Globally, the prevalence of Type 2 diabetes is rising. The most affected populations are those that have undergone recent and rapid transition towards a Western lifestyle, characterised by energy-dense diets and physical inactivity.¶ Two major hypotheses have attempted to explain the variation in diabetes prevalence, both between and within populations, beyond the contributions made by adult lifestyle. The thrifty genotype hypothesis proposes that some populations are genetically well adapted to surviving in a subsistence environment, and are predisposed to develop diabetes when the dietary environment changes to one that is fat and carbohydrate rich. The programming hypothesis focuses on the developmental environment, particularly on prenatal and early postnatal conditions: nutritional deprivation in utero and early postnatal life, measured by low birthweight and disrupted child growth, is proposed to alter metabolism permanently so that risk of diabetes is increased with subsequent exposure to an energy-dense diet. Both hypotheses emphasise discord between adaptation (genetic or developmental) and current environment, and both now put forward insulin resistance as a likely mechanism for predisposition.¶ Diabetes contributes significantly to morbidity and mortality among Australia’s Indigenous population. Indigenous babies are more likely to be low birthweight, and typical patterns of child growth include periods of faltering and rapid catch-up. Although there have been numerous studies in other populations, the programming hypothesis has not previously been tested in an Australian Indigenous community. The framework of the programming hypothesis is thus expanded to consider exposure of whole populations to adverse prenatal and postnatal environments, and the influence this may have on diabetes prevalence.¶ The present study took place in Cherbourg, a large Aboriginal community in southeast Queensland with a high prevalence of diabetes. Study participants were adults with diagnosed diabetes and a random sample of adults who had never been diagnosed with diabetes. Data were collected on five current risk factors for diabetes (general and central obesity, blood pressure, age and family history), in addition to fasting blood glucose levels. A lifestyle survey was also conducted. Participants’ medical records detailing weight growth from birth to five years were analysed with regard to adult diabetes risk to determine whether childhood weight and rate of weight gain were associated with subsequent diabetes. Adult lifestyle factors were xiialso explored to determine whether variation in nutrition and physical activity was related to level of diabetes risk.¶ Approximately 20% of adults in Cherbourg have diagnosed diabetes. Prevalence may be as high as 38.5% in females and 42% in males if those who are high-risk (abnormal fasting glucose and three additional factors) are included. Among those over 40 years, total prevalence is estimated to be 51% for females and 59% for males.¶ Patterns of early childhood growth may contribute to risk of diabetes among adults. In particular, relatively rapid weight growth to five years is associated with both general and central obesity among adult women. This lends some qualified support to the programming hypothesis as catch-up growth has previously been incorporated into the model; however, although the most consistent association was found among those who gained weight more rapidly, it was also found that risk is increased among children who are heavier at any age.¶ No consistent associations were found between intrauterine growth retardation (as determined by lower than median birthweight and higher than median weight growth velocity to one and three months) and diabetes risk among women or men. A larger study sample with greater statistical power may have yielded less ambiguous results.¶ Among adults, levels of physical activity may be more important than nutritional intake in moderating diabetes risk, although features of diet, such as high intake of simple carbohydrates, may contribute to risk in the community overall, especially in the context of physical inactivity. A genetic component is not ruled out. Two additional areas which require further investigation include stress and high rates of infection, both of which are highly relevant to the study community, and may contribute to the insulin resistance syndrome.¶ Some accepted thresholds indicating increased diabetes risk may not be appropriate in this population. Given the relationship between waist circumference and other diabetes risk factors and the propensity for central fat deposition among women even with low body mass index (BMI), it is recommended that the threshold where BMI is considered a risk be lowered by 5kg/m2 for women, while no such recommendation is made for men.¶ There are a number of social barriers to better community health, including attitudes to exercise and obesity, patterns of alcohol and tobacco use and consumption of fresh foods. Some of these barriers are exacerbated by gender roles and expectations.¶

La grande diversité des réponses de stress observée entre individus a pour origine des facteurs génétiques en interaction avec des facteurs environnementaux. Certaines réponses peuvent être moins adaptées et accroitre la vulnérabilité de l’individu aux divers troubles et pathologies liées au stress. La CBG est une glycoprotéine plasmatique impliquée dans la biodisponibilité des glucocorticoïdes, un des principaux médiateurs de la réponse au stress. Des études génétiques ont montré que des polymorphismes du gène codant la CBG ont un impact significatif sur la réponse des glucocorticoïdes au stress. Pour comprendre les mécanismes de l’impact de la CBG sur l’action des glucocorticoïdes et les conséquences sur les réponses endocriniennes et comportementales de stress, notre équipe a développé un modèle de souris déficiente pour le gène Cbg. Ces souris présentent une réponse diminuée des glucocorticoïdes au stress, associée à un niveau élevé de comportement émotionnel de type dépressif. Cette thèse a pour but d’explorer plus en profondeur les altérations physiologiques et comportementales des souris Cbg ko. Nous avons montré que le niveau plus faible de glucocorticoïdes observé chez la souris Cbg ko provient d’une élimination plasmatique plus importante. Une étude chez la souris Cbg ko femelles a montré que les estrogènes se surimposent à la déficience en CBG pour induire des comportements de type dépressif. Nous avons également démontré que la déficience en CBG conduit a une atténuation de la sensibilité comportementale et endocrinienne au stress chronique. Enfin, nous avons observé une détérioration de la mémoire long terme de ces souris. Par ailleurs, nous montrons que dans des conditions de stress chronique associé à un régime alimentaire déséquilibré le métabolisme du glucose était altéré chez les animaux déficients en CBG. Ces résultats renforcent l’importance du rôle de la CBG influençant l’ensemble des mécanismes d’actions des glucocorticoïdes par la modulation de leurs niveaux et de leur disponibilité. / The great diversity in the response to stress observed among individuals originates from their genetic background in interaction with environmental factors. Some responses can be less adaptive and increase the vulnerability to develop stress-associated disorders. CBG is a plasma glycoprotein that regulates the bioavailability of glucocorticoids, one of the main mediators of the stress response. Genetic studies pointed out variations in the gene coding for CBG as a major factor influencing the glucocorticoid response to stress. To better understand the mechanisms involved and the consequences on endocrine and behavioral responses to stress, our team has developed a mouse model of CBG deficiency. These mice present blunted glucocorticoid response to stress associated with increased despair-like behaviors. This thesis aimed at further exploring the physiological and behavioral alterations presented by the Cbg ko mice. We showed that the lower glucocorticoid levels observed in Cbg ko mice stems from their higher clearance from plasma. A study performed on Cbg ko female mice revealed that estrogens outpass CBG deficiency in inducing despair-like behavior. Additionally, we evidenced that CBG deficiency leads to lower behavioral and endocrine sensitivity to chronic stress, and we observed impairment of hippocampal-dependent long-term memory in these mice. Finally, we found that chronic stress combined to high-fat diet leads to alteration in glucose metabolism in CBG deficient animals. These findings reinforce the important role of CBG influencing the broad range of actions of glucocorticoids by modulating their levels and availability.