京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21833号 / 農博第2346号 / 新制||農||1068(附属図書館) / 学位論文||H31||N5205(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 澤山 茂樹, 教授 佐藤 健司 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

The prevalence of both Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing worldwide, and the trends are unfortunately expected to continue. AD has recently been tied with mitochondrial dysfunction and insulin resistance, creating a mechanistic tie between AD and T2DM. Unfortunately, insulin resistance is often increased with aging and therefore, all individuals are at risk of brain mitochondrial dysfunction. Without proper mitochondrial function, the brain will degenerate, causing impaired cognitive function and reduced quality of life. The purpose of this study is two-fold: first, to understand the role of ceramides in insulin-induced brain mitochondrial dysfunction, and; second, to understand how ketones can restore brain mitochondrial function in aged brains. To evaluate the role of insulin resistance and ceramides in brain mitochondrial function, we induced hyperinsulinemia in ApoE4 mice. In addition to insulin, one group received myriocin injections to inhibit ceramide biosynthesis. We observed significant increases in brain ceramides in the insulin-treated group, which correlated with disrupted brain mitochondrial function. However, the group receiving myriocin alone, and, importantly, myriocin with insulin, had normal lipid profiles and normal mitochondrial bioenergetics. Altogether, these findings support the hypothesis of the key role of ceramides in insulin resistance-induced mitochondrial dysfunction within the brain. Next, young adult (5 months old) and old (28 months old) rats were assigned to either standard chow diets or very-low-carbohydrate, high-fat, ketogenic diets for 4 weeks. Following the treatment period, we analyzed brain mitochondrial function and oxidative stress. We found that the old rats fed the ketogenic diet had improved mitochondrial function in comparison to the old rats consuming standard rodent chow. In addition, the old rats fed a standard diet had significantly higher levels of oxidative stress than the aged rats on the very-low-carbohydrate, high-fat diet. These findings revealed that ketones can protect brain mitochondrial function in aging. Collectively, these results suggest that insulin resistance has a role in the development of brain mitochondrial dysfunction due to ceramide accumulation, while ketones can help mitigate some of the negative consequences of aging, perhaps some due to insulin resistance, on brain mitochondrial function.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Objective: The objective of this study was to characterize the composition of the gut microbiota in type 2 Diabetes Mellitus (T2DM) patients with adequate and inadequate metabolic control, and its relationship with fiber consumption. Results: A total of 26 patients with type 2 diabetes mellitus (T2DM) were enrolled, of which 7 (26.9%) cases had adequate metabolic control (HbA1c < 7%) and 19 (73.1%) inadequate metabolic control (HbA1c ≥ 7%). It was observed that among patients with controlled T2DM, 2 (28.6%) cases presented good intake of fiber and 5 (71.4%) cases a regular intake. In contrast, in patients with uncontrolled T2DM, 13 (68.4%) patients reported a regular intake and 6 (31.6%) a poor intake. In relation to the identification of the gut microbiota, both groups presented a similar characterization. There were differences in the population of bacteria identified in both groups, however, the results were not statistically significant. The most frequently identified bacteria in controlled and uncontrolled T2DM patients were Prevotella (71.4% vs 52.6%), followed by Firmicutes (71.4% vs 42.1%), Proteobacteria (71.4% vs 36.8%) and Bacteroidetes (57.1% vs 37.8%). On the other hand, Fusobacterium, Actinobacteria were not identified in either of the two groups of study. / Revisión por pares

