<p> Fetal exposure to cigarette smoke is associated with an increased risk of adult-onset metabolic abnormalities. In Canada, nicotine replacement therapy (NRT) is recommended as a safe smoking cessation aid for pregnant women. However, our laboratory has demonstrated that fetal and neonatal nicotine exposure results in glucose intolerance in adult rats. The goal of this thesis was to determine the mechanism(s) underlying the observed dysglycemia following fetal and neonatal nicotine exposure, with a specific focus on the effects of nicotine on pancreatic development and postnatal beta cell function.</p> <p> Nulliparous female Wistar rats received daily subcutaneous injections of either saline or nicotine bitartrate (1 mg/kg/d) for 2 weeks prior to mating until weaning (postnatal day 21 - PND21 ). Pancreatic tissue was collected from male offspring at birth (PND1), 3, 7, 15 and 26 weeks of age. For the critical windows study, dams received nicotine or saline during different stages of pancreatic development, including: A) pre-mating only, B) pre-mating + pregnancy only, C) pre-mating, pregnancy and lactation, or D) pre-mating + lactation only. For the intervention study, nicotine-exposed dams received either normal chow or diet containing antioxidants (1000 IU/kg vitamin E, 0.25% w/w coenzyme Q10 and 0.05% w/w α-lipoic acid) during mating, pregnancy and lactation.</p> <p> Results from this thesis demonstrate that exposure to nicotine during both fetal and neonatal development (but neither stage alone) causes a permenant loss of beta cell mass beginning at birth, and adult-onset dysglycemia in rodents. Furthermore, nicotine exposure induces pancreatic oxidative stress and mitochondrial-mediated beta cell apoptosis in neonates, followed by a progressive decline in mitochondrial structure and function. Maternal treatment with a dietary antioxidant cocktail during pregnancy and lactation protected the developing beta cells from nicotine-induced apoptosis and mitochondrial swelling. These data indicate that the safety of NRT use during pregnancy should be re-evaluated.</p> / Thesis / Doctor of Philosophy (PhD)

Objective: To assess whether the prevalence of low physical activity levels and time spent watching TV differ depending on glycemia status. Methods: A secondary analysis using data from a population-based study was conducted. Two were the outcomes: physical activity levels, derived from the International Physical Activity Questionnaire, and sitting time watching TV. The exposure was glycemia status, defined based on results of the oral glucose tolerance tests (OGTT): euglycemia, dysglycemia, and T2DM. The T2DM group was further split into: aware and unaware of T2DM diagnosis. Prevalence ratios (PR) and 95% CI were reported using Poisson regression models. Results: Data of 1607 individuals, mean age 48.2 (SD: 10.6) years, 809 (50.3%) females, were analyzed. Dysglycemia and T2DM was present in 16.9% (95% CI: 15.1%–18.8%) and 11.0% (95% CI: 9.5%–12.6%) of participants, respectively. A total of 605 (37.6%; 95% CI: 35.2%–39.9%) participants had low levels of physical activity and 1019 (63.3%; 95% CI: 60.9%–65.7%) subjects spent ≥2 h per day sitting watching TV. In multivariable model, there was no significant association between glycemia status and physical activity levels (PR = 1.14; 95% CI: 0.95–1.36). Similar result was found between glycemia status and sitting time watching TV. However, those aware of T2DM diagnosis were more likely to have low levels of physical activity (PR = 1.31; 95% CI: 1.06–1.61) compared to the euglycemia group. Conclusions: We found a no relationship between glycemia status and physical activity level or sitting time watching TV, pointing out similar levels of physical (in)activity among those with euglycemia, dysglycemia and T2DM. Individuals aware of having T2DM were 30% more likely to have low physical activity levels compared to the euglycemic group. There is a need to increase physical activity levels among T2DM individuals. / Revisión por pares

Background: Type 2 diabetes affects approximately 8% of the world’s population. Individuals of South Asian ancestry tend to develop metabolic abnormalities, leading to diabetes, at lower measures of absolute obesity and approximately 10 years earlier than white Caucasians. Current literature is unclear on the source of this ethnic heterogeneity; the variation in risk cannot be explained by lifestyle factors alone. The overarching aim of this thesis is to explore the role of genetic variants and epigenetic differences to explain the greater risk for type 2 diabetes among South Asians. Methods: We first conducted a systematic review of the literature to ascertain the genetic risk from known single nucleotide polymorphisms (SNPs) among South Asians. We then compared these risk estimates to those from white Caucasians in a cohort of 69,033 individuals. Second, using the EpiDREAM prospective cohort study of individuals at high-risk for diabetes, we assessed the impact of genetic burden for impaired pancreatic beta-cell function alone and together with abdominal obesity on glucose traits. Ethnic heterogeneity in this interaction was also studied. Lastly, using data from two Canadian birth cohorts of South Asian and white Caucasian ancestry, we investigated ethnic differences in the epigenetic architecture for genes known to be implicated birth weight and length, as both are associated with the future risk of adult diabetes. Results: The systematic review identified 15 SNPs robustly associated with type 2 diabetes in both South Asians and white Caucasians. The magnitude of risk and allele frequency of these genetic variants did not differ between the ethnic groups. Additionally, we identified 8 novel polymorphisms implicated in diabetes only among South Asians. Second, using data from the EpiDREAM study, we identified an interaction between cumulative genetic burden of beta-cell impairment, measured using an un-weighted genotype score, and abdominal obesity on glucose traits in South Asians, but not white Caucasians. Third, our investigation of differential DNA methylation between the ethnic groups revealed seven CpG sites for which changes in methylation corresponded to alterations in birth weight among white Caucasians, but not South Asians. An independent agnostic genome-wide search identified methylation levels at three CpG sites that appear to uniquely modulate birth weight in South Asians. Conclusions: Overall, our results indicate that the greater risk for metabolic traits in South Asians likely does not result from common genetic variants shared by both South Asians and white Caucasians. Rather, differences in risk may be additionally influenced by unique risk variants in South Asians. Furthermore, it appears that the risk from a genetic impairment in South Asians may be magnified by abdominal obesity. / Thesis / Doctor of Philosophy (PhD)

No description available.

