Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by consistently high blood glucose, resulting from a combination of insulin resistance and reduced capacity of β-cells to secret insulin. While the exact causes of T2DM is yet unknown, obesity is known to be a major risk factor as well as co-morbidity for T2DM. As the global prevalence of obesity continues to increase, the association between obesity and T2DM warrants further study. Traditionally, mathematical models to study T2DM were mostly empirical and thus fail to capture the dynamic relationship between glucose and insulin. More recently, mechanism-based population models to describe glucose-insulin homeostasis with a physiological basis were proposed and offered a substantial improvement over existing empirical models in terms of predictive ability. The primary objectives of this thesis are (i) examining the predictive usefulness of semi-mechanistic models in T2DM by applying an existing population model to clinical data, and (ii) exploring the relationship between obesity and T2DM and describe it mathematically in a novel semi-mechanistic model to explain changes to the glucose-insulin homeostasis and disease progression of T2DM. Through the use of non-linear mixed effects modelling, the primary mechanism of action of an antidiabetic drug has been correctly identified using the integrated glucose-insulin model, reinforcing the predictive potential of semi-mechanistic models in T2DM. A novel semi-mechanistic model has been developed that incorporated a relationship between weight change and insulin sensitivity to describe glucose, insulin and glycated hemoglobin simultaneously in a clinical setting. This model was also successfully adapted in a pre-clinical setting and was able to describe the pathogenesis of T2DM in rats, transitioning from healthy to severely diabetic. This work has shown that a previously unutilized biomarker was found to be significant in affecting glucose homeostasis and disease progression in T2DM, and that pharmacometric models accounting for the effects of obesity in T2DM would offer a more complete physiological understanding of the disease.

African American women (AAW) are at a high risk for type 2 diabetes, a debilitating and potentially fatal disease for which there is no cure. The purpose of this study was to extend the research of Mosca et al. (2012) by examining the relationship between caregiver status and self-reported health status for AAW 18 years or older diagnosed with type 2 diabetes. The chronic care model (CCM) provided the theoretical framework for this study. The CCM promoted routine care for patients with chronic illnesses to migrate from acute care to proactive, planned, and risk-based protocols. A binomial logistic regression investigated the relationship between caregiver status, categorized as paid or unpaid, and self-reported health status, which was dichotomized as either good to excellent health or poor to fair health. There was a statistically significant relationship between primary caregiver status and self-reported health status among AAW diagnosed with Type 2 diabetes after controlling for age, education, and marital status (p < .004). Based on the fitted binomial logistic regression model, there were 186 cases of AAW with type 2 diabetes; having a paid caregiver was associated with a lower odds of having good to excellent health (OR = 0.294). About 12.3% of the variance in self-report health status was attributable to caregiver status. Overall, 82.6% of predictions were accurate. Nearly all participants required frequent assistance from a caregiver in the preceding 12 months. These findings suggest a critical need for healthcare service providers to educate caregivers as a means to deliver post-acute care to AAW diagnosed with type 2 diabetes, consistent with the CCM.

