Abstract Gestational diabetes (GDM) indicates increased risk for diabetes and the metabolic syndrome in women. Research on prenatal exposure to GDM as a risk factor for metabolic diseases is conflicting. Overweight (body mass index ≥ 25 kg/m2) is a strong risk factor for GDM and metabolic diseases; however, there are few published previous studies distinguishing the separate effects of overweight and GDM on the later risk for metabolic diseases in women and their children. The present study evaluated pre-pregnancy overweight and GDM as determinants of long-term risk for diabetes and hypertension in women, and the metabolic consequences of prenatal exposures to maternal pre-pregnancy overweight and different types of maternal diabetes in children. The results are based on prospective, clinical data from Oulu University Hospital (n = 63 mothers and their children), and the Northern Finland Birth Cohort 1986 (NFBC 1986, n = 9,362 mothers and their 9,479 children). Compared to normal-weight mothers with normal glucose tolerance in pregnancy, the NFBC 1986 mothers with simultaneous pre-pregnancy overweight and GDM had strikingly high risks for developing diabetes (hazard ratio, HR 47.2; 95% confidence interval 25.5–87.4) and hypertension (HR 9.2 [6.1–13.9]) twenty years after delivery. The risks for these diseases were elevated in mothers with pre-pregnancy overweight even when they had normal glucose tolerance during pregnancy (HR diabetes 12.6 [7.4–21.6], HR hypertension 2.9 [2.1–3.9]). GDM per se indicated increased risk only for diabetes (HR 10.6 [4.2–27.0]). In the cohort from Oulu University Hospital, increased fasting insulin concentration (P = 0.04), first phase insulin response (P = 0.03), and HOMA-B (P = 0.008) were already observed at pre-school age in the offspring of mothers with Type 1 diabetes compared with offspring of mothers with GDM. In the NFBC 1986 offspring, the prevalence of metabolic syndrome was 2.4% at age 16 years, using the International Diabetes Federation pediatric definition. Abdominal obesity, a waist girth over half one’s length, defined approximately 85% of the adolescents with metabolic syndrome. The risks for overweight and abdominal obesity were high in those with prenatal exposure to both maternal pre-pregnancy overweight and GDM (odds ratio for overweight 4.1 [1.9–8.6], for abdominal obesity 3.8 [1.7–8.8]). In children of normal-weight women, prenatal exposure to GDM was not associated with increased risk of these outcomes. Based on this study, preventing and reducing overweight in fertile age seems to be a key target for preventing metabolic diseases in women and their children.

Introduction – Animal studies suggested that NFKB1, SOCS3 and IKBKB genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and nutrition affecting obesity-related phenotypes. Methods – We used multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR) to better detect gene/environment interactions in data from the Toronto Nutrigenomics and Health Study (n=1639) using dichotomized body mass index (BMI) and waist circumference (WC) as obesity-related phenotypes. Exposure variables included genotypes on 54 single nucleotide polymorphisms, dietary factors and ethnicity. Results – MDR identified interactions between SOCS3 rs6501199 and rs4969172, and IKBKB rs3747811 affecting BMI in whites; SOCS3 rs6501199 and NFKB1 rs1609798 affecting WC in whites; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in South Asians. PLR found a main effect of SOCS3 rs12944581 on BMI among South Asians. Conclusion – MDR and PLR gave different results, but support some results from previous studies.

