies (surgery and drug therapy), therefore, the need to develop new innovative therapeutic approaches. The objective of this work was to characterize a diabetic neuro-angiopathy mouse model, reproducible of human pathology and to assess the effects of neuronal guidance molecules in recovery of the neuro-vascular function. Firstly, we characterized a model and exploratory techniques to study the neuro-vascular functions in diabetic mice. After hindlimb ischemia induction, we observed that revascularization were impaired in diabetic animals compared to non diabetic animals. This alteration is associated of the nerve function defect. Indeed, the electrophysiological parameters, nerve blood flow, the number of capillaries in sciatic nerve and nerve regeneration are strongly affected in diabetic animals. Then, to rescue the revascularization or nerve regeneration, we proposed that the therapeutic targeting of molecules of neuronal guidance, ephrin-B2 and Semaphorin-3A (Sema-3A) would improve neuro-vascular functions. After ischemia induction, peripheral mononuclear blood mononuclear cells (PBMNC) from diabetic patients or subjects controls, pre-treated with ephrin-B2/Fc, were then injected in diabetic animals. A significant improvement of revascularization was observed in both groups, animals treated with ephrin-B2/Fc compared to untreated animals or treaties with PBMNC unstimulated. Finally, after hindlimb ischemia, we administrated a pharmacological inhibitor of Sema-3A, the SM-345431 (Vinaxanthone) in diabetic and control animals. We showed this selective inhibition significantly improved the post-ischemic revascularization, regulates the MAPK Erk1/2 and p38 signaling pathway, increased the levels of CXCL12, VEGF and TGF-β1. In our experiment conditions, we did not observe the significant effects of SM-345431 on peripheral nerve function between treated and untreated animal groups. Finally, our work showed that cell therapy using PBMNC stimulated with ephrin-B2/Fc, or the intramuscular injection of Sema-3A inhibitor referred to pro-angiogenic and/or pro-neuroregenerative, appears as a strategy promising and likely to improve the quality of life of diabetic patients

Aside from an indirect effect of PPARgamma activation to reduce insulin resistance and to facilitate adiponectin release, PPARgamma agonist could also exert direct effects on blood vessels. I provided a first line of experimental evidence demonstrating that PPARgamma agonist rosiglitazone up-regulates the endothelin B receptor (ETBR) expression in mouse aortas and attenuates endothelin-1-induced vasoconstriction through an endothelial ET BR-dependent NO-related mechanism. ETBR up-regulation inhibits endothelin-1-induced endothelin A receptor (ETAR)-mediated constriction in aortas and mesenteric resistance arteries, while selective ETBR agonist produces endothelium-dependent relaxations in mesenteric resistance arteries. Chronic treatment with rosiglitazone in vivo or acute exposure to rosiglitazone in vitro up-regulate the ETsR expression without affecting ETAR expression. These results support a significant role of ETBR in contributing to the increased nitric oxide generation upon stimulation with PPARgamma agonist. This study provides additional explanation for how PPARgamma activation improves endothelial function.
Firstly, I demonstrated that adipocyte-derived adiponectin serves as a key link in PPARgamma-mediated amelioration of endothelial dysfunction in diabetes. Results from ex vivo fat explant culture with isolated arteries showed that PPARgamma expression and adiponectin synthesis in adipose tissues correlate with the degree of improvement of endothelium-dependent relaxation in aortas from diabetic db/db mice. PPARgamma agonist rosiglitazone elevates the adiponectin release and restores the impaired endothelium-dependent relaxation ex vivo and in vivo, in arteries from both genetic and diet-induced diabetic mice. The effect of PPARgamma activation on endothelial function that is mediated through the adiponectin- AMP-activated protein kinase (AMPK) cascade is confirmed with the use of selective pharmacological inhibitors and adiponectin -/- or PPARgamma+/- mice. In addition, the benefit of PPARgamma activation in vivo can be transferred by transplanting subcutaneous adipose tissue from rosiglitazone-treated diabetic mouse to control diabetic mouse. I also revealed a direct effect of adiponectin to rescue endothelium-dependent relaxation in diabetic mouse aortas, which involves both AMPK and cyclic AMP-dependent protein kinase signaling pathways to enhance nitric oxide formation accompanied with inhibition of oxidative stress. These novel findings clearly demonstrate that adipocyte-derived adiponectin is prerequisite for PPARgamma-mediated improvement of endothelial function in diabetes, and thus highlight the prospective of subcutaneous adipose tissue as a potentially important intervention target for newly developed PPARgamma agonists in the alleviation of diabetic vasculopathy.
To summarize, the present investigation has provided a few lines of novel mechanistic evidence in support for the positive roles of PPARgamma and PPARdelta activation as potentially therapeutic targets to combat against diabetic vasculopathy.
Type 2 diabetes mellitus and obesity represent a global health problem worldwide. Most diabetics die of cardiovascular and renal causes, thus increasing the urgency in developing effective strategies for improving cardiovascular outcomes, particularly in obesity-related diabetes. Recent evidence highlights the therapeutic potential of peroxisome proliferators activated receptor (PPAR) agonists in improving insulin sensitivity in diabetes.
While agonists of PPARalpha and PPARgamma are clinically used, PPARdelta is the remaining subtype that is yet to be a target for current therapeutic drugs. Little is available in literature about the role of PPARdelta in the regulation of cardiovascular function. The third part of my thesis focused on elucidating cellular mechanisms underlying the beneficial effect of PPARdelta activation in the modulation of endothelial function in diabetes. PPARdelta agonists restore the impaired endothelium-dependent relaxation in high glucose-treated aortas and in aortas from diabetic db/db mice through activation of a cascade involving PPARdelta, phosphatidylinositol 3-kinase, and Akt. PPARdelta activation increases Akt and endothelial nitric oxide synthase and nitric oxide production in endothelial cells. The crucial role of Akt is confirmed by selective pharmacological inhibitors and transient transfection of dominant negative Akt plasmid in these cells. Treatment with PPARdelta agonist GW501516 in vivo augments endothelial function in diabetic db/db and diet-induced obese mice. The specificity of GW501516 for PPARdelta is proven with the loss of its effect against high glucose-induced impairment of endothelium-dependent relaxation in aortas from PPARdelta knockout mice. In addition, oral administration of GW501516 in vivo fails to improve endothelial function in diet-induced obese PPARdelta deficient mice.
Tian, Xiaoyu.
Adviser: Huang Yu.
Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: .
Thesis (Ph.D.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 132-165).
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, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Indiana University-Purdue University Indianapolis (IUPUI)
Medication adherence remains a problem among Type-2 diabetes (T2D) patients despite availability of effective treatments. Three analyses of extant data sets were conducted to examine barriers to using medication as prescribed as an alternate method to assess medication adherence: 1) development and psychometric evaluation of the Murage-Marrero-Monahan-Medication barriers (4M) scale to assess patients’ perceived barriers; 2) patient demographic factors associated with barriers to using medication as prescribed, and 3) the association between patients’ perceived barriers to medication use and cardiovascular disease (CVD) risk factor control.Twelve focus groups and a cross-sectional study of 362 T2D patients contributed to develop and evaluate psychometric properties of the 4M scale. A cross-sectional survey of 964 T2D patients was used for the other two studies. Analysis of covariance identified demographic factors associated with reported barriers. Multivariable logistic regression was used to identify barriers associated with CVD risk factors (glucose, blood pressure and lipids) categorized as either poor or good control. Exploratory factor analysis with Varimax rotation resulted in a 19-item 4M scale with acceptable psychometric properties. As a five-domain (or single-domain) structure, coefficient alpha ranged from 0.70 to 0.83 (0.92). Both structures demonstrated discriminant validity and known-group validity. Age was inversely associated with all identified barriers while income was inversely associated with poor communication with providers and side effects. A unit increase in the overall barrier mean score on the 4M scale was associated with 92% increase in the odds of having poor control of two or more CVD risk factors compared to good control of all three risk factors (adjusted OR=1.92, 95% CI: 1.16–3.17; p<0.05). The 4M scale demonstrated acceptable psychometric properties in assessing barriers to using medication among T2D patients. Poor medication adherence has been previously associated with CVD risk. In this study, greater barriers were associated with poorer control of CVD risk factors making barriers a potential alternative to medication adherence, whose current assessment methods are limited. The 4M scale has the advantage to identify specific barriers inhibiting medication use that can facilitate patient-provider discussions and the development of targeted interventions.
Some parts of this dissertation work were jointly funded by Program Announcement 04005 from the Centers for Disease Control and Prevention (Division of Diabetes Translation) and the National Institute of Diabetes and Digestive and Kidney Diseases. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the funding agency(s).