Prevalensen av fetma ökar drastiskt i stora delar av världen och utgör en stor riskfaktor för att utveckla insulinresistens och typ 2 diabetes. Fettväven kan bli mycket stor om för mycket energi tas upp av kroppen. Vid extrem övervikt är fettväven i kroppen i ett stresstillstånd, vilket gör att risken för att utveckla metabola sjukdomar som t.ex. typ 2 diabetes ökar. Fett lagras i olika fettdepåer i kroppen. Inlagringen i djupare kroppsdelar, runt och i inre organ s.k. visceralt fett, skiljer sig från fettväven som lagras direkt under huden s.k. subkutant fett. Nyare rön visar att mer visceral fettväv ökar risken för att utveckla insulinresistens och typ 2 diabetes. Fettcellen är tillsammans med muskel- och leverceller de viktigaste för glukosmetabolismen. Fettcellen är en stor cell, som man lätt kan se med blotta ögat. Storleken på ellerna varierar dock kraftigt i en och samma fettvävnad. Upptag av glukos från maten vi äter regleras av hormonet insulin. Insulinresistens är ett tillstånd då cellerna svarar dåligt på insulin, vilket gör att glukoshalten i blodet ökar. Detta förekommer vid typ 2 diabetes, men även vid andra tillstånd där cellerna blir stressade, t.ex. kirurgiska ingrepp. Insulinsignaleringen i fettcellen är komplex och signalöverföringen inne i cellen sker främst via en kaskad av fosforyleringar, där olika proteiner i en signalkedja fosforyleras eller defosforyleras. Slutligen leder denna fosforyleringskaskad till insulinets sluteffekter som t.ex. upptag av glukos, proteinsyntes och celltillväxt. Efter att insulin bundit till och fosforylerat/aktiverat insulinreceptorn delas signalen upp inne i cellen i två huvudvägar; den metabola signalvägen och den mitogena signalvägen. Insulinreceptorsubstrat 1, IRS1, är ett stort protein som insulinreceptorn verkar direkt på. Fosforylering av aminosyran tyrosin på IRS1 är mycket viktigt för fortsatt insulinsignalering i fettcellen. IRS1 fosforyleras även på aminosyran serin som svar på bl.a. insulin. Serinfosforyleringen av IRS1 hämmar eller stimulerar insulinsignaleringen, ofta genom återkoppling av insulinsignalen. Syftet med den här avhandlingen är att beskriva möjliga cellulära mekanismer i insulinsignaleringen vid insulinresistens som resultat av kirurgisk stress eller vid typ 2 diabetes i fettceller från människa. Häri har upptaget av glukos analyserats och jämförts i fettceller från olika fettdepåer. Viscerala fettceller har högre basalt och insulinstimulerat glukosupptag och mer glucostransportörprotein än subkutana fettceller. Däremot är det ingen skillnad i insulinkänslighet angående glukosupptaget i de olika typerna av fettceller. Vidare fann vi att den kirurgiskt orsakade insulinresistensen hos subkutana fettceller från människa återgår till det normala efter övernattinkubering av cellerna i odlingsmedium. Insulinresistensen vid typ 2 diabetes är däremot permanent och har en annan mekanism än den reversibla, stress-relaterade insulinresistensen. Insulinresistansen vid typ 2 diabetes beror på att signalöverföringen mellan olika proteiner i cellen är defekt. Insulinreceptorns förmåga att fosforylera IRS1 på aminosyran tyrosin är nedsatt hos patienter med typ 2 diabetes. Fosforyleringen av IRS1 på serin 307 (i den humana sekvensen) ökar snabbt hos icke-diabetiska fettceller som svar på insulin. Denna serinfosforylering verkar behövas för att IRS1 effektivt ska tyrosinfosforyleras och därmed leda insulinsignalen vidare inne i cellen. Fosforyleringen av IRS1 på serin 307 är kraftigt nedsatt hos subkutana fettceller från patienter med typ 2 diabetes. Fosforyleringen av IRS1 på serin 312 är däremot liknande i fettceller från icke-diabetiker och diabetiker (Öst et.al. (2007) Faseb.J. doi: 10.1096/fj.07-8173com). Fosforyleringen av IRS1 på serin 312 är mest involverad i insulinsignaleringens negativa återkoppling. Fosforyleringen av serin 307 sker snabbt och vid låga insulinkoncentrationer, medan fosforyleringen på serin 312 sker först efter lång inkubering och vid höga insulinkoncentrationer. Detta är en ny mekanism på cellulär nivå som möjligen kan beskriva insulinresistansen i fettceller från människa. Tillsammans styrs återkopplingen via den stimulerande fosforyleringen (serin 307) eller den hämmande fosforyleringen (serin 312) och kontrollerar insulinsignaleringen i cellen. Fosforyleringarna sker möjligen via samma proteinkinas och/eller proteinfosfatas och kan bli mål för terapeutiska läkemedel mot typ 2 diabetes i framtiden. / The prevalence of obesity is increasing in most parts of the world and is a strong risk factor for the development of insulin resistance and type 2 diabetes. Adipose tissue is important in whole body energy balance and grows in size with excess energy intake. Adipose tissue in different regions of the body has different characteristics and adipocytes coming from intraabdominal fat depots, are more associated with insulin resistance than adipocytes from subcutaneous fat depots. Insulin signalling is complex and consists of two major signalling pathways in the cell; the metabolic signalling pathway and the mitogenic signalling pathway. After insulin binding to the insulin receptor a cascade of protein phosphorylations and dephosphorylations is started, eventually leading to the target effects of the hormone. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), a protein directly downstream of the insulin receptor, is essential for further insulin signalling. Serine phosphorylation of IRS1 also affects insulin signalling through inhibitory or stimulatory effects. Adipocytes are together with muscle cells and liver cells central in the development of type 2 diabetes. The focus of this thesis is to describe mechanisms in insulin signalling in primary human adipocytes in insulin resistant states, surgical stress or type 2 diabetes. Visceral adipocytes from humans were analysed and compared to subcutaneous adipocytes. Visceral adipocytes were slightly bigger than subcutaneous adipocytes. Furthermore, visceral adipocytes had an increased level of the glucose transporterprotein GLUT4 and a higher basal and insulin-stimulated glucose uptake, but the sensitivity to insulin was the same. Here it was found that surgical insulin resistance is reversible after overnight incubation of the adipocytes and the impaired insulin sensitivity is at the level between IRS1 and PKB/Akt in insulin signalling. In contrast, the insulin resistance in type 2 diabetes is irreversible and the impaired insulin sensitivity is at the level of insulin receptor-mediated tyrosine phosphorylation of IRS1. Adipocytes from patients with type 2 diabetes were investigated and it was found that diabetic adipocytes have an attenuated insulin-stimulated phosphorylation of IRS1 at serine 307 (corresponding to serine 302 in the mouse sequence). In adipocytes from non-diabetic individuals, the phosphorylation of IRS1 at serine 307 occurred rapidly at low concentrations of insulin. This phosphorylation was associated with the tyrosine phosphorylation of IRS1. The phosphorylation of IRS1 at serine 312 (corresponding to serine 307 in the mouse sequence) in response to insulin was similar in adipocytes from non-diabetic individuals and from patients with type 2 diabetes (Öst et.al. (2007) Faseb.J. doi: 10.1096/fj.07-8173com) and occurred only at high concentrations after prolonged incubation with insulin. This thesis reports the investigation of mechanisms in insulin signalling at a cellular and molecular level in primary human adipocytes. The insulin resistance resulted from surgical stress is different from that in type 2 diabetes and adipocytes from patients with type 2 diabetes have impaired insulin sensitivity at the level of IRS1. Together, the phosphorylation of IRS1 at serine 307 and serine 312 may control insulin signalling through feedback mechanisms in primary human adipocytes.

Le diabète de type 2 (DT2) atteint environ 387 millions de personnes à l’échelle mondiale. Ces individus ont souvent recours à une polymédication pour contrôler leur glycémie, mais également pour prévenir et contrôler les comorbidités micro- et macrovasculaires associées au diabète. Or, aux doses usuelles, certains patients atteints de DT2 ont une réponse aux médicaments différente de celle des patients non-diabétiques. Des variabilités dans les dosages et les effets de certains médicaments, tels le clopidogrel, la warfarine, la cyclosporine et la tacrolimus, sont observées chez les patients diabétiques. Cette variabilité interindividuelle dans la réponse aux médicaments chez les patients avec DT2 constitue une problématique importante, car elle peut causer des échecs thérapeutiques, des effets indésirables et des toxicités médicamenteuses. Un des mécanismes sous-jacent proposé afin d’expliquer cette variabilité interindividuelle dans la réponse aux médicaments chez les patients diabétiques est que leur capacité à éliminer les médicaments par métabolisme soit affectée. De fait, des évidences supportent un lien entre les maladies avec composantes inflammatoires et une modulation de l’activité des enzymes du métabolisme. Certains médiateurs inflammatoires peuvent moduler l’expression et l’activité des protéines enzymatiques telles les cytochromes P450 (CYP450s), un système enzymatique majeur dans le métabolisme des médicaments. Plusieurs organes expriment différentes isoenzymes des CYP450s lesquelles