京都大学 / 0048 / 新制・課程博士 / 博士(人間・環境学) / 甲第20464号 / 人博第814号 / 新制||人||195(附属図書館) / 28||人博||814(吉田南総合図書館) / 京都大学大学院人間・環境学研究科共生人間学専攻 / (主査)教授 林 達也, 教授 石原 昭彦, 准教授 久代 恵介 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DGAM

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Obesity is a disease that increases risk of developing metabolic diseases including insulin resistance (IR), metabolic syndrome (MS), and type 2 diabetes (T2D). Adipose tissue expansion during obesity leads to immune cell infiltration, causing local inflammation and disruption of lipid homeostasis. There is an association between exposure to environmental chemicals, like p,p’-DDE, a metabolite of p,p’-DDT, and diagnosis of obesity, dyslipidemia, IR, and prevalence of MS and T2D. DDE accumulates in fatty tissues and has been shown to have immunomodulatory properties, affecting macrophage and T cell populations. Potential mechanisms were studied by which DDE could modulate adipocyte and immune cell function and facilitate an increased risk of obesity and immune dysregulation, potentially through cyclooxygenase-2 (COX-2). 3T3-L1 preadipocytes and J774A.1 macrophages were studied for the effects of DDE on adipogenesis and macrophage reactivity, respectively. 3T3-L1 cells were induced to differentiate to adipocytes using a sub-optimal differentiation cocktail with increasing concentrations of DDE (0.5uM-100uM). It was determined that DDE enhanced adipogenesis in a concentration dependent manner and the expression of adipogenic and lipogenic genes, indicating that DDE enhances adipogenesis. In J774A.1 cells, the ability of DDE or 10uM NS-398, a specific COX-2 inhibitor, to inhibit the production of the prostaglandins PGE2, PGD2, PGF2a, was assessed in vitro and in a cellree system. DDE or NS-398 followed by immune challenge reduced cellular PG secretion and reduced PG production in a cell free system, indicating that DDE may interfere with lipid mediator signaling. Additionally, DDE or NS-398 exposure altered gene expression in J774A.1 cells following M1 or M2 polarization stimulus. Lastly, male C57Bl mice were exposed to 2mg/kg DDE for 5 days and the macrophage population of the adipose stromal vascular fraction was analyzed by flow cytometry. Adipose from DDE treated animals contained approximately 40% F4/80+CD11b+ macrophages. These results indicate that DDE may alter the homeostasis of adipose tissue by both enhancing adipogenesis and altering the reactivity of the resident macrophage population in a manner that may contribute to adipose dysfunction. These data suggest a possible mechanism by which DDE exposure may contribute to adiposity and adipose tissue dysfunction commonly seen in metabolic disease.

Type 2 diabetes mellitus (T2DM) is classified as a metabolic disorder characterized by hyperglycemia that results from defects in insulin action and/or secretion, and currently affects 8.3% of the US population according to the CDC’s 2011 National Diabetes Fact Sheet. Several contributing factors have been identified to development of this disease. Published evidence indicates type 2 diabetes mellitus (T2DM) patients display lower overall paraoxonase activity and that this may be partially due to genetic variations in the paraoxonase-1 (PON-1) gene. Some bioaccumulative organochlorine (OC) pesticides have been shown to contribute to increased T2DM prevalence. In addition, these OC compound levels have been associated with alterations in adipocyte cytokine levels as well as increased inflammatory markers. Three hundred blood samples with clinical and demographic information were obtained from two US Air Force hospitals. A total of 151 non-diabetics and 149 T2DM subjects were evaluated for PON-1 activity, PON-1 Q192R and L55M genetic polymorphisms, OC compound concentrations, inflammatory marker levels and adipokine concentrations. PON-1 activity, using diazoxon as the substrate, was decreased in the T2DM subjects. Some of the PON-1 genetic polymorphisms tested were also associated with decreased PON-1 activity. OC compound levels were increased in the T2DM subjects. The non-diabetic subjects possessing elevated DDE and trans-nonachlor were associated with increased inflammation, a common hallmark of early T2DM development. Additionally, elevated OC levels were seen in association with altered adipokine concentrations. Overall, a decrease in the antioxidant properties of PON-1 as well as factors contributing to chronic low level inflammation such as elevated OC plasma concentration appear to be significant contributors to T2DM prevalence in the population studied.