Objective: Researches which studied the relation of dietary greenhouse gas emissions with health outcomes are few, inconsistent and most of them are modelling studies which have not investigated empiric dietary emission patterns. In this study, we employ a posteriori data dimension reduction method, treelet transform, to identify dietary and diet related emission patterns concurrently. We aim to evaluate if these patterns are correlated, if they areassociated with diabetes and if emission patterns can be used as a proxy for dietary patterns for assessment of association with diabetes. Design: Food items from dietary questionnaire were aggregated to 34 food groups. GHGE was estimated by linking food intakes with life cycle assessment data on emission. Dietary and emission patterns were identified by employing treelet transform on food intake and corresponding greenhouse gas emission data. Multivariate logistic regression was performed to investigate associations between quintiles of dietary patterns and diabetes. Adjusted mean values of emission estimates were obtained for the identified dietary patterns. Adjusted proportions of diabetes across quintiles of emission patterns were computed. Setting: Västerbotten Intervention Program Subjects: women (n 38,118); men (n 36,042) between the age of 35 and 65 years Results: Four dietary and four corresponding emission patterns in women, five dietary and five corresponding emission patterns in men were identified. Moderate to strong correlations were observed between dietary and corresponding emission patterns. Prudent dietary pattern (PP) in women was inversely associated with dysglycemia [ORQ5 vs. Q1 = 0.82 (95% CI 0.69—0.97, Ptrend =0.003)]. PP in women was also inversely associated with diabetes [ORQ5 vs.Q1 = 0.37 (95% CI 0.17—0.78, Ptrend = 0.002)]. However, adherence to this dietary pattern was associated with higher dietary emission. Finally, none of the corresponding emission patterns, were associated with adjusted proportions of either dysglycemia or diabetes. Conclusion: Treelet transform produces correlated dietary and emission patterns which are sparse and easily interpretable. However, some differences in loading structures between dietary and emission patterns result in different conclusion regarding the association with diabetes, rendering the usage of emission patterns as proxies of dietary patterns inappropriate. Results from our study also show that healthy dietary patterns do not necessarily reduce greenhouse gas emission.

Abstract Type 1 diabetes is considered to be a T cell-mediated autoimmune disease characterized by destruction of the pancreatic beta cells. Its prediction is currently based on diabetes-associated autoantibodies, giving a cumulative risk of 84% during 15 years of follow-up since seroconversion. Prediction of the timing of clinical onset has remained challenging, however. This thesis examines glucose metabolism in autoantibody-positive children with a high risk of developing type 1 diabetes. Out of a total of 14,876 children with an increased genetic risk followed up from birth in the Finnish DIPP study, 567 developed ≥2 autoantibodies during the follow-up and 255 of these (45%) were diagnosed with type 1 diabetes until the end of December 2011. The glucose parameters measured were HbA1c, OGTT and random plasma glucose with 3 to 12 months interval. Seven-day continuous glucose monitoring (CGM) was performed on an age and sex-matched cohort. We showed that rising HbA1c, impaired glucose tolerance in OGTT, random plasma glucose values of ≥7.8mmol/l and potentially CGM can predict type 1 diabetes with a median time to diagnosis of approximately one year. Our results suggest that especially HbA1c and random plasma glucose are cost-effective and improve the prediction of diabetes. These markers may be useful for monitoring the response to treatment in prevention studies. / Tiivistelmä Tyypin 1 diabetesta pidetään T-soluvälitteisenä autoimmuunitautina, joka johtaa haiman beetasolujen tuhoutumiseen. Tyypin 1 diabeteksen ennustaminen perustuu tällä hetkellä diabetekseen assosioituviin vasta-aineisiin, jotka antavat 84% kumulatiivisen riskin 15 vuoden seurannassa. Taudin puhkeamisen ajankohdan ennustaminen on kuitenkin edelleen vaikeaa. Tämä väitöskirja käsittelee glukoosiaineenvaihduntaa vasta-ainepositiivisilla lapsilla, joilla on suurentunut riski sairastua tyypin 1 diabetekseen. Suomalaisessa DIPP-tutkimuksessa vasta-aineiden kehittymistä on seurattu yhteensä 14876 lapselta. Seurannan aikana 567 lasta kehitti ≥2 autovasta-ainetta ja näistä 255 (45%) sairastui tyypin 1 diabetekseen joulukuun loppuun 2011 mennessä. Glukoosiaineenvaihduntaa seurattiin tutkimalla HbA1c, OGTT ja satunnaisia verensokeriarvoja 3-12 kuukauden välein. Ikä ja sukupuolivakioidussa kohortissa tehtiin jatkuvan sokeripitoisuuden seuranta (CGM). Tutkimuksessamme nouseva HbA1c, heikentynyt sokerin sieto OGTT-kokeessa, satunnainen verensokeri ≥7.8 mmol/l ja mahdollisesti CGM ennustavat tyypin 1 diabeteksen puhkeamista. Tulostemme perusteella erityisesti kustannustehokkaat HbA1c ja satunnainen verensokeri parantavat diabeteksen ennustamista. Nämä parametrit saattavat olla hyödyllisiä myös preventiotutkimuksissa hoitovasteen seurannassa.