peuvent contribuer au métabolisme local des médicaments et ainsi influencer leurs concentrations atteintes dans les organes cibles. L’objectif de cette étude est d’évaluer les effets du DT2 sur l’expression et l’activité des CYP450s afin d’identifier leur contribution à la variabilité interindividuelle dans la réponse aux médicaments en utilisant la souris diabétique sous diète riche en gras (DIO) comme modèle. Les travaux effectués dans le cadre de ce mémoire démontrent que les souris DIO présentent une modulation de l’expression et de l’activité des CYP450s. Nos résultats montrent que cette modulation est spécifique à certaines isoenzymes et variable selon les tissus. Ces travaux supportent que la présence du diabète avec obésité affecte les CYP450s hépatiques et extra-hépatiques, lesquels peuvent ainsi influencer les concentrations systémiques et les concentrations tissulaires, respectivement. D’une perspective future et translationnelle, notre étude mènera à une meilleure compréhension de la capacité d’élimination des médicaments chez les patients diabétiques et par conséquent, à proposer des dosages appropriés pour des médicaments métabolisés par les CYP450s chez les patients diabétiques : une avancée dans l’approche de la médecine personnalisée. / Around 387 million people worldwide suffer from type 2 diabetes (T2D). Patients with T2D often require polypharmacy, not only to ensure glycaemic control, but also to prevent and control micro- and macrovascular comorbidities associated with T2D. However, clinical practice reveals that some diabetic patients show highly variable responses to different drugs in comparison with non-diabetic patients. Variable drug dosages and effects are observed for drugs such as clopidogrel, warfarin, cyclosporine and tacromilus. This intersubject variability in drug response in diabetic patients is an important issue as it may results in treatment failure, adverse effects or even drug toxicity. One of the underlying mechanisms suggested to explain the intersubject variability in drugs responses in diabetic patients is their modified ability to eliminate drugs through metabolism. Evidence support the association between inflammatory diseases, such as T2D, and an activity modulation of metabolism enzymes. It is known that these inflammatory processes can modulate the expression and activity of enzyme proteins, such as the cytochromes P450 (CYP450s), a major enzyme system in drug metabolism. Moreover, several organs express various CYP450s isoenzymes that may contribute to the local drug metabolism, thus influence the drugs concentration within the target organs. Therefore, the aim of this study is to assess the effects of T2D on the expression and activity of CYP450s in order to identify their responsibility in the intersubject response variability to drugs using diet-induced obesity (DIO) mice as a model. The work carried out as part of this thesis shows that there is a modulation of the expression and activity of CYP450s isoenzymes in the DIO mouse model. Our results indicate that this modulation occurs in an isoenzyme-specific and tissue-dependent fashion. This work supports that the presence of diabetes with obesity affects hepatic and extrahepatic CYP450s, which may influence the systemic and local drug concentrations, respectively. In a future and translational perspective, our study will lead to a better understanding of the drug elimination capacity in diabetic patients, and thus will prompt an appropriate dosage adjustment for drugs metabolized by CYP450s in diabetic patients: a step forward towards a more personalized medicine approach.

Diabetes Mellitus has continued to drastically affect the health of the world and many complications can prove fatal. As long as this metabolic disease persist, research discoveries will need to continue to be made so that patient outcomes and healthcare are dramatically enhanced. In recent years, GLP-1 has been the topic of conversation for diabetes research, due to its promising effects in promoting insulin sensitivity. Furthermore, bile acids and their receptors (TGR5 & FXR) have shown promise in their actions in the regulation of GLP-1, and thus glucose homeostasis. Here we have shown the detection and increased expression of TGR5 and GLP-1, and decreased expression of FXR in diabetic mouse intestinal mucosa tissues. We have also shown the detection and increased expression of these receptors in STC-1 cells. More importantly we have linked the connection of increased glucose concentration (hyperglycemia) to increased TGR5 activation to increased GLP-1 release, thus leading to increased insulin sensitivity and altered diabetic outcomes.

