Mélangez obésité, diabète et chirurgie bariatrique et vous obtiendrez ce mémoire. Il y sera question d’obésité, de son étiologie et de ses complications. Parmi celles-ci, nous traiterons majoritairement du diabète de type 2 (DT2) et de sa pathophysiologie. Lorsque nous combinons ces deux maladies, nous nous trouvons devant une combinaison complexe qui demande une intervention thérapeuthique. La plus efficace connue à ce jour est, sans contredit, la chirurgie bariatrique. La résolution du DT2 se produit rapidement après la chirurgie bariatrique, et ce indépendamment de la perte de poids. À ce jour, les mécanismes qui pourraient expliquer ces phénomènes sont mal compris. L’amélioration du DT2 varie selon le type de procédures. La dérivation biliopancréatique (DBP) est la chirurgie qui a le plus grand impact sur le renversement de la résistance à l’insuline, avec une résolution de la maladie jusqu’à 98 % des patients. Différents mécanismes ont été proposés, pour expliquer cet effet, comme la modulation de certaines hormones gastro-intestinales telles que le GLP-1 et le GIP. Ces hormones varient après la chirurgie en raison du réarrangement de l’anatomie intestinale. De plus, la restriction calorique sévère est connue depuis longtemps pour ses effets rapides sur l’homéostasie du glucose. À l’aide de notre étude nous avons voulu déterminer le rôle de la restriction calorique dans l’amélioration rapide de la sensibilité à l’insuline ainsi que la fonction des cellules β suite à la DBP. Pour ce faire nous avons administré un repas test avant et après la DBP soit au jour 3-4-5 post-opératoire afin de mesurer l’apport calorique, les courbes d’excursion glycémique ainsi que la sensibilité et la sécrétion d’insuline. Nous avions un groupe DT2 pairé à des sujets normo glycémiques (NG). Dans une autre étude effectuée parallèlement, un autre groupe de DT2 a subit le même repas test avant et après une restriction calorique identique à celle mesurée en post-opératoire. Ce même groupe était aussi en post opératoire. Les résultats ont démontrés une améloration du HOMA-IR chez les DT2 au jour 3 post DBP ainsi qu’après la restriction calorique. L’index de disposition (ID) s’améliore rapidement chez les DT2 autant après la DBP qu’après la restriction calorique. L’ID était plus haut chex les NG et ne changeait pas suivant la DBP. Les changements du glucagon like peptide-1, du gastric inhibitory peptide, du peptide tyrosine tyrosine, la ghrelin et du polypeptide pancréatique n’étaient pas associés avec la variation de l’ID observé chez les participant Il s’est avéré que l’amélioration de la résistance à l’insuline et de la fonction des cellules β sont similaires après trois jours de restriction calorique comparativement avec la DBP; et ce indépendamment des changements au niveau des incrétines. La restriction calorique est donc un mécanisme majeur dans la résolution du DT2 après la DBP. Mon mémoire fournit les bases physiologiques et cliniques afin de mieux comprendre ces mécanismes.

Diabetes typ 2 är en endokrin sjukdom där insulinfrisättningen från pankreas betaceller är nedsatt, vilket leder till insulinresistens. Det är en tyst och smygande sjukdom som främst upptäcks när patienter har utvecklat komplikationer. De vanligaste komplikationerna är ögon, njure, fot och hjärt- och kärlsjukdomar. Ärftlighet, hög ålder, fysisk inaktivitet och fetma är vanliga orsaker till diabetes typ 2, vilket gör att livsstilsförändringar exempelvis ökad fysisk aktivitet, viktminskning och sunda matvanor är betydelsefullt vid behandlingen av sjukdomen. Aktuellt examensarbete syftar till att beskriva vuxna patienters upplevelser av livsstilsförändringar vid diabetes typ 2. Det bygger på en litteraturstudie bestående av åtta kvalitativa artiklar. Resultatet består av följande huvudteman, en förändrad tillvaro, känna sig åsidosatt och känna sig hälsosam. Dessa huvudteman är uppbyggda av fem subteman så som ”kroppen spelar roll”, ”en inre kamp för livsstilsförändringar”, ”behov av information”, patientens möte med sjukvården”, ”bryta gamla vanor” och ”upplevelser av livsstilsförändringar”. Resultatet visar att drabbas av diabetes typ 2 innebär förändringar i patientens vardag, vilket ger känslan av en förändrad tillvaro. Det framkommer i resultatet att patienterna får ett otillfredsställande möte med hälso- och sjukvårdspersonal, vilket leder till att de känner sig åsidosatta. Därtill får patienterna en bristfällig information om diabetes typ 2, vilket innebär att de erhåller en ofullständig upplysning om livsstilsförändringar och komplikationer. Slutligen upplevde patienterna livsstilsförändringar som nödvändiga men svåra och energikrävande. Slutsatsen tydliggör patienternas behov av stöd, undervisning och vägledning, vilket är bra att sjuksköterskan blir medvetet om.

