Les Polychlorobiphenyls (PCBs) sont des polluants organiques persistants (POPs). L’exposition humaine à ces composés est associée à un accroissement du risque de développement du diabète de type 2 (DT2). D’autres composés présents dans l’alimentation, comme les hydrocarbures aromatic polycyclic (PAH) tel que le benzo (a) pyrene (BaP), sont des ligands du récepteur aryl-hydrocabures (AhR) et augmentent ce risque. Le premier travail rapporté est une étude in vitro, sur les 3T3-L1, des effets "cocktail" de l’exposition à des PCBs (PCB118 et 153) et au BaP. Sur ce modèle, il apparait que le BaP et les PCBs réduisent en partie l’expression des gènes de l’adipogénèse (ADGG) et stimulent l’expression des gènes de l’inflammation (INFG). La seconde étude réalisée chez la souris, a permis d’évaluer les effets "cocktail" d’une exposition chronique au PCB118 et au BaP. Des paramètres biochimiques et l’expression des ADGG et INFG ont été mesurés dans différents tissus. Après ingestion de BaP, l’expression de deux ADGG (Glut4 and Lipin1) et trois INFG (MCP1, CXCL10, IFNγ) sont augmentés dans le tissue adipeux. Ces effets sont soit abolis, soit réduits en réponse à une co-exposition simultanée avec le PCB118. Ceci indique que les effets de chacun des composés peuvent être masqués l’un par l’autre. Dans les autres tissus, on observe également une modulation globale négative par le PCB des effets du BaP. L’ensemble de ces résultats sont discutés en référence au risque de TD2 induits par les POPs, ainsi qu’aux cibles moléculaires potentielles du BaP comme AhR et des PCBs comme CAR et PXR. On discute du rôle possible de l’IFNγ produit par les cellules immunitaires associées au tissu adipeux / The Polychlorobiphenyls (PCBs) are one of the persistent organic pollutants (POPs). Human exposure to these compounds is associated with an increased risk of developing of type 2 diabetes (DT2). Other chemical compounds, such as polycyclic aromtic hydrocarbon (HAP) such as the benzo (a) pyrene (BaP), that presented in food chain are ligands of the aryl hydrocarbon receptor (AhR) and they increase this risk. The first work reported is an in vitro study on the model of pre-adipocyte, 3T3-L1, on the "cocktail" effects of co-exposure to PCBs (PCB118 and 153) and BaP. On this model, it appears that BaP and PCBs partially reduce the expression of genes related to adipogenesis (ADGG) and stimulate the expression of genes related to inflammation (INFG). The second study was conducted in vivo which allow us to evaluate the "cocktail" effects of a chronic exposure to PCB118 and BaP in mice. Biochemical parameters and the expression of ADGG and INFG were measured in different tissues. After the ingestion of BaP, expression of two ADGGs (Glut4 and Lipin1) and three INFGs (MCP1, CXCL10, IFNγ) were increased in the adipose tissue. These effects are either abolished or reduced in response to simultaneous co-exposure with PCB118. This indicates that the effects of each compounds can be masked by one another. In the other tissues, there is also a global negative modulation by PCB on the effects induced by BaP. All these results are discussed with reference to the risk of DT2 induced by POPs, as well as potential molecular targets of BaP (such as AhR) and PCBs (as CAR and PXR). The possible role of IFNγ, produced by the immune cells, associated with adipose tissue is discussed

Bakgrund: Diabetes typ 2, en globalt ökande folksjukdom, kräver aktiv egenvård och livsstilsförändringar för att minimera komplikationer. Egenvård blir därmed en central aspekt i behandlingen av denna sjukdom. Metod: En Litteraturöversikt av 10 vetenskapliga artiklar med kvalitativ design har genomförts. Dataanalysen har skett i fem steg enligt Friberg. Syfte: Syftet var att beskriva sjuksköterskors erfarenheter av patienter med diabetes typ 2 och egenvård. Resultat: Resultatet redogörs med två teman som är uppdelade i sex subteman: betydelsen av relationen till patienten (Kommunikation, Att skapa relation) samt sjuksköterskans roll i förändringsprocessen (Attityders betydelse, Att överbrygga hinder, Att utbilda patienter). Slutsats: Denna litteraturöversikt belyser viktiga aspekter av sjuksköterskors roll med patienter som har diabetes typ 2 och egenvård. Kommunikation, ehälsa och kontinuerlig kompetensutveckling är centrala faktorer. Utmaningar och hinder för patienters följsamhet, inklusive kulturella och ekonomiska faktorer identifieras. / Background: Type 2 diabetes, a globally increasing health challenge with