Background: Diabetes is a common and costly disease that is expected to continue even to grow in prevalence and health expenditures over the coming decades. Type 2 diabetes is the most common diabetes type and is characterized by insulin resistance and relative insulin deficiency. Type 2 diabetes develops over a long period and is often undetected over years. During this time, people almost always first develop any of the pre-diabetic states, i.e. impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or a combination of both (IFG&amp;IGT). This thesis focuses on type 2 diabetes only. In the following, the term diabetes is used to refer to type 2 diabetes only. Diabetes is associated with a sedentary lifestyle and obesity. While those are not the only factors contributing to the development and maintenance of diabetes, several studies have shown that prevention of diabetes among individuals at high risk through lifestyle change is possible, effective and cost-effective, especially targeting diet and exercise to reduce weight. No previous study had, however, estimated the cost-effectiveness of diabetes prevention strategies from a population-based perspective including healthy individuals and also considered IFG and IGT as two distinct pre-diabetic states. Objective: The overall objective of this thesis was to establish, describe and evaluate a model that can assess the cost-effectiveness of lifestyle intervention programs to prevent diabetes. Methods: First, a Markov Model was established using data from the literature. The cost of a German diabetes prevention program was estimated. Second, risk equations for change to worsened glucose states were estimated using factor analysis and logistic regression based on consecutive data from the Västerbotten Intervention Program (VIP). The risk equations described transition probabilities in the final model and were based on several risk factors such as age, sex, physical activity and smoking status. Third, information on the Short-Form 36 questionnaire from the VIP population was transformed into Short-Form 6D. Health utility weights (HUW) by glucose group and four risk factors were estimated using beta regression. Fourth, an updated Markov model was established using an updated model structure compared to the one in Paper I, program costs of Paper I, risk equations of Paper II, health utility weights of Paper III and updated cost and mortality estimates. Results: The first model in Paper I showed that lifestyle intervention programs have the potential to be cost-effective with a high degree of uncertainty. The risk equations in Paper II indicated that the impact of each risk factor depended on the starting and ending pre-diabetes state, where high levels of triglyceride, hypertension, and high body mass index were the strongest risk factors to transit to a worsened glucose state. The overall mean HUW in Paper III was 0.764 with healthy individuals having the highest HUW, those with diabetes the lowest and those in pre-diabetic states ranging in between. The intervention described in Paper IV was cost-effective for all sex and age scenarios ranging from 3,833 EUR/QALY gained (women, 30 years) to 9,215 EUR/QALY gained (men, 70 years). The probability that the intervention is cost-effective was high (85.0-91.1%). Conclusion: We established a model that can estimate the cost-effectiveness of different scenarios of initiatives to prevent diabetes. The prevention or the delay of the onset of diabetes is feasible and cost-effective. A small investment in a healthy lifestyle with the change in physical activity and diet together with weight loss can have a decent, cost-effective result. The full range of possibilities this model offers has not been evaluated so far. We have, however, shown that implementing a lifestyle intervention program like the Västerbotten Intervention Programme would be cost-effective.

L’expansion des maladies métaboliques dans les sociétés modernes exige plus d’activités de recherche afin d’augmenter notre compréhension des mécanismes et l’identification de nouvelles cibles d’interventions cliniques. L’obésité, la résistance à l’insuline (RI) et la dyslipidémie, en particulier sont tous des facteurs de risque associés à la pathogenèse du diabète de type 2 (DT2) et des maladies cardiovasculaires. Ainsi, la dyslipidémie postprandiale, notamment la surproduction des lipoprotéines hépatiques et intestinales, contribue d’une façon significative à l’hypertriglycéridémie. Quoique plusieurs études cliniques et fondamentales chez l’homme et les modèles animaux aient mis en évidence les rôles importants joués par le foie et l’intestin dans la dyslipidémie, les mécanismes moléculaires en cause ne sont pas bien élucidés. L’une des voies principales régulant le métabolisme lipidique est la voie de la protéine kinase AMPK. L’épuisement de l’ATP intracellulaire