<p>This thesis outlined a novel operationalization and extension of the thrifty phenotype and fetal overnutrition hypotheses, two evolutionary developmental hypotheses stemming from the developmental origins of health and disease perspective, for developmental pathways from prenatal risk through child growth to early puberty. Support has accumulated for both, but previous studies have not clearly determined which hypothesis better predicts early puberty. Using the Fragile Families and Child Wellbeing Study (<i>n</i>=4898), the thrifty phenotype and fetal overnutrition pathways were tested against each other, separately by sex, and race/ethnicity for adrenal, and gonadal pubertal markers. Results indicated that in general, both hypotheses were supported. Contrary to hypotheses, the thrifty phenotype pathway did not predict perceived pubertal timing better in boys and the fetal overnutrition pathway did not predict perceived pubertal timing best in girls. Instead, both pathways predicted puberty equally well between girls and boys and the fetal overnutrition pathway stemming from maternal gestational weight gain was stronger than the pre-pregnancy BMI pathway. Individual paths of the hypothesized pathways were generally supported when analyzed by race/ethnicity group separately, but support for the entire pathways were sparse. Implications of this work are that pubertal timing may be similarly programmed by restrictive and overnutrition prenatal risks, both should be prioritized, and that interventions for maternal gestational weight should be prioritized over interventions for pre-pregnancy BMI for reducing rates of early puberty. </p>

D. Tech. (Food Service Management, Department of Hospitality, Tourism and PR Management, Faculty of Human Sciences)|, Vaal University of Technology| / Background South Africa is one of the developing countries faced with the co-existence of undernutrition and overnutrition, often experienced within the same household. On the one hand, hunger, undernutrition and micronutrient deficiencies are linked to poverty and household food insecurity. Simultaneously, South Africans are exposed to ‘nutrition in transition’, where overweight and chronic diseases of lifestyle, such as diabetes mellitus, cardiovascular diseases and cancer are on the rise as part of the overnutrition profile. Sound nutrition is important throughout the lifecycle to combat under- and overnutrition and nutrition-related diseases. In urban areas, the grandmother or another senior female family member is often responsible for caring for the children in the household during the day. This includes physical, emotional and nutritional care. It is therefore essential for the caregiver to have good nutrition knowledge, to provide not only in her own needs, but also in those of the children. A nutrition education programme is one strategy for improving the nutrition knowledge of caregivers of children. Objective The primary objective in this study was to develop, tailor, implement and evaluate a nutrition education programme (NEP) for Sesotho-speaking females and caregivers of children in the Boipatong Township in the Vaal Region of South Africa and to test its impact in the short and longer term. Nutrition knowledge regarding four South African food-based dietary guidelines (FBDGs) was empirically tested before and after the intervention and then compared to a control group. In addition, dietary intake was assessed to detect any changes after the intervention in the medium term. Methodology In this both quantitative and qualitative methodologies were applied. Two frameworks, the United Nations Children’s Fund (UNICEF) Framework of Malnutrition (2004) and the Food and Agriculture Organisation (FAO) Framework for Nutrition Education (1997), gave structure to the planning, implementation and evaluation of the research project. This study’s nutrition education programme was based on a socio-ecological model to guide behavioural change in terms of healthy food choices. In the preparation phase, a situational analysis was performed by means of a cross-sectional analytical design using descriptive statistics. Socio-demographic and self-reported health information was obtained. Nutrition knowledge, based on the South African food-based dietary guidelines (FBDGs), was measured, and dietary intake was assessed and compared with the estimated average requirements (EARs) for their age categories. Phase two, the formulation phase, used an experimental design. The acceptability and understanding of the existing national nutrition education (NE) material for individuals with low living standards (LSM) was investigated in this phase of the nutrition education programme (NEP). A culturally tailored booklet was developed in English, translated into Sesotho, pilot tested and implemented as part of the nutrition education programme. Lesson plans were developed and pilot tested. A non-randomised control trial was used in the implementation and evaluation phases. The effect of the nutrition education programme on nutrition knowledge was quantitatively measured in a pre- and post-test design at each discussion session in the short term, using paired t-tests in the experimental group of caregivers. The evaluation phase tested the impact of the nutrition education in the longer term. Nutrition knowledge was measured quantitatively in a before-after intervention test design by means of a self-completed structured questionnaire, based on the four South African FDBGs included in the programme. A control group who was not subjected to any intervention was used to complete the same questionnaire before and after the intervention in the same time period as the experimental group. In the experimental group, dietary intake was assessed before and after the intervention to detect changes in dietary intake. No dietary intake was measured in the control group, as changes could be attributed to influences beyond the control of this study. Two randomly selected focus groups of the experimental group were run to provide deeper insight into their perceptions regarding the acceptability and understanding of the NEP and NE material. Results The situational analysis of the preparation phase revealed a poor community that displayed typical patterns of nutrition in transition, at risk of malnutrition. The median age of the sample of caregivers was 44 years (IQR 32-62). Income and consumption poverty was confirmed by 80.5 percent of households spending R300 or less on food, with 75 percent of households having between four and seven people living in the dwelling. Dietary results were indicative of food poverty and poor food choices, possibly due to monetary constraints. A