a rising prevalence, requires active self-care and lifestyle changes to minimize complications. Self-care thus becomes a central aspect in the treatment of this disease. Method: Literature review with a qualitative design and inductive approach analyzed using Friberg's five-step analysis method. Purpose: The purpose was to describe nurses' experiences with type 2 diabetes patients and self-care. Results: The result is presented with two themes divided into six subthemes: the significance of the relationship with the patient (Communication, establishing a relationship) and the nurse's role in the process of change (The importance of attitudes, Overcoming barriers, To educate patients). Conclusion: This literature review highlights important aspects of nurses' roles with patients with type 2 diabetes and self-care. Communication, eHealth, and continuous competence development are central factors. Challenges and barriers to patient adherence, including cultural and economic factors, are identified.

Pour beaucoup d’entre nous, y compris pour de nombreux immunologistes, le rôle du système immunitaire est restreint à un rôle de défense contre différents pathogènes, tels que les bactéries et les virus. Pourtant, il devient de plus en plus incontestable que le système immunitaire est impliqué dans de nombreux autres phénomènes que peuvent être le cancer, l’obésité et la réparation tissulaire. Au cours de cette thèse, nous nous sommes intéressés à l’implication des cellules immunitaires, et plus particulièrement des cellules immunitaires innées, dans le mécanisme de réparation tissulaire. Par la suite, nous avons approfondi ce travail en nous focalisant sur les dérégulations de la réparation tissulaire. Ces dérégulations peuvent donner lieu notamment à des phénomènes de « sur-réparation » telle que la fibrose. La fibrose est définie comme un dépôt excessif de matrice extracellulaire par les fibroblastes en réponse à des molécules profibrotiques tels que le TGFβ ou l’IL-13. Nous nous sommes donc intéressés au rôle de la réponse immunitaire innée dans la fibrose en nous concentrant sur deux types de cellules immunitaires innées : les macrophages et les cellules lymphoïdes innées de type 2 (type 2 innate lymphoïde cells, ou « ILC2 »). Nous avons choisi comme modèle d’étude la sclérodermie systémique, maladie auto-immune caractérisée principalement par la fibrose pouvant toucher la peau et/ou les organes internes. Outre la fibrose, cette pathologie est également associée à des anomalies vasculaires et immunitaires. Les mécanismes liant ces trois caractéristiques sont encore mal définis et mal connus. Il est donc nécessaire de comprendre la physiopathologie de cette maladie et d’établir précisément l’implication de la réponse immunitaire dans la fibrose afin d’offrir un traitement thérapeutique pour les patients sclérodermiques et plus généralement pour toutes les maladies fibrotiques. Dans un premier temps, nous montrons, en cytométrie de flux, une diminution des ILC2 dans le sang des patients sclérodermiques par rapport aux témoins (0,007 ± 0,007% vs. 0,01 ± 0,01%, p=0,001). Chez les sujets sclérodermiques, cette baisse de la fréquence des ILC2 circulantes est inversement corrélée à l’atteinte de la fibrose cutanée définie par le score de Rodnan (R=-0,35, p=0,0062). Nous observons une augmentation de ces cellules dans la peau sclérodermique comparé à celle des contrôles (5,015 ± 2,8% vs. 2,816 ± 1,8%). Ce résultat est positivement corrélé au score de Rodnan (r=0,58, p=0,01). Nous obtenons des résultats similaires en immunofluorescence. Un phénotypage des ILC2 dermales nous a permis d’observer une diminution de l’expression de KLRG1 dans la peau des malades. En collaboration avec l’équipe du Pr. Batteux, nous avons étudié le rôle des ILC2 dans un modèle murin de sclérodermie. Nous observons une augmentation cutanée des ILC2 et cela même avant l’établissement de la fibrose au niveau de la peau des souris sclérodermiques (16677 ± 3068 vs. 9091 ± 474). Puis, nous montrons, in vitro, que les ILC2 stimulées par le TGFb perdent l’expression de KLRG1. Au contact des ILC2 stimulées par le TGFb, les fibroblastes deviennent pro-fibrotique en comparaison à l’incubation avec des ILC2 non stimulées. Ces résultats apportent de nouvelles connaissances dans la physiopathologie de la sclérodermie systémique et plus particulièrement dans la fibrose caractérisant cette maladie, ce qui offre des perspectives thérapeutiques potentielles. L’approche conceptuelle du rôle du