entraîne une activation de l’AMPK qui va œuvrer pour rétablir l’équilibre énergétique en stimulant des voies génératrices d’ATP et en inhibant des voies anaboliques consommatrices d’ATP. Les effets positifs de l’activation de l’AMPK comprennent l’augmentation de la sensibilité à l’insuline dans les tissus périphériques, la réduction de l’hyperglycémie et la réduction de la lipogenèse, d’où son importance dans les interventions cliniques pour la correction des dérangements métaboliques. Il est à souligner que le rôle de l’AMPK dans le foie et l’intestin semble plus complexe et mal compris. Ainsi, la voie de signalisation de l’AMPK n’est pas bien élucidée dans les situations pathologiques telles que le DT2, la RI et l’obésité. Dans le présent projet, notre objectif consiste à caractériser le rôle de cette voie de signalisation dans la lipogenèse hépatique et dans le métabolisme des lipides dans l’intestin chez le Psammomys obesus, un modèle animal d’obésité, de RI et de DT2. À cette fin, 3 groupes d’animaux sont étudiés (i.e. contrôle, RI et DT2). En caractérisant la voie de signalisation de l’AMPK/ACC dans le foie, nous avons constaté une augmentation de l’expression génique des enzymes clés de la lipogenèse (ACC, FAS, SCD-1 et mGPAT) et des facteurs de transcription (ChREBP, SREBP-1) qui modulent leur niveau d’expression. Nos analyses détaillées ont révélé, par la suite, une nette augmentation de l’expression de l’isoforme cytosolique de l’ACC, ACC1 (impliqué dans la lipogenèse de novo) concomitante avec une invariabilité de l’expression de l’isoforme mitochondrial ACC2 (impliqué dans la régulation négative de la β-oxydation). En dépit d’un état adaptatif caractérisé par une expression protéique et une phosphorylation (activation) élevées de l’AMPKα, l’activité de la kinase qui phosphoryle et inhibe l’ACC reste très élevée chez les animaux RI et DT2. Au niveau de l’intestin grêle des animaux RI et DT2, nous avons démontré que l’augmentation de la lipogenèse intestinale est principalement associée avec une diminution de la voie de signalisation de l’AMPK (i.e. expression protéique et phosphorylation/activation réduites des deux isoformes AMPKα1 et AMPKα2). La principale conséquence de la diminution de l’activité AMPK est la réduction de la phosphorylation de l’ACC. Étant donné que le niveau d’expression totale d’ACC reste inchangé, nos résultats suggèrent donc une augmentation de l’activité des deux isoformes ACC1 et ACC2. En parallèle, nous avons observé une réduction de l’expression protéique et génique de la CPT1 [enzyme clé de la β-oxydation des acides gras (AG)]. L’ensemble de ces résultats suggère une inhibition de l’oxydation des AG concomitante avec une stimulation de la lipogenèse de novo. Enfin, nous avons démontré que l’intestin grêle est un organe sensible à l’action de l’insuline et que le développement de la résistance à l’insuline pourrait altérer les deux voies de signalisation (i.e. Akt/GSK3 et p38MAPK) essentielles dans plusieurs processus métaboliques. En conclusion, nos résultats indiquent que l’augmentation de la lipogenèse qui contribue pour une grande partie à la dyslipidémie dans la résistance à l’insuline et le diabète serait due, en partie, à des défauts de signalisation par l’AMPK. Nos observations illustrent donc le rôle crucial du système AMPK au niveau hépatique et intestinal, ce qui valide l’approche thérapeutique consistant à activer l’AMPK pour traiter les maladies métaboliques. / Understanding the cellular mechanisms involved in the development of insulin resistance, and later on the occurrence of type 2 diabetes and its metabolic complications, is a perquisite step toward the identification of new therapeutic targets to fight against the development of these metabolic diseases. In the present studies, we used the gerbil Psammomys obesus, a well-established animal model of obesity, insulin resistance (IR) and type 2 diabetes (T2D), to characterize the hepatic and intestinal signaling abnormalities associated with lipid metabolism disorders during the pathogenesis of IR and T2D. Thus, we are able to demonstrate that the development of these metabolic diseases in Psammomys obesus animals, is accompanied by increased hepatic and intestinal lipogenesis with very high efficiency to form triglycerides rich-lipoproteins. In the liver, we observed an increase in mRNA levels of key lipogenic enzymes (ACC, FAS, SCD-1 and mGPAT) and transcription factors (SREBP-1, ChREBP), which modulate the expression level of lipogenic enzymes. Thereafter, our detailed analysis of the AMPK/ACC signaling pathway revealed a rise in the gene expression of the cytosolic ACC1 isoform of ACC(involved in de novo lipogenesis) concomitant with a constant expression of the mitochondrial ACC2 (negative regulator of β-oxidation). In spite of an adaptive state characterized by higher protein expression