Mississippi has a very high prevalence of coronary artery disease (CAD) and type 2 diabetes (T2D), especially among African Americans compared to Caucasians. This project determined the L55M genotypes of paraoxonase 1 (PON1) in 187 people and evaluated associations of PON1 single nucleotide polymorphisms (SNPs), Q192R and L55M, with CAD and T2D in a Mississippian (southern) population. Significant associations were found with PON1 SNPs and race: genotypes LL, LM, QR, and RR showed significant associations with race (p values 0.0000955, 0.0024, 0.00001244, and 0.00001676, respectively), and combined genotypes LMQQ and LMRR were significantly associated with race (p values = 0.0001013 and 0.000473, respectively). While no significant associations were found between PON1 SNPs and CAD (p values > 0.2374), combined genotype LMQQ and genotype LM trended towards the likelihood of having T2D with p values = 0.0723 and 0.0931, respectively, and are suggestive of a potential biomarker for T2D risk.

Background: Over the last decade, diabetes health coaching, also referred to as diabetes coaching, has emerged as a patient-centered intervention to assist individuals with type 2 diabetes mellitus (T2DM) in acquiring independence with self-management. The structure and delivery of such interventions have varied greatly while showing improvements in glycemic control. However, literature continues to show a gap around the patient experience of receiving diabetes coaching support. Objective: To explore the perceived experience of receiving telephone-based diabetes health coaching among community-based adults with T2DM within the Canadian context. Methods: A qualitative exploration with an interpretive descriptive design was carried out. Participants from the intervention group of a larger randomized controlled trial who had received a telephone-based diabetes coaching intervention over one year were invited to participate in a telephone interview with open-ended questioning. Findings: A total of 12 participants were interviewed and four major themes were identified. (1) Adapting to life with T2DM reflects how coaching helped individuals to integrate diabetes into their lives by addressing misconceptions, providing knowledge, encouraging awareness, and easing transition onto insulin. (2) Heightened mindfulness of diabetes-related wellness captured the greater attention participants’ gave to their overall well-being and self-management behaviours. (3) Behaviour change guided by the participant highlights the differences in participants’ motivation, readiness to make changes, external factors that influenced their ability to make self-management behaviour changes. (4) Lastly, valuing a supportive relationship illustrates that participants felt the unique coach-client relationship was reliable, holistic, non-judgmental, and encouraging. Conclusion: Overall, participants found diabetes coaching to be positive and highlighted the various ways it was able to support their ability to more effectively self-manage their diabetes. / Thesis / Master of Science in Nursing (MSN)

Objective: The project aimed to compare marginal structural models, and propensity score adjusted models with Cox Proportional Hazards models to address confounding by indication due to time-dependent confounders. These methods were applied to data from approximately 120,000 women in the Women’s Health Initiative to evaluate the causal effect of antidepressant medication with respect to diabetes risk. Methods: Four approaches were compared. Three Cox Models were used. The first used baseline covariates. The second used time-varying antidepressant medication use, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates. The third used time-varying antidepressant medication use, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates and propensity to taking antidepressants at baseline. Our fourth method used a Marginal Structural Cox Model with Inverse Probability of Treatment Weighting that included time-varying antidepressant medication, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates. Results: All approaches showed an increase in diabetes risk for those taking antidepressants. Diabetes risk increased with adjustment for time-dependent confounding and results for these three approaches were similar. All models were statistically significant. Ninety-five percent confidence intervals overlapped for all approaches showing they were not different from one another. Conclusions: Our analyses did not find a difference between Cox Proportional Hazards Models and Marginal Structural Cox Models in the WHI cohorts. Estimates of the Inverse Probability of Treatment Weights were very close to 1 which explains why we observed similar results.

The incidences of diabetes are on the constant rise, and thus need an alternative dietary approach to improve glucose metabolism in type II diabetes patients. Fruits and vegetables have long been known for their beneficial fiber, phenolics and antioxidants, and by incorporating these dietary components into our everyday diet have proven beneficial in controlling the glucose metabolism. In this study, Prime-Jan and Kiowa blackberry cultivars were evaluated for their anti-diabetic properties using a variety of in vitro assays. Overall, the Kiowa blackberry reigned supreme over the Prime-Jan blackberry in the majority of functionality assays, more specifically alpha-amylase, alpha-glucosidase, total soluble phenolics and DPPH free radical scavenging activity. In an attempt to incorporate anti-hypertensive properties into this study, we chose to integrate the Bartlett pear, known as the most widely consumed pear in the United States and recognized for its moderate ACE inhibition. Our results indicated a combination of 70% pear to 30% blackberry as the most beneficial ratio for exhibiting high alpha-amylase (96.5%) and alpha-glucosidase inhibition (95.6%). Additionally, the 70/30 combination exhibited high DPPH free radical scavenging activity (80.7%), total soluble phenolics (1.9 mg/g FW), while also maintaining moderately high ACE inhibition (25.2%). Therefore, there is vast potential for a combination of 70% pear to 30% blackberry to serve as a beneficial alternative in the diet of patients suffering from type 2 diabetes.