système immunitaire dans la réparation tissulaire proposée dans cette thèse renouvelle notre vision de l’immunité et ouvre potentiellement un nouveau champ, encore sous-estimé, de thérapies ciblant le système immunitaire. / For many of us, including many immunologists, the role of the immune system is limited to a defense role against different pathogens such as bacteria and viruses. Yet it is becoming increasingly clear that the immune system is involved in many other phenomena such as cancer, obesity and tissue repair.During this thesis, we were interested in the involvement of immune cells, and more particularly innate immune cells, in the tissue repair mechanism. Subsequently, we deepened this work by focusing on the deregulations of tissue repair. These deregulations can lead to "over-repair" phenomena such as fibrosis. Fibrosis is defined as an excessive deposition of extracellular matrix by fibroblasts in response to profibrotic molecules such as TGFβ or IL-13. We therefore focused on the role of the innate immune response in fibrosis by focusing on two types of innate immune cells macrophages and innate lymphoid cells of type 2 (ILC2). We chose systemic scleroderma, an autoimmune disease characterized mainly by fibrosis that can affect the skin and/or internal organs, as our study model. In addition to fibrosis, this pathology is also associated with vascular and immune abnormalities. The mechanisms linking these three characteristics are still poorly defined and poorly understood.It is necessary to understand the physiopathology of this disease and to establish precisely the involvement of the immune response in fibrosis in order to offer therapeutic treatment for scleroderma patients and more generally for all fibrotic diseases.First, we show, in flow cytometry, a decrease of ILC2 in the blood of scleroderma patients compared to controls (0.007 ± 0.007% vs. 0.01 ± 0.01%, p=0.001). In scleroderma subjects, this decrease in the frequency of circulating ILC2 is inversely correlated with skin fibrosis defined by Rodnan's score (R=-0.35, p=0.0062). We observe an increase in these cells in the scleroderma skin compared to controls (5.015 ± 2.8% vs. 2.816 ± 1.8%). This result is positively correlated to Rodnan's score (r=0.58, p=0.01). We obtain similar results in immunofluorescence. In collaboration with Prof. Batteux's team, we studied the role of ILC2 in a mouse model of scleroderma. We observe an increase in cutaneous ILC2 even before fibrosis is established in the skin of scleroderma mice (16677 ± 3068 vs. 9091 ± 474). Then, we show, in vitro, that ILC2 stimulated by TGFb lose the expression of KLRG1. Upon contact with TGFb-stimulated ILC2, fibroblasts become pro-fibrotic compared to incubation with unstimulated ILC2.These results bring new knowledge in the physiopathology of systemic scleroderma and more particularly in the fibrosis characterizing this disease, which offers potential therapeutic prospects.The conceptual approach to the role of the immune system in tissue repair proposed in this thesis renews our vision of immunity and potentially opens up a new and still underestimated field of therapies targeting the immune system.STAR

Approximately 8.3% of the U. S. population has type 2 diabetes. Preventing the onset and improving the management type 2 diabetes are crucial for health care professionals. The purpose of this project was to develop and evaluate a type 2 diabetes prevention and management education program in a primary care setting using group medical appointments (GMAs). The chronic care model provided the framework for the study. The education program consisted of information from the Centers for Disease Control on the management of type 2 diabetes to be delivered by clinic staff using a GMA approach, a timeline for implementing the education program, and evaluation strategies for assessing patient health outcomes. Staff participants included 9 females and 1 male. One week after the presentation, staff responded to open-ended questions addressing the plan for prevention and management of type 2 diabetes. Findings indicated that staff unanimously approved the content of the program, thought the program could realistically be implemented, thought the proposed evaluation methods were appropriate, and thought the program would have a positive influence on patient health outcomes. Prevention and management education programs using a GMA approach may be used to reduce incidence and improve management of type 2 diabetes.