and phosphorylation (activation) of AMPKα, the kinase that phosphorylates and inhibits ACC, the activity of the later remains very high in IR and T2D animals. In the small intestine of IR and T2D animals, we demonstrated that the increase in intestinal lipogenesis is mainly associated with a decrease of AMPK signaling pathway (i.e. reduced expression and protein phosphorylation/activation of the two AMPKα1 and AMPKα2 isoforms). The main consequence of the decline in AMPK activity is the reduction of ACC phosphorylation. Given that, the expression levels of ACC remain unchanged; our results thus suggest an increased activity of both ACC isoforms, ACC1 and ACC2. Next, we observed a reduction in protein and gene expression of CPT1 [key enzyme in fatty acid (FA) β-oxidation]. Taken together, these results suggest an inhibition of FA β-oxidation concomitant with a stimulation of de novo lipogenesis. Finally, we demonstrated that the small intestine is an insulin sensitive organ and that the development of IR affects two signaling pathways (i.e. Akt/GSK3 and p38MAPK) essentials for several metabolic processes. In conclusion, our results indicate that increased lipogenesis, in IR and T2D, which exacerbate the dyslipidemia associated with these diseases, might be, at least partially, a result of AMPK signaling defects. In addition, our observations illustrate the crucial role of AMPK/ACC in the liver and intestine and validate AMPK as a potential target to treat the metabolic diseases.

Objective: To identify whether perceived stress is a risk-factor for higher cortisol levels and greater insulin resistance in Type 2 diabetic patients, using data from participants with and without diabetes in the National Survey of Midlife Development in the United States (MIDUS), specifically MIDUS II, Project 4. The following hypotheses were tested: (H1a) greater perceived stress would be associated with higher cortisol for Type 2 diabetic participants, (H1b) the perceived stress/cortisol relationship would be stronger for people with Type 2 diabetes than for those without it, (H2) greater perceived stress would be associated with higher Homeostatic Model Assessment-Insulin Resistance (HOMA-IR, insulin-resistance) for Type 2 diabetic participants, (H3a) subjective well-being would moderate the perceived stress/insulin resistance relationship for Type 2 diabetic participants, and (H3b) depression would moderate the perceived stress/insulin resistance relationship for Type 2 diabetic participants. Method: MIDUS, a longitudinal study of over 7,000 American adults, explores biopsychosocial factors that could contribute to variance in mental/physical health. Only complete data were utilized. Type 2 participants (n=115) consisted of 54 males and 62 females ranging in age from 36 to 81 years. Non-diabetic participants (n=1097) consisted of 470 males and 627 females ranging in age from 34 to 84 years. Results: None of the predicted relationships were statistically significant. Waist to hip ratio was significantly related to insulin resistance (r = .31, p = .001). Conclusions: Future studies should collect information about the type and duration of stressors in addition to perceptions about stress for those with Type 2 diabetes.

Contexte: Le diabète de type 2 est un problème de santé publique important. La pratique régulière de l’activité physique contribue à la prévention de cette maladie chronique. Toutefois, peu de recherches portent sur l’association entre l’activité physique de transport, notamment la marche utilitaire, et le diabète. Objectif : L’objectif de cette étude est d’examiner l’association entre la présence d’un diagnostic de diabète de type 2 et les pratiques de marche utilitaire dans un échantillon transversal. Méthode : Cette étude est une analyse secondaire de données provenant d’un projet de recherche sur l’implantation d’un système de vélos libre-service. 7012 adultes ont été recrutés par téléphone au printemps 2009, à l’automne 2009 et à l’automne 2010. La marche utilitaire a été mesurée en utilisant des questions adaptées du International Physical Activity Questionnaire (IPAQ). L’association entre la marche utilitaire et le diabète auto-rapporté a été examinée au moyen d’analyses de régression logistique multivariées. L’influence des variables socio- démographiques, du niveau d’activité physique autre et de l’indice de masse corporelle a été contrôlée. Des analyses de sensibilité ont aussi été faites, utilisant un seuil différent pour le temps de marche utilitaire. Résultats : Dans le modèle final, la marche utilitaire est associée à une prévalence du diabète plus faible (RC=0,721; IC 95% : 0,547-0,950). Conclusion: La pratique de la marche utilitaire est associée à une prévalence plus faible de diabète auto-rapporté. La promotion de ce type d’activité physique aurait sa place dans la prévention du diabète