low energy intake (median 5323 kJ/day; IQR 3369-7949), was observed. Only 13.9 percent reached the estimated energy requirement (EER) of 7855 kJ per day for their age category. The overall mean average requirements of the diet was 0.7 but the possiblity of micronutrient deficiencies could not be excluded with a MAR of 0.6 for vitamins and minerals respectively. The median nutrition knowledge was 50 percent (IQR 42-54%) The lowest score was obtained for the FBDG ‘Enjoy a variety of food’ (33.4%; 95% CI 1.1), followed by the FBDG on animal protein (40.3%; 95% CI 1.0). It was decided to augment these two FBDGs with the plant protein FBDG (54.3%; 95% CI 1.8). Despited a relatively good knowledge measured in the caregivers, none of the plant protein food items appeared in the top 20 food items most frequently consumed. The formulation phase included the testing of existing nutrition education material. Messages were well understood (60.5%). However, caregivers found the images contained in the pamphlets and the design of the pamphlets confusing. A definite need was identified for new, culturally acceptable NE material in the caregivers’ home language, Sesotho (74%). During the implementation phase the lectures were presented and the change in the short-term nutrition knowledge of the FBDGs was measured at every session by means of a pre-post-test design. The median age of the caregivers was 63 years (52-78). A significant change in nutrition knowledge was found for each FBDG in terms of the mean number of questions answered correctly by the participants between the results of each pre- and post-test. In the evaluation phase, the impact of the NEP was measured in the Boipatong experimental group and compared, regarding nutrition knowledge, to a control group in the longer term (three months after completion of the intervention). Median nutrition knowledge before the intervention was 49 percent (IQR 46-57) compared to 70 percent (IQR 68-73) after the intervention – an increase of 21 percent. In contrast, the control group showed an increase of only five percent. The results showed that the eating habits of many of the caregivers still fell substantially short of internationally recognised standards (estimated energy requirement (EER) and estimated average requirement (EAR)), and this could contribute to undernutrition as well as to an increased risk of diet-related chronic disease. A median kilojoule intake of 4788 kJ (IQR 3415-6596) per day before and 4651 kJ (IQR 3369-6664) per day after the intervention was registered. Carbohydrate foods remained an important source of energy. Calcium presented a major concern, as none of the participants reached the EAR despite a slight increase in the intake of milk (volume and frequency) after the intervention, as validated by the top 20 food lists and as measured by a nutrient average requirement (NAR) of 0.1 to 0.7 before and after the intervention respectively. The mean average requirements (MAR) remained relatively stable, at 0.7 (median) before the intervention and 0.6 after the intervention. The NEP thus had an insignificant positive effect on dietary intake, except for calcium, iodine and vitamin C intake, which showed significant increases. No relationships could be found between the MAR as an indicator of dietary quality and nutrition knowledge. However, this does not mean that an NEP is not a suitable strategy. Changes in food choices and dietary intake should be measured in the longer term, since lifestyle changes are challenging to adopt when people, especially those in deprived communities, do not have the financial means to make healthy food choices. Conclusion When planning nutrition education strategies to improve the health status of communities in deprived areas, one is faced with the difficulty of households with a low socio-economic status and poor dietary intake, which increases the risk of food and nutrition insecurity. The nutrition education programme, developed, tailored and implemented as an intervention strategy to address an identified need of caregivers, was effective in improving nutrition knowledge. Four of the South African dietary guidelines were used in the nutrition education programme tailored to the specific profile that emerged from the situational analysis and the development of supportive nutrition education material. Lesson plans and the Sesotho and English booklets are available for use in other nutrition education programmes. The study contributed to the understanding of food choices of the urban community of Boipatong as well as of the nutrient inadequacies observed. Nutrition knowledge alone is not enough to bring about changes in food choices when the means to do so are lacking. Poverty and nutrition are closely linked and thus difficult to separate.

Background: As overnutrition rises along with nutrition transition in low- and middle-income settings such as Bangladesh, evaluating metabolic risk factors using overnutrition measures in adolescents is important. Before doing such evaluation, a preliminary step should be taken to attest the independence of overnutrition measures from total height. Moreover, sitting height measures are recognized as important metabolic risk indicators. This study aims to understand the association of attained height –total and sitting– with overnutrition measures including body mass index (BMI), percent body fat (PBF), fat mass index (FMI) and fat free mass index (FFMI) and to assess modification by sex. Methods: Cross-sectional analysis of the MINIMat study’s 15-year follow-up data from October 2017 to December 2018 was undertaken. The associations of attained height –total and sitting– with each of the overnutrition measures were analysed using multiple linear regressions. Results: Overnutrition measures were non-independent of total height among male adolescents. The taller they were, the higher their BMI would be. This increase of BMI along with the height would have been contributed relatively more by the increase of fat free mass (FFM) than that of fat mass (FM). When total heights of both sexes were kept equal at the median, female adolescents had lower lean mass (FFMI) and higher fat mass (FMI) than the males although there was no difference in BMI on average between them. Sitting height was associated with all overnutrition measures with varying extents depending on the sex. Conclusion: When assessing overnutrition measures, it is important to examine beyond BMI and into FMI and FFMI. Again, when assessing the metabolic risks using overnutrition measures among adolescents, normalizing those indices for height is important to be considered to avoid inferring the implication from growth as risks.