Nitric oxide is released from the endothelium and causes relaxation of vascular smooth muscle by stimulating guanylate cyclase to produce guanosine 3’,5’-cyclic monophosphate (cGMP) which, in turn, is degraded by phosphodiesterase type 5 (PDE5). Inhibition of PDE5, with drugs like sildenafil citrate, promotes NOstimulated relaxation of vascular smooth muscle. The overall aim of the work contained within this thesis was to further characterise the systemic vascular effects of PDE5 inhibition. Four clinical studies were performed. The aims of the first study were to investigate in healthy men the effect of smoking on endothelium-dependent vasomotor function measured as the change in peripheral arterial wave reflection with inhaled salbutamol, and the effect of acute sildenafil 100 mg on this response. Smokers (n=12) exhibited a reduced response to inhaled salbutamol compared to non-smokers (n=11) [mean(standard deviation) area under the curve of the change in central augmentation index following salbutamol 400 μg: -29(143) AU in smokers vs -159(124) AU in non-smokers, P=0.03]. In the smokers, there was a trend to an improvement in the response to salbutamol following sildenafil [-96(266) AU vs -29(143) AU with matched placebo; P=0.2]. The co-administration of glyceryl trinitrate (GTN) and sildenafil is absolutely contraindicated because of the potential for profound hypotension. The aim of the second study was to characterise the time course of this interaction. Twenty men with stable angina, maintained on their usual medicines, were administered sublingual GTN 400 μg 1, 4, 6 and 8 hours after sildenafil 100 mg or matched placebo. Compared to the combination of GTN and placebo, the combination of GTN and sildenafil resulted in greater mean maximum reductions from baseline in sitting systolic blood pressure (BP) at 1, 4 and 8 hours, and in sitting diastolic BP at all time points (all P<0.05). Compared to placebo, sildenafil alone reduced systolic BP at 1, 4, 6 and 8 hours (P<0.01 at 1 hour and P<0.05 at 4, 6, and 8 hours) and diastolic BP at 4, 6, and 8 hours (all P<0.01). Analysis of the change in BP from the measures taken before each GTN challenge suggested that the interaction on BP might be synergistic at 1 hour after sildenafil, but no more than additive at 6 and 8 hours after sildenafil. Symptoms consistent with hypotension occurred following GTN in 6 subjects at 1 hour and 3 subjects at 4 hours after sildenafil, but in no subjects at 6 and 8 hours after sildenafil or at any time after placebo. In the third study, 25 otherwise untreated hypertensives were given sildenafil 50 mg or matched placebo three times daily for 16 days and the effects on ambulatory BP, clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity and brachial artery flow-mediated dilatation were measured. Three subjects were withdrawn because of side effects and the data from the remaining 22 subjects were analysed. Sildenafil reduced ambulatory BP [change from baseline in average daytime BP: systolic -8(9) mmHg vs 2(9) mmHg with placebo, P<0.01; diastolic -6(5) mmHg vs 0(6) mmHg, P<0.01] and clinic BP [change from baseline to 1 hour after drug administration on day 16: systolic -5(11) mmHg vs 4(10) mmHg, P<0.01; diastolic -5(5) mmHg vs 2(7) mmHg, P<0.01]. Sildenafil, but not placebo, reduced arterial wave reflection [central augmentation index from 32(9)% at baseline to 30(10)% at 1 hour after administration on day 16, P<0.05; radial augmentation index from 88(13)% to 84(13)%, P<0.01], but the change in arterial wave reflection was not statistically significant compared to the change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The fourth study investigated the potential of combined PDE5 inhibition and organic nitrate for the management of treatment-resistant hypertension (TRH). In 6 patients with TRH, maintained on their usual antihypertensives sildenafil 50 mg alone, isosorbide mononitrate (ISMN) 10 mg alone and co-administered sildenafil and ISMN all acutely reduced systolic BP and diastolic BP compared to placebo (quantified as the area under the curve of the change from baseline to 4 hours after drug administration; all P≤0.01). The combination produced a greater reduction in systolic BP than did either sildenafil alone (P=0.03) or ISMN alone (P=0.01) and a greater reduction in diastolic BP than did sildenafil alone (P=0.02). Compared to placebo, from 1 to 3 hours after drug administration BP was on average 13/10 mmHg lower with sildenafil alone, 18/14 mmHg lower with ISMN alone and 26/18 mmHg lower with the combination. The following conclusions were made. (1) Smokers exhibit impaired vascular responsiveness to inhaled salbutamol, indicating systemic endothelial dysfunction, which may be improved by sildenafil. (2) In men with stable angina there is an interaction on BP reduction between sildenafil 100 mg and sublingual GTN 400 μg for at least 8 hours after sildenafil administration, but this interaction is no more than additive from 6 hours after sildenafil administration. (3) Regular sildenafil monotherapy reduces BP in hypertension. (4) In patients with TRH maintained on their usual antihypertensives sildenafil alone and ISMN alone both acutely reduce BP and there is additional BP reduction when these drugs are given in combination.