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. Several models have been developed for describing the glucose-insulin system. Silber and Jauslin developed a semi-mechanistic integrated glucose insulin (IGI) model which simultaneously describe glucose and insulin profiles in either healthy subjects or type 2 diabetis mellitus (T2DM) patients. The model was developed for describing the basal system, i.e. when no drugs are present in the body. In this thesis the IGI model was extended to also include the effects of anti-diabetic drugs on glucose homeostasis. The model was extended to describe postprandial glucose and insulin excursions in T2DM patients treated with either biphasic insulin aspart or the GLP-1 receptor agonist liraglutide. These extensions make the model a useful tool in drug development as it can be used for elucidating the effects of new products as well as for clinical trial simulation. In this thesis several modelling tasks were also performed to get a more mechanistic description of the glucose-insulin system. A model was developed which describes the release of the incretin hormones glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 following the ingestion of various glucose doses. The effects of these hormones on the beta cell function were incorporated in a model describing both the C-peptide and insulin concentrations in healthy subjects and T2DM patients during either an oral glucose tolerance test or an isoglycaemic intravenous glucose infusion. By including measurements of both C-peptide and insulin concentrations in the model it could also be used to characterize the hepatic extraction of insulin.

This thesis reports the work of using simulated annealing to design more efficient fuzzy logic systems to model problems with associated uncertainties. Simulated annealing is used within this work as a method for learning the best configurations of type-1 and type-2 fuzzy logic systems to maximise their modelling ability. Therefore, it presents the combination of simulated annealing with three models, type-1 fuzzy logic systems, interval type-2 fuzzy logic systems and general type-2 fuzzy logic systems to model four bench-mark problems including real-world problems. These problems are: noise-free Mackey-Glass time series forecasting, noisy Mackey-Glass time series forecasting and two real world problems which are: the estimation of the low voltage electrical line length in rural towns and the estimation of the medium voltage electrical line maintenance cost. The type-1 and type-2 fuzzy logic systems models are compared in their abilities to model uncertainties associated with these problems. Also, issues related to this combination between simulated annealing and fuzzy logic systems including type-2 fuzzy logic systems are discussed. The thesis contributes to knowledge by presenting novel contributions. The first is a novel approach to design interval type-2 fuzzy logic systems using the simulated annealing algorithm. Another novelty is related to the first automatic design of general type-2 fuzzy logic system using the vertical slice representation and a novel method to overcome some parametrisation difficulties when learning general type-2 fuzzy logic systems. The work shows that interval type-2 fuzzy logic systems added more abilities to modelling information and handling uncertainties than type-1 fuzzy logic systems but with a cost of more computations and time. For general type-2 fuzzy logic systems, the clear conclusion that learning the third dimension can add more abilities to modelling is an important advance in type-2 fuzzy logic systems research and should open the doors for more promising research and practical works on using general type-2 fuzzy logic systems to modelling applications despite the more computations associated with it.