Thesis advisor: John Michalczyk / Why do we eat the foods that we do? This question is one that is not often considered by individuals as they go about their daily lives, but can have large implications on public health – for, there is a strong, physiological connection between food consumption and one’s health and wellbeing. Accordingly, when reflecting upon the health of a nation it is often important to consider its nutritional status. Ultimately, many determinants can contribute to how and why an individual eats certain foods, as can be seen in Ecuador. In this Latin American country, for instance, historical, socioeconomic, cultural, behavioral, socioeconomic, and environmental factors (among others) can be seen to influence the different diets – and by extension, the nutritional statuses – of different ethnic, regional, and geographic populations. Though common across Ecuador, discrepancies among these groups are particularly noticeable in the highland region, the Sierra. Overall, this paper examines the different forms of malnutrition, their implications on one’s health, and their prevalence across Ecuador. Additionally, it considers how the Ecuadorian diet was shaped, and how different subcuisines lend themselves to varying forms of malnutrition. Specifically, this paper focuses on the Sierra, given that levels of malnutrition are noticeably higher in this region, and that this highland area is home to large rural and indigenous communities who are most significantly impacted by the region’s nutritional conditions. / Thesis (BS) — Boston College, 2017. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Arts and Sciences Honors Program. / Discipline: .

Les données épidémiologiques indiquent que le diabète maternel est associé de manière significative aux anomalies congénitales des reins et des voies urinaires (CAKUT), ce qui implique un risque accru de CAKUT chez la progéniture des mères diabétiques par rapport à la population globale. Les causes de CAKUT sont multifactorielles, impliquant des facteurs génétiques et environnementaux. Le récepteur de l’angiotensine II de type 2 (AT2R) est l’un des gènes candidats impliqués dans le CAKUT humain et murin. Bien que de nombreuses études soutiennent l’influence des facteurs génétiques et environnementaux sur le développement rénal et la pathogenèse de CAKUT, les effets du gène AT2R et du milieu hyperglycémique in utero sur le développement rénal et les effets à long terme chez les enfants de mères diabétiques ne sont pas clairs. Cette thèse a pour objectif d'étudier l'influence de chaque facteur individuellement, ainsi que l'interaction entre ces deux facteurs. Premièrement, nous avons examiné si le déficit en AT2R (AT2RKO) altère la glomérulogenèse via la formation, la maturation et l'intégrité des podocytes. Nous avons observé que la glomérulogenèse était diminuée chez les embryons E15 AT2RKO, mais le nombre de néphrons ne présentaient aucune différence entre les nouveaux-nés AT2RKO et les souris de type sauvage. Les souris AT2RKO présentaient une dysplasie rénale avec un volume de touffes glomérulaires et un nombre de podocytes inférieurs à l’âge de trois semaines. Nos études ont démontré que la perte d’AT2R via l’augmentation de la génération des dérivés réactifs de l’oxygène (ROS) induite par la NADPH oxydase 4 (Nox4) stimulait l’interaction avec la protéine Hhip (‘Hedgehog interacting protein’), ce qui déclenchait en outre soit l’apoptose des podocytes par l’activation des voies de la caspase- 3 et de la p53, soit la transition épithéliale-mésenchymateuse des podocytes (EMT) par l’activation de la signalisation TGFβ1–Smad2/3. L'ARNm de Hhip glomérulaire était régulé positivement dans les biopsies rénales chez les patients atteints de glomérulosclérose segmentaire focale (FSGS). Les résultats suggèrent que le déficit en AT2R est associé à une perte ou un dysfonctionnement des podocytes et est dû, au moins en partie, à une expression accrue de Hhip ectopique dans les podocytes. Deuxièmement, nous avons cherché à établir les mécanismes sous-jacents par lesquels un milieu hyperglycémique in utero et un régime riche en graisses (HFD) après le sevrage accélèrent la programmation périnatale des lésions rénales. Nous avons observé que la progéniture des mères atteintes de diabète sévère avait un phénotype de restriction de croissance intra-utérine (IUGR) et avait développé une hypertension légère et des signes d'atteinte rénale à l'âge adulte. De plus, la progéniture nourrie avec une HFD post-sevrage présentait un rattrapage rapide de la croissance puis des lésions rénales associées à une augmentation de l’expression rénale de TGFβ1 et du collagène de type IV, à la production de ROS et à une accumulation de lipides rénaux, mais