M.Cur.
The former Transkei is a predominantly rural region of the Eastern Cape Province. The poor infrastructure in this area results in inaccessibility of the available health services. The majority is ill equipped to deliver optimum diabetes care. There is an increase of lower limb amputations and lack of knowledge among patients with diabetes in the former Transkei. These complications can be prevented by patient education on self-management and appropriate footcare procedures. This qualitative study was conducted to explore and describe the experiences and footcare practices of diabetic patients who live in the rural areas of Transkei. A sample of 15 participants was drawn from Umtata Hospital Diabetic Clinic register through predetermined selection criteria. The sample consisted of five men aged 49 - 74 years, and ten women aged 30 - 64 years. Five patients (two men and three women) had foot ulcers or an amputation, while ten patients had no obvious foot problems. In-depth phenomenological interviews were conducted with all 15 patients. Interviews were tape recorded in Xhosa, transcribed, and translated into English for analysis. Direct observation of footcare was done with eight patients from the sample. Content analysis of the phenomenological interviews was facilitated by a protocol; and a checklist guided direct observation of footcare. A debate took place among the three coders to come to a consensus about the themes that emerged from their individual analyses. Guba's model of trustworthiness was utilised to ensure that the findings of this study reflect the truth. Ethical considerations were based on the guidelines cited by the Democratic Nursing Organisation of South Africa (1998: 2.3.1-2.3.4) and the South African Medical Research Council (1993: 32-44). Findings revealed predominantly negative experiences in the internal and external environments of the persons with diabetes; as well as poor footcare knowledge and practices. The recommendations relate to improving diabetes as well as footcare knowledge and skills through education; promoting adherence to diabetes treatment regimens; providing emotional support; improving the selfimage of persons with diabetes; changing health beliefs; improving the quality of diabetes care in public health facilities; and increasing diabetes awareness among employers of diabetic persons.

Includes publications published as a result of ideas developed in this thesis, inserted at end.
Includes bibliographical references (leaves 210-242)
242 leaves
Examines goal setting in people with diabetes as part of chronic disease management in a rural setting. The studies were performed in Eyre Peninsula with a significant (10-20%) Aboriginal population.
Thesis (M.D.) -- University of Adelaide, Dept. of General Practice, 2005

Includes publications published as a result of ideas developed in this thesis, inserted at end.
"April 2005"
Includes bibliographical references (leaves 210-242)
242 leaves :
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Examines goal setting in people with diabetes as part of chronic disease management in a rural setting. The studies were performed in Eyre Peninsula with a significant (10-20%) Aboriginal population.
Thesis (M.D.)--University of Adelaide, Dept. of General Practice, 2005