This thesis investigates the functional consequences of neutralising the negative charges on the bacteriophage T7 antirestriction protein ocr. The ocr molecule is a small highly negatively charged, protein homodimer that mimics a short DNA duplex upon binding to the Type I Restriction Modification (RM) system. Thus, ocr facilitates phage infection by binding to and inactivating the host RM system. The aim of this study was to analyse the effect of reducing the negative charge on the ocr molecule by mutating the acidic residues of the protein. The ocr molecule (117 residues) is replete with Asp and Glu residues; each monomer of the homodimer contains 34 acidic residues. Our strategy was to begin with a synthetic gene in which all the acidic residues of ocr had been neutralised. This so called ‘positive ocr’ (or pocr) was used as a template to gradually reintroduce codons for acidic residues by adapting the ISOR strategy proposed by D.S.Tawfik. After each round of mutagenesis an average of 4-6 acidic residues were incorporated into pocr. In this fashion a series of mutant libraries in which acidic residues were progressively introduced into pocr was generated. A high-throughput in vivo selection assay was developed and validated by assessing the antirestriction behaviour of a number of mutants of the DNA mimic proteins wtOcr and Orf18 ArdA. Further to this, selective screening of the libraries allowed us to select clones that displayed antirestriction activity. These mutants were purified and in vitro characterisation confirmed these mutants as displaying the minimum number of acidic residues deemed critical for the activity of ocr. This in vitro process effectively simulated the evolution of the charge mimicry of ocr. Moreover, we were able to tune the high-throughput assay to different selection criteria in order to elucidate various levels of functionality and unexpected changes in phenotype. This approach enables us to map the “in vitro” evolution of ocr to identify acidic residues that are required for protein expression, solubility and function proceeding to a fully functional antirestriction protein.

This report takes an approach of laying the first steps to create an artificial pancreassystem as treatment for type 1 diabetes. This includes a thoroughly performedanalysis of the most intrusive physical factors, such as hormonal activity, time offset,errors of measurement and metabolism. Such factors raise a need forcompensation. A compensation that will enable the development of the link betweena continuous glugose monitoring(CGM)-device and an insulin infusion pump,a system that can be described as an Artificial Pancreas.Through analysis of measured glucose series, a mathematicalapproximation is presented to solve the time offset of CGM.The approximation gives sufficient results but with room for improvementFrom the analysis of affecting factors, a compensation model isdeveloped. The model is designed as a closed loop which is suitable for timecontinuous systems. The output of the compensation model equation presented here is adirective that would be read by an insulin pump.

Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied. Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

Background: Obstructive Sleep Apnea (OSA) is a chronic breathing disorder that is estimated to affect 20% of the US adult population. Intermittent hypoxia and sleep fragmentation caused by OSA likely affects cardiometabolic function. Individuals with OSA might be at risk of developing hypertension and type 2 diabetes (T2DM), with a dose-response relationship related to OSA severity. The objective of this study was to estimate the association between severity of OSA at diagnosis with 1) incidence of hypertension incidence of hypertension and 2) incidence of T2DM. Methods: We conducted a retrospective cohort study of Kaiser Permanente members diagnosed with OSA during 2000-2005. Adults without baseline hypertension or T2DM were eligible. Patients were excluded if hypertension or T2DM was diagnosed within one year prior to OSA diagnosis, and right censored at the end of follow-up or at the time Kaiser Permanente membership ended. Kaplan-Meier curves and Cox Proportional Hazard models were used to estimate the association between OSA severity and incident hypertension and incident diabetes. Results: Overall 719 patients were diagnosed with OSA during the study periods; 614 were included as those at risk of developing either hypertension (N=265) or T2DM (N=489). Overall, 261 had severe OSA at diagnosis. Those with severe OSA were more likely to be middle aged, overweight, and have prevalent hypertension or T2DM. Among those without prevalent hypertension at OSA diagnosis, 47.4% (126/266) were subsequently diagnosed with hypertension. Among those without prevalent T2DM at OSA diagnosis, 16.3% (80/491) were subsequently diagnosed with T2DM. After adjusting for BMI and prevalent T2DM, the hazard rate of incident hypertension among patients with severe OSA was 1.35 (95%CI: 0.88-2.06) compared to the rate among patients with mild OSA. The hazard rate of incident T2DM among patients with severe OSA was 1.49 (95%CI: 0.83-2.67) compared to the rate among patients with mild OSA after adjusting for BMI and prevalent hypertension. Discussion: We found high incidence rates of hypertension and T2DM among adults diagnosed with OSA. Severe OSA at diagnosis was associated with increased risk of either incident hypertension or T2DM, but not significantly (for p≤0.05).