Sustainable Built Environments Senior Capstone Project / For over a century, Pima Indians living just south of Phoenix, Arizona on the Gila River Indian Reservation have suffered from an epidemic of type 2 Diabetes Mellitus. Over half of the Pima population living on the reservation is diagnosed with diabetes while the socioeconomic conditions of the tribal community are in an unstable and dilapidated state (Unnatural Causes 2008). Fifty percent of the Pimas living on the Gila River Indian Community live below the poverty level (Unnatural Causes 2008). Displacement from traditional customs and neglect from the U.S. federal government are just some of the detrimental impacts the people have faced over the last century (Unnatural Causes 2008). The discussions within this paper will attempt to address how and why the Pima Indians have experienced such severe changes in lifestyle and economy over the last century and what affect this has had on the physical health of the people in the community. By addressing these overarching issues, one should find that socioeconomics and conditions of physical health are strongly connected. Looking even closer though, specifically at the epidemic of type 2 diabetes and the contributing risk factors that this population suffers from, one will begin to question how within just a matter of 3 decades the number of diagnosed cases of type 2 diabetes doubled among the Pima and how the rates are some of the highest recorded in the entire world. Moreover, the underlying issue is not simply a cause of poor diet, change in activity levels and unfavorable genetics, rather - being robbed of a critical natural resource, forced to adapt to unfavorable economic changes and in the end, the U.S. government failure to intervene – are truly the underlying causes that have impacted the health of the Pima Indians of Southern Arizona. The Pimas are people of their natural environment. Having a long history of living along the Gila River, the Pima were water irrigation engineers (Unnatural Causes 2008). Cultivating local crops, living off the land and providing for themselves using waters of the Gila River in an arid climate is as much a part of their culture as is their ancestral bloodline. The research presented in these discussions will look at the identical ancestry of Pima Indians living in Southwestern Sonora, Mexico in the Sierra Madre Mountains of Maycoba in order to evaluate the Pima tribe’s predisposition to the disease. The significance of looking at these groups is that their genetic history is the same based upon linguistic and genealogy studies (Schulz, Bennett, Ravussin, Kidd, Kidd, Esparza, Valencia, 2006). However, the Pima living in Sonora have not seen the same ever-increasing rates of type 2 diabetes or even obesity, as their northern counterparts have. Notably, the Mexican Pima have not experienced the same environmental changes (i.e. drought) either. Subsequently, the Pima of Sonora have been able to continue their traditional ways of life including subsistence farming and healthy diet and exercise. A historical background of the Arizona Pimas will be provided, from their cultural traditions as irrigation engineers to their participation in federal subsidy programs and their current economic state. In-depth historical accounts will also be made for the history of water law in the Southwestern United States, including what drove white settlers’ demand for water west of the Mississippi over the course of two centuries, to the attempts to mitigate the severity of drought on Native American reservations through multiple legislative acts. Information regarding the Mexican Pima’s current economy, levels of physical activity and typical diet will be presented in comparison to the present health and economic conditions of the Arizona Pima.

Published research on diabetes in Ghana is quite limited and relates mainly to incidence and prevalence of the disease with little research on the patients experiences of coping with the diabetes. It is estimated that diabetes affects 6.3% of the Ghanaian population with type 2 diabetes accounting for 90-95% of all cases of diabetes. In Ghana, individuals diagnosed with type 2 diabetes mellitus are confronted with difficulties including the high cost of treatment of the condition, stigmatization, and interruptions to normal physiological processes. In addition, the patients experience, limited clinic accessibility, inadequate drug availability, inadequate numbers of trained staff, as well as limited availability of equipment needed for adequate care of the condition. The review of literature for this current thesis also showed that none of the studies on coping were undertaken in Ghana, but were conducted in the western world where socio-cultural factors are quite diverse from the Ghanaian situation. In the light of the challenges facing diabetic patients as well as the gap observed in literature, the study set out to explore the coping strategies of patients with type 2 diabetes mellitus at a hospital in Ghana. A hermeneutic phenomenological approach to qualitative research was utilized. Twenty seven (27) in-depth interviews carried out with newly diagnosed patients with type 2 