sans hypertension systémique. Des études in vitro ont démontré que le HFD ou les acides gras libres accéléraient le processus de programmation périnatale des lésions rénales, via une expression accrue de CD36 et de la protéine de liaison aux acides gras (Fabp4) qui cible les ROS, le facteur nucléaire-kappa B et le TGFβ1. Ces résultats indiquent que l'exposition précoce à l'HFD chez les enfants de mères diabétiques ayant subi une IUGR augmente le risque d'apparition de lésions rénales à l’âge adulte, mais pas d'hypertension. En résumé, AT2R joue un rôle essentiel dans la glomérulogenèse et influence l'intégrité et la fonction du podocyte via des altérations de l'expression de Hhip. En outre, les enfants de mères diabétiques ont un risque accru d'hypertension et de lésions rénales; la surnutrition postnatale accélère les lésions rénales chez ces enfants. Bien que le gène AT2R et le milieu hyperglycémique in utero aient tous les deux un impact sur le développement du rein et sur les maladies rénales ultérieures, l'interaction entre ces deux facteurs doit encore faire l'objet d'études supplémentaires. / Epidemiologic data indicate that maternal diabetes significantly associates with congenital anomalies of the kidney and urinary tract (CAKUT), which implies an increased chance of CAKUT in the offspring of mothers with diabetes compared to the general population. The causes of CAKUT are multifactorial, involving genetic and environmental factors. The angiotensin II receptor type 2 (AT2R) is one of the candidate genes to be implicated in both human and murine CAKUT. Although numerous studies support the influence of genetic and environmental factors on kidney development and the pathogenesis of CAKUT, the impacts of the AT2R gene and hyperglycemic milieu in utero on kidney development and long-term outcomes in the offspring of diabetic mothers remain unclear. This thesis aims to investigate the influence of each factor individually, as well as their interaction. Firstly, we investigated whether AT2R deficiency (AT2R knock-out (KO)) impairs glomerulogenesis via podocytes formation, maturation and integrity. We observed that glomerulogenesis is decreased in AT2RKO embryos at embryonic day 15 (E15), but actual nephron numbers are no different between AT2RKO and wild-type newborn mice. AT2RKO mice exhibited renal dysplasia with lower glomerular tuft volume and reduced podocyte numbers at the age of three weeks. Our studies demonstrated that loss of AT2R via NADPH oxidase 4 (Nox4)-derived reactive oxygen species (ROS) generation stimulates ectopic hedgehog interacting protein (Hhip) expression, which further triggers either podocyte apoptosis by the activation of the caspase-3 and p53 pathways or podocyte epithelial–to– mesenchymal transition (EMT) by the activation of TGFβ1–Smad2/3 signaling. Glomerular Hhip mRNA is upregulated in kidney biopsies of patients with focal segmental glomerulosclerosis (FSGS). The results suggest that AT2R deficiency is associated with podocyte loss/dysfunction and is mediated, at least in part, via increased ectopic Hhip expression in podocytes. Secondly, we aimed to establish the underlying mechanisms by which a hyperglycemic milieu in utero and a post-weaning high-fat diet (HFD) accelerate the perinatal programming of kidney injury. We observed that the offspring of dams with severe maternal diabetes have an intrauterine growth restriction (IUGR) phenotype and develop mild hypertension and evidence of kidney injury in adulthood. Moreover, those offspring fed with a post-weaning HFD result in rapid catch-up growth and subsequent profound kidney injury associated with the augmentation of renal TGFβ1 and collagen type IV expression, increased production of ROS, and accumulation of renal lipids, but not systemic hypertension. In vitro studies demonstrated that HFD or free fatty acids accelerate the process of perinatal programming of kidney injury, via increased CD36 and fatty acid-binding protein 4 (Fabp4) expression, which targets ROS, nuclear factor-kappa B and TGFβ1 signaling. These results indicate that early postnatal exposure to HFD in IUGR offspring of diabetic dams increases the risk of later developing kidney injury, but not hypertension. In summary, AT2R plays an essential role in glomerulogenesis and influences the podocyte integrity and function via alterations of Hhip expression. In addition, the offspring of diabetic mothers have an increased risk of hypertension and kidney injury; postnatal overnutrition further accelerates kidney injury in those offspring. Although both AT2R and hyperglycemic milieu in utero have an impact on kidney development and later kidney diseases, the interaction between these two factors still needs further studies.