Zinc oxide is a semiconducting material that has received lot of attention due to its numerous proeprties such as wide direct band gap, piezoelectricity, and numerous low cost and robust methods of synthesizing nanomaterials. Its piezoelectric properties have been harnessed for use in energy production through nanogenerators, and to tune carrier transport, birthing a field known as piezotronics. However, one weakness of ZnO is that it is notoriously difficult to dope p-type. Antimony was investigated as a p-type dopant for ZnO, and found to have a stability of up to 3 years, which is completely unprecedented in the literature. Furthermore, a variety of zinc oxide structures ranging from ultra-long nanowires to thin films were produced and their piezotronic properties were demonstrated. By making p-n homojunctions using doped and undoped ZnO, enhanced nanogenerators were produced which could see application in gesture recognition. As a proof of concept, a simple photodetector was also derived from a core-shell nanowire structure. Finally, the ability to integrate this material with other semiconductors was demonstrated by growing a heterojunction with silicon nanowires, and investigating its electrical properties. All this work together lays the foundation for a fundamentally new material that could see application in future electronics, optoelectronics, and human-machine interfacing.

The purpose of this phenomenological study was to explore the perceptions and meanings of type II diabetes among Mexican American farmworking women working in California’s Northern San Joaquin Valley. Perceptions of type II diabetes play a major role in how Mexican American farmworking women feel about diabetes and these perceptions influence diabetes treatment strategies and health care decisions. Yet, little is known about the perceptions and meanings that farmworking women attribute to type II diabetes. A qualitative interdisciplinary research methodology (integrating knowledge from social work and nursing) involving open-ended, in-depth interviews with a nonprobabilistic sample of 17 Mexican American farmworking women was used to gain an understanding of how farmworking women make meaning of type II diabetes. Based on Kleinman’s (1980) explanatory model, salient themes in the areas of illness, causation, treatment and perceptions were identified. The study showed that farmworking women have a predominantly cultural perspective of diabetes. A large majority of women applied cultural beliefs and traditional home remedies to the treatment of diabetes; although many were not opposed to incorporating western medicine into cultural treatment strategies. Causation of diabetes was attributed to a transformation of blood and destabilization of the pancreas as a result of Susto (fright), an ethno-specific illness. Home remedy and dosing strategies were categorized and farmworking women revealed subjective definitions of high blood glucose and heredity that are dissimilar to western biomedicine. Understanding how farmworking women conceptualize and make meaning of type II diabetes and including these important culturally influenced beliefs and treatment strategies into interdisciplinary health care practices and service delivery systems can serve as a basis for modifying current medical theoretical orientations about diabetes education, treatment and maintenance strategies and service provision for this particularly vulnerable population. Additionally, the inclusion of cultural beliefs and treatment strategies can engender trust and facilitate meaningful, reciprocal relationships between patients and health care providers, which are considered essential for developing culturally meaningful, effective treatment, and competent and responsible service provision. / text

African-American women (AAW) have had the largest increase in diagnosed diabetes in the US. Few studies have focused solely on dietary changes (one of the foundations for diabetes self-care), particularly in the context of family and the role of AAW. The purpose of this descriptive ethnographic study was to explicate cultural influences on food practices of AAW with type 2 diabetes (T2DM) in order to inform the health care community as well as future development of culturally-tailored interventions. Specific aims were to describe typical daily food practices and identify cultural influences on food practices of AAW with T2DM. Symbolic Interactionism, a sensitizing framework for viewing AAW with T2DM as a subculture, guided this study. Purposeful sampling was used to recruit 20 AAW who: were between 35 and 70 years of age, had been diagnosed with T2DM, shopped and prepared meals for their families, and attended church functions where food was served . Data collection consisted of one-one-one interviews and participant observation of church fellowship dinners, grocery shopping, and food preparation. A social anthropological approach to content analysis was used to describe behavioral regularities in food practices. Trustworthiness was maintained by an audit trail. Findings indicate that for informants in this study, who had diabetes ranging from 2 to 30+ years, there is a constant struggle between cultural food practices and eating healthier because of diabetes, particularly within the home setting where a majority of daily food practices take place. Difficulties in making dietary modifications result from conflicts between the need to change dietary practices to control diabetes and personal food preferences, as well as the preferences of people within the participants' social network. In addition, difficulties derive from AAW's emotional dedication to the symbolism of food and traditional cultural food practices. AAW are the gatekeepers for family food practices and are the keys to healthy dietary practices. This study begins to fill the research gap regarding cultural dietary food practices of this population. With increased knowledge, researchers and health care providers will be better able to improve AAW food practices, and ultimately improve diabetes control in this high-risk population. / text