diabetes, between August and October 2009 at a hospital in Ghana. Interviews were conducted in the local Ghanaian Twi language and English. Participants who could not speak English were interviewed in Twi language and later translated into English by the researcher. Data analysis used Creswell (1998) approach to qualitative data analysis, which provided a rich description of the essential structures of the phenomenon under study. The study identified patients’ perceptions as to the causes of diabetes mellitus, the social meanings attributed to diabetes (with particular attention paid to the language by Ghanaian people to describe disease condition), and subsequently reactions and resolutions to diagnosis. Patients discussed treatment options, while at the same time remaining hopeful of finding a cure. All patients had a firm spiritual belief system that underpinned their understanding of the causation and treatment of their illness. This combined with various degrees of understanding and acceptance of western explanations of illness influenced the coping strategies employed by patients, which variously reported as positive, negative, and alternative strategies. The study establishes a platform upon which health providers can develop educational programmes for diabetic patients in Ghana, which will address misconceptions about diabetes mellitus in Ghana and the importance of programmes of care, which take account of and build upon the cultural context of ‘being Ghanaian’. Diabetes, at least for Ghanaian patients is more than a biomedical disease. In this sense a biomedical framework in and of itself will not enable healthcare providers to effectively manage this chronic disease in the Ghanaian population, but through the inclusion of an understanding of their spiritual beliefs, healthcare providers can understand the realities of what it is like for Ghanaian diabetes patients to live with diabetes. It is argued that a stronger collaboration and integration between traditional healthcare systems and orthodox healthcare systems will provide the optimum opportunity to maximize patient care in Ghana. Future research should concentrate on better understanding how lay knowledge and health related attitudes, beliefs and behaviours are associated with diabetes in Ghana.

People with type 2 diabetes are at increased risk of age-related cognitive impairment. Previous literature has focused on case-control studies comparing rates of cognitive impairment in patients with and without diabetes. Investigations of potential risk factors for cognitive impairment (including those with increased prevalence in diabetes, such as macrovascular disease, and diabetes-specific factors such as hypoglycaemia) in study populations consisting exclusively of patients with type 2 diabetes have been largely neglected. Moreover, previous studies have failed to take advantage of the extensive characterisation and prospective nature of longitudinal cohort studies to investigate the relative predictive ability of a wider range of potential risk factors for cognitive decline. Using data from the prospective Edinburgh Type 2 Diabetes Study (ET2DS) the present thesis aimed (i) to determine associations of cognitive decline with macrovascular disease and with severe hypoglycaemia, and (ii) to compare a wider range of potential risk factors in their ability to predict cognitive decline. In 2006/2007, 1066 patients with type 2 diabetes (aged 60 to 75 years) attended the baseline ET2DS clinic and 831 returned for the follow-up at year 4. Subjects were extensively characterised for risk factor profiles at baseline, and at year 4 for incidence of severe hypoglycaemia. Socioeconomic status was estimated using postcode data. Scores on seven tests of age-sensitive ‘fluid’ cognitive function, which were administered at baseline and at year 4, were used to derive a general cognitive component (‘g’). A vocabulary-based test, administered at baseline, estimated pre-morbid ability. Findings are reported in three parts. 1.) Macrovascular disease and cognition: Subjects with higher levels of biomarkers indicative of subclinical macrovascular disease, including plasma N-terminal pro-brain natriuretic peptide and carotid intima-media thickness, had significantly steeper four-year cognitive decline, independent of traditional cardiovascular risk factors, stroke, socioeconomic status and estimated pre-morbid cognitive ability. For ankle-brachial pressure index, the association fell just short of statistical significance. Effect sizes were overall modest, with fully adjusted standardised beta coefficients ranging from 0.06 to -0.12. Little evidence was found for associations of the symptomatic markers of macrovascular disease with four-year change in cognitive function that was independent of participants’ pre-morbid ability and socioeconomic status. 