dans une perspective de santé publique. / Background: Type 2 diabetes is an important public health problem. Regular involvement in physical activity contributes to the prevention of this chronic disease. However, limited research has examined associations between transportation physical activity, especially utilitarian walking, and diabetes. Purpose: To examine the association between utilitarian walking and the prevalence of diabetes in a cross-sectional sample. Methods: Secondary analysis of data from a research project on the reach and potential impact of the implementation of a public bicycle share program was conducted. A sample of 7012 adults were recruited to telephone surveys in spring 2009, fall 2009, and fall 2010 via random-digit dialing with oversampling in locations where the public bike share was available. Utilitarian walking was estimated using questions adapted from the International Physical Activity Questionnaire (IPAQ). Multivariable logistic regression models examined the association between utilitarian walking and diabetes. The influence of socio- demographic covariates, involvement in other physical activities, and body mass index were controlled and sensitivity analyses were performed. Sensitivity analyses were performed using a different cut-off for utilitarian walking time. Results: In final models, utilitarian walking was associated with a lower likelihood of self-reporting diabetes (OR=0.721; 95% CI: 0.547, 0.950). Conclusion: Adoption of utilitarian walking is associated with a lower likelihood of reporting diabetes. Replication of these results in longitudinal studies could have implications for strategies to encourage people to incorporate more walking into their daily routine.

Le tissu adipeux blanc n'est pas un simple réservoir énergétique, il secrète également de nombreuses molécules appelées adipokines. En condition basale, les adipokines participent à l'homéostasie générale en permettant la régulation de diverses fonctions et voies métaboliques. Au cours du développement de l'obésité, la physiologie du tissu adipeux est fortement perturbée. Cela se traduit par des dysfonctionnements parmi lesquels l'établissement d'un état inflammatoire chronique à bas bruit. Ces perturbations au sein du tissu adipeux concourent à la dysrégulation de l'expression des adipokines, conduisant à un dysfonctionnement de certaines voies métaboliques, au niveau adipocytaire mais aussi au niveau systémique ce qui aboutit à un état d'insulino-résistance pouvant déboucher sur le développement d'un diabète de type 2. De nombreuses études épidémiologiques montrent qu'une carence en vitamine D est associée à diverses pathologies telles que certains cancers, certaines maladies auto-immunes ou maladies cardiovasculaires. Par ailleurs, il existe une corrélation inverse entre les taux plasmatiques de 25(OH)D et la prévalence de l'obésité, de l'hypertension artérielle, et du diabète de type 2. Cependant, le lien de causalité entre carence en vitamine D et obésité n'est à ce jour pas clairement démontré. Le but de cette thèse est donc de mieux comprendre le lien qui existe entre carence en vitamine D, obésité et désordres physiologiques associés. / White adipose tissue is not a simple energy reservoir, it also secretes several molecules called adipokines. In standard conditions, adipokines are involved in general homeostasis permitting the regulation of numerous functions and metabolic pathways. During the development of obesity, adipose tissue physiology is severely disrupted. This results in dysfunction such as low-grade inflammatory status. The accumulation of these disturbances within adipose tissue generates a dysregulation of adipokines secretion. This will have for consequences a failure of some metabolic pathways resulting in insulin-resistant state leading to type 2 diabetes. Several epidemiological studies show a link between vitamin D deficiency and numerous pathologies like cancers, immunity deseases or cardiovascular deseases. In addition, there is an inverse correlation between plasma levels of 25(OH)D and the prevalence of obesity, hypertension and type 2 diabetes. However, the link between vitamin D deficiency and obesity is not well established. The aim of this thesis is to better understand the link between vitamin D deficiency, obesity and physiological disorders associated. For this purpose, we have evaluated vitamin D effects on adipose tissue and adipocyte biology (inflammation, glucose uptake) and subsequently effects of vitamin D supplementation on diet-induced obesity. In a first study in vitro, we have showed an anti-inflammatory effect of vitamin D on adipocyte. This effect appears to be VDR-dependant and implies a modulation of NF&#954;B signaling pathway. This study could partly explain le link between vitamine D deficiency and low-grade inflammation associated with obesity.