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Typ 2-diabetes är en folkhälsosjukdom som ökar drastiskt på både en nationell och global nivå. Behandlingen av typ-2 diabetes utgår till stor del utifrån att patienten genomför en god egenvård. För att stötta patienter i sin egenvård har användandet av E-hälsa ökat i hälso- och sjukvården. Genom rätt anpassad information och samråd med sjuksköterskan gällande egenvård vid typ-2 diabetes kan E-hälsa vara en möjlighet till att stärka patienten i sin egenvård. Litteraturöversiktens syfte är att belysa patienters upplevelser av E-hälsa som stöd i egenvård vid typ 2-diabetes. Metoden som valdes var en litteraturöversikt baserat på 16 vetenskapliga artiklar. I resultatet framkom två teman; E-hälsans inverkan på egenvård och utformning av teknik. E-hälsans inverkan på egenvård framställdes ur tre underteman; Patienter upplevde en ökad kontroll, E-hälsa påverkade patienters engagemang och kunskap skapar förutsättningar. Utformning av teknik framställdes ur två underteman; Personcentrerad E-hälsa och avsaknad av mänskliga möten. För att E-hälsa ska utvecklas och uppnå vision E-hälsa 2025, är det av vikt att ta del av patienters upplevelser för att sjuksköterskan ska kunna tillmötesgå patienters vårdbehov.

Immigrants are at elevated risk for not having their diabetes treatment appropriately intensified, likely resulting in poorly-controlled diabetes and increased morbidity and mortality. Immigrant status is a powerful sociodemographic cue, yet its influence on providers' diabetes treatment decisions remains unknown. The study objective was to determine the effect of patient immigrant status on provider decisions to (1) take no action, (2) add an oral hypoglycemic agent (OHA), (3) add/switch to insulin, or (4) refer the patient to an endocrinologist. Participants were 140 medical students/professionals ('providers'). Providers viewed profiles (videos+vignettes) for virtual patients different in immigrant status (born in Mexico or U.S.; other characteristics held constant). Analyses were completed at the group and individual levels. Group levels indicated providers were less likely to refer foreign-born patients to endocrinology than U.S.-born patients (p=0.03). No differences were detected for the other three treatment likelihood ratings. Individual results indicated that about half of provider decisions were influenced by patient immigrant status (i.e., Cohen's d≥0.50) across all four decisions. Effect size data show an almost even split between higher treatment ratings for foreign-born vs. U.S.-born patients for three decisions (take no action, add an OHA, add/switch to insulin), explaining why group-level differences for these ratings did not emerge. This study found that providers are less likely to refer foreign-born patients to endocrinology, potentially leading to therapeutic inertia. In addition, half of individual-level provider decisions were meaningfully influenced by patient immigrant status. However, traditional group-level analyses mask these important individual-level differences. These systematic differences in treatment based on non-relevant factors could lead to unintended adverse outcomes for the foreign-born population.

>Magister Scientiae - MSc / Current research classifies Type 2 diabetes as most prevalent non-communicable diseases in South Africa. Approximately 285 million people are affected globally with an expected increase to 595 million by the year 2035. Synthetic first-line drugs in the treatment of Type 2 diabetes, have been shown to have an efficacy rate of approximately 43% as a result of poor drug uptake and metabolism. Furthermore, given South Africa’s uniquely diverse botanical heritage, herbs commonly used traditional medicine have shown promise in the treatment of Type 2 diabetes.

Obesity, a major risk factor in the development of Type 2 Diabetes (T2D), is commonly associated with insulin resistance and hyperinsulinemia. The long accepted view has been that insulin resistance drives hyperinsulinemia; however, there are multiple lines of evidence that hyperinsulinemia can precede and drive insulin resistance. The signals and mechanisms by which chronic excess nutrients promote pancreatic β-cell dysfunction remain poorly understood. This prompted us to define the signaling events that contribute to basal insulin hypersecretion induced by excess glucose. Of particular interest is signaling through mechanistic target of rapamycin complex 1 (mTORC1), a nutrient sensitive kinase complex whose hyperactivation has been shown to promote hyperinsulinemia. Clonal ß-cells (INS-1 cells) with and without mTORC1 inhibition were pre-exposed to physiological (5mM) or excess (11mM) glucose for 4 to 24 hrs. Basal insulin secretion, respiration and metabolites were measured. Pre-exposure to excess glucose resulted in sustained mTORC1 hyperactivation, basal insulin secretion, higher basal respiration and increased maximal respiratory capacity, due to accelerated mitochondrial pyruvate metabolism. Inhibition of mTORC1 reduced basal insulin secretion, basal respiration and maximal respiratory capacity. Moreover, cells challenged with excess glucose had increased levels of glycolysis and TCA cycle intermediates. Our results suggest that hyperactivation of mTORC1 induced by excess glucose results in increased energy demand and in the generation of metabolic factors that can lead to basal insulin hypersecretion. Therefore, targeting mitochondrial pyruvate metabolism and /or mTORC1 signaling could potentially lead to specific therapies to control hyperinsulinemia and diabetes progression.