2.) Severe hypoglycaemia and cognition: Subjects with lower cognitive ability at baseline were at two-fold increased risk of experiencing their first-ever incident severe hypoglycaemia during follow-up. The rate of four-year cognitive decline was significantly steeper in those exposed to hypoglycaemia compared with hypoglycaemia-free participants, independently of cardiovascular risk factors, microand macrovascular disease and of estimated pre-morbid cognitive ability. Effect sizes again were overall modest (Cohen’s d = 0.2 to 0.3 for statistically significant differences in four-year cognitive decline between subjects with and those without hypoglycaemia, following multivariable adjustment) 3.) Consideration of a wider range of risk factors and cognition: A stepwise linear regression model including a total of 15 metabolic and vascular risk factors identified inflammation, smoking and poorer glycaemic control (in addition to some of the subclinical markers of macrovascular disease) as predictive of a steeper four-year cognitive decline. Other traditional cardiovascular risk factors, diabetic retinopathy, clinical macrovascular disease and a baseline history of severe hypoglycaemia were not included in this model. The interpretation of the latter finding is limited, however, by the fact that the stepwise regression procedure may exclude true predictors from a model when they correlate with already included risk factors. This thesis has demonstrated associations of later-life cognitive decline in people with type 2 diabetes with markers of subclinical macrovascular disease and poor glycaemic control (including hypoglycaemia) as well as other cardiometabolic risk factors (inflammation, smoking). Findings suggest that associations are relatively weak and complex due to inter-relationships amongst risk factors, and indicate a role of pre-morbid ability and socioeconomic status (which as risk factors are difficult to modify) in the relationships of risk factors with cognitive decline. Future research including case-control studies to compare risk factor associations between people with type 2 diabetes and non-diabetic older adults and randomised controlled trials to evaluate potential causal effects of individual modifiable risk factors on cognitive decline, will help to evaluate the mechanisms underlying the observation that people with type 2 diabetes are at risk of cognitive impairment in later life.

Hypertension and type two diabetes mellitus (Type 2 DM) are serious chronic illnesses that impact on the lives of millions of people around the world. Various epidemiological studies have shown a relationship between early life events such as intrauterine growth retardation (IUGR) resulting in low birth weight and the development of these chronic illnesses in adult life. To explain the link between these two events, it has been suggested that an ‘insult’ at a critical time point of development can ‘program’ alterations in gene expression, organ size, and cell number. This has been termed “the early life origins of disease’. There is also evidence that these programmed effects are not limited to the first generation but can also be passed to subsequent generations. With changes in lifestyle in modern society, the prevalence of obesity is increasing, in association with problems such as type 2 DM, hypertension, fatty liver, atherosclerosis and the metabolic syndrome. Obesity during pregnancy is linked to problems such as gestational diabetes, hypertension and early miscarriage as well as a higher risk of congenital malformations. Maternal obesity has also been recognised as one of the factors capable of ‘programming’ the offspring, increasing the risk of childhood and adult disorders such as obesity and hypertension. In this thesis I have used two animal models to explore the underlying mechanisms of programming and its intergenerational effects: i) a rat model of prenatal glucocorticoid over-exposure (the dexamethasone-programmed rat) and ii) a mouse model of obesity during pregnancy. Using the dexamethasone-programmed rat, I have shown that prenatal glucocorticoid overexposure reduces fetal and placental weight in the first generation (F1) offspring, in association with alterations in gene expression in placenta and liver. In addition, I have shown effects on fetal and placental weights and gene expression in the second generation (F2) offspring. The observed changes in gene expression in the F2 offspring differ from those in the first generation. Thus, although effects on fetal growth are seen in both generations, the underlying mechanisms appear to be different. We also observed marked parent of origin effects on fetal and placental growth and gene expression in the second generation. In the mouse model of maternal obesity, birth weight was decreased in the F1 offspring. At weaning, the offspring of obese mothers were heavier than controls, however this difference in weight was not persistent. At three months of age, F1 female offspring of obese mothers showed altered expression of hepatic genes important in lipid regulation and metabolism. More striking changes were seen in the F2 generation in which there was an effect of paternal exposure to maternal obesity to decrease birth weight. There were also parent of origin effects on organ weights and insulin levels at six months of age. These results provide evidence for the transmission of programming effects to a second generation in two different programming models and suggest that the mechanisms leading to these effects differ between generations.