Type 2 diabetes is a worldwide and costly disease that requires complex cellular metabolic breakdown for its development. The onset of this disease is indicated by an abnormal elevated blood glucose level (hyperglycemia) and coexistence with hypertension. Apple and blueberry are the two popular fruits in the U.S. that are high in bioactive phenolic compounds. The objectives of this thesis were to investigate the synergistic health benefits of apple cider and blueberry juice for potential management of early stages of type 2 diabetes using in vitro enzyme assay models and enhance their synergistic effects through fermentation using probiotic strains of lactic acid bacteria. Apple cider and whole blueberry juice were combined at 5 different ratios. Synergistic interaction of the phenolic bioactives between the two juice sources was observed in all assays. For maintenance of high α-glucosidase, α-amylase and ACE inhibition activities, a proportion of 80% apple cider and 20% whole blueberry juice was selected as the optimum combination reflecting maximum health benefits to potentially manage hyperglycemia and hypertension associated with type 2 diabetes. The 80/20 apple cider and blueberry juice combination was fermented at 24 and 48 h using Lactobacillus helveticus R0052 and Bifidobacterium longum isolate. High inhibition of α-glucosidase, α-amylase and ACE enzymes was observed in apple cider/blueberry juice combination. Strong antimicrobial activity against H. pylori was exerted by L. helveticus- and B. longum-fermented sample at 48 h. A possible mode of action through the synergy between lactic acid and proline oxidation pathway was suggested.

Low-hierarchy selenoproteins are sensitive to selenium (Se) deficiency and are proposed to confer the protection of body Se against age- and development-related diseases. Selenoprotein H (SELENOH), a low-hierarchy selenoprotein, is greatly downregulated by both dietary Se deficiency and age. To explore physiological roles of SELENOH, Selenoh knockout mice were employed. Segregation analyses demonstrated reduced frequencies of homozygotes and heterozygotes among the neonates of the breeding combinations of Selenoh+/- males vs. Selenoh+/- or Selenoh-/- females, demonstrating essential roles of SELENOH in embryogenesis. Litter sizes from these two breeding groups were comparable with control, suggesting a role of SELENOH in zygotic but not somatic embryogenesis. By contrast, SELENOH was dispensable for longevity in mice. Selenoh-/- males showed azoospermia and a 34%-63% reduction in testis mass in the mice. Histological examination and the analyses of stage-specific markers by qRT-PCR indicated that the Selenoh-/- spermatocytes were arrested in the pachytene stage. Furthermore, GPX4 plausibly accounted for some of the Se loss in the testes because the knockout resulted in a 90% decrease in GPX4 mRNA level. Interestingly, the knockout increased the Selenop and Gpx1 mRNA levels by over 2.3- and 1.9-folds, respectively, but decreased the mRNA amount of Selenov by 99.9% in the testes. As a key component of the meiotic cohesion complex to promote sister chromatid cohesion, Rec8 mRNA amount was reduced by 91.1% in the Selenoh-/- testes aged 42 days. SELENOH knockout did not affect body weight or food intake but resulted in glucose intolerance and insulin resistance in the mice. Additionally, SELENOH knockout reduced the mRNA amounts of Gpx1, Gpx4, and Txnrd1 in the liver and Gpx4 in the skeletal muscle. These findings suggest that SELENOH plays a role in glucose metabolism and regulates body Se metabolism in mice. In summary, results of these three studies unveil essential roles of SELENOH in embryogenesis, spermatogenesis, and glucose tolerance in mice. SELENOH plausibly plays upstream roles to optimize these physiological events in association with the transcriptional regulation of several selenoproteins and meiotic proteins. Future studies are warranted to understand the mechanisms by which SELENOH maintains such developmental and metabolic processes.