MMed, Internal Medicine, Faculty of Health Sciences,University of the Witwatersrand / Aims: To determine whether impairment of the executive functioning domain of cognition could be detected by a battery of simple bedside cognitive tests of executive function associated with inadequate glycaemic control. Methods: People with type 2 diabetes attending a tertiary referral diabetic clinic who consented to participate in the study underwent a brief battery of cognitive testing (the Bedside Executive Screening Test) designed to detect executive function impairment. Glycaemic control was determined using glycated haemoglobin levels (HbA1c). Inadequate glycaemic control was defined as HbA1c ≥ 7.0%. Results: Executive function impairment was detected in 51 (52%) of the 98 study participants. The presence of executive function impairment was significantly associated with poor glycaemic control (HbA1c ≥ 7.0%) (odds ratio 4.9, 95% confidence interval 1.3 – 18.8, p=0.019). There were no significant differences between patients with and without executive function impairment with regard to age, target organ damage, patient reported adherence, and hypoglycaemic therapy. Patients with a lower level of education were more likely to demonstrate executive impairment when glycaemic control was poor (p=0.013). Conclusion: Executive function impairment is common in a population of people with difficult-to-manage type 2 diabetes. The presence of executive impairment is significantly associated with poor glycaemic control.

archives@tulane.edu / Gestational diabetes mellitus (GDM) increases the lifetime risk of developing type 2 diabetes mellitus (T2DM) in the mother; however, biological mechanisms remain relatively unknown, and known risk factors have shown to be incomplete. Both epidemiological and experimental research suggest that environmental exposure to particulate matter (PM2.5) may initiate and further progress chronic diseases such as T2DM. This study investigates the association between PM2.5 exposure and the risk of T2DM among women with a history of GDM. Associations between prevalent and incident T2DM with PM2.5 utilized two PM2.5 metrics: 1) annual average PM2.5 concentration and 2) annual average modeled PM2.5 exposure, calculated from daily PM2.5 concentration levels provided by the USRA/NASA Marshal Space Flight Center. Data from the Southern Community Cohort Study, who at recruitment reported a previous diagnosis of GDM, for whom T2DM, risk factor, and follow-up information were available, was provided. In total, 2403 participants were included in the analysis of prevalent T2DM, and 1036 participants were included in the analysis of incident T2DM. Associations between proximity to roadways and race with PM2.5 metrics were also conducted. Participants that live close to roadways were exposed to higher annual average PM2.5 concentrations and annual average modeled PM2.5 exposures. When stratified by race, non-Black participants were exposed to higher averages. After adjustment, a significant association was observed between annual average PM2.5 concentration and incident T2DM (hazards ratio (HR)= 1.022, 95% confidence interval (CI): 1.003, 1.040). No association was observed between annual average PM2.5 concentrations and prevalent T2DM. Annual average modeled PM2.5 exposure was not associated with either prevalent or incident T2DM. Results were partly consistent with previous literature. Additional studies with a greater range of air pollution exposures, including higher levels, additional pollutants, and more tailored exposure models, are warranted to investigate hypothesized associations. / 0 / Ashley Bell