Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(農学) / 甲第18319号 / 農博第2044号 / 新制||農||1021(附属図書館) / 学位論文||H26||N4826(農学部図書室) / 31177 / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 河田 照雄, 教授 伏木 亨, 教授 金本 龍平 / 学位規則第4条第1項該当

Metabolic syndrome is taking epidemic proportions, especially in developed countries. Each risk factor component of the syndrome independently increases the risk of developing coronary artery disease. The risk factors are obesity, dyslipidemia, hypertension, diabetes type 2, insulin resistance, and microalbuminuria. Nuclear receptors is a family of receptors that has recently received a lot of attention due to their possible involvement in metabolic syndrome. Putting the receptors into context with their co-factors and ligands may reveal therapeutic targets not found by studying the receptors alone. Therefore, in this thesis, interactions between genes in nuclear receptor pathways were analysed with the goal of investigating if these interactions can supply leads to biomarkers for metabolic syndrome. Metabolic syndrome donor gene expression data from the BioExpressä, database was analysed with the APRIORI algorithm (Agrawal et al. 1993) for generating and mining association rules. No association rules were found to function as biomarkers for metabolic syndrome, but the resulting rules show that the data mining technique successfully found associations between genes in signaling pathways.

bjetivo. Evaluar la asociación entre síndrome metabólico (SM) y carga glicémica (CG) de la ingesta alimentaria en niños y adolescentes obesos atendidos en consulta endocrinológica de un hospital de referencia pediátrica en Lima, Perú. Población y método. Estudio transversal en niños y adolescentes obesos (índice de masa corporal ≥ percentil 95) de 10 a 15 años. Se clasificó como SM según los criterios de la International Diabetes Federation. Se aplicó un recordatorio de 24 horas y se calculó la CG total y por comida. Se evaluó la asociación entre los terciles de CG (comparación con el inferior) y SM usando razones de prevalencia ajustadas (RPa) por variables demográficas, antecedentes familiares, de actividad física y consumo total de carbohidratos en modelos de regresión de Poisson con varianza robusta. Resultados. De 273 niños y adolescentes obesos, 52,4% fueron varones y 94,9% fueron físicamente inactivos. La mediana de CG fue de 213 (164,8- 287,4) y la de ingesta calórica diaria fue 2275 (1851-3024) kcal, dada principalmente por carbohidratos (62%). La prevalencia de SM fue de 22,3%; los componentes con mayor prevalencia fueron la obesidad abdominal (81,7%) y los valores de lipoproteínas de alta densidad (HDL, del inglés high density lipoprotein) bajos (63,7%). Por último, se encontró una asociación entre el consumo elevado de CG y el riesgo de presentar SM (RPa 4,5; IC 95%: 1,3-15,3). Conclusiones. Existe una asociación entre el alto consumo de CG y la presencia de SM en niños y adolescentes con obesidad. / Objective. To study the association between the metabolic syndrome (MS) and the glycemic load (GL) of food intake among obese children and adolescents seen in consultation by the endocrinology team in a pediatric referral hospital in Lima, Peru. Population and Method. Cross-sectional study among obese children and adolescents (body mass index ≥ 95 percentile), 10-15 years old. The MS was classified according to criteria of the International Diabetes Federation. A 24 hour reminder was used, and the overall and per meal GL was calculated. The association between the GL tertiles (comparison with the lower tertile) and the MS was assessed using prevalence ratios adjusted by demographic outcome measures, family history, physical activity and total carbohydrate consumption in Poisson regression models with a robust variance. Results. Out of 273 obese children and adolescents, 52.4% were male and 94.9% did not engage in any physical activity. Glycemic load median value was 213 (164.8-287.4) and the daily calorie intake value was 2275 (1851-3024) kcal, consisting mainly of carbohydrates (62%). MS prevalence was 22.3%; the most prevalent components were abdominal obesity (81.7%) and low values of high density lipoprotein (HDL) (63.7%). Lastly, an association was observed between a high consumption of GL and the risk of developing MS (aRP 4.5; 95% CI: 1.3-15.3). Conclusions. There is an association between a high consumption of GL and the presence of MS among obese children and adolescents.

Abstract The purpose of this study was to elucidate the background of valproate-related weight gain and hyperinsulinaemia both in men and women by studying markers of insulin resistance and metabolic syndrome. In addition, the role of leptin, a messenger between adipose tissue and the central nervous system was studied. Valproate has a broad spectrum of antiepileptic activity and is widely used for the treatment of epilepsy. It has been the drug of choice for generalised epilepsy, such as juvenile myoclonic epilepsy, and it is also effective for treatment of partial seizures. In addition, valproate is used to treat other diseases, such as bipolar psychiatric disorders and migraine. The results show that valproate-treated patients have higher serum insulin levels in relation to body mass index than control subjects. This indicates that the high serum insulin levels are not a consequence of increased body mass, especially, as the body mass index did not differ between the VPA treated patients and the control groups. Valproate therapy started at a young age may more often result in elevated serum insulin levels and associated other untoward metabolic changes. Furthermore, according to the present data, high serum insulin levels are a consequence of compromised metabolism of insulin in the liver, rather than reflecting reduced insulin sensitivity. However, the valproate-treated patients cluster risk factors for cardiovascular diseases, although the occurrence of metabolic syndrome is not more common in valproate-treated patients than in control subjects. Leptin does not play an independent role in valproate-related weight gain.

Abstract Metabolic syndrome (MetS) is a combination of disorders that increase one's risk for type 2 diabetes (DM2) and cardiovascular disease (CVD). Both lifestyle and genetic factors have been established to be involved in the aetiology of MetS. Improving our knowledge about the pathophysiology of MetS could provide more effective therapeutic approaches and reduce the risk of developing DM2 and CVD. Lower levels of adiponectin, an adipose-derived protein, has been shown to be associated with the components of MetS. Common variants in a number of candidate genes related to MetS have been shown to be associated with changes in the serum adiponectin level. This study was designed to evaluate the putative effects of military lifestyle, as well as common polymorphisms of the peroxisome proliferator activated receptor gamma 2 (PPARγ2), insulin receptor substrate-1 (IRS-1) and adiponectin (APM1) genes on serum adiponectin level in a cohort of Finnish servicemen. Results of this study have showed that serum adiponectin significantly decreased during the six-month follow up in military service compared to baseline levels. This decrease was even shown in subjects that experienced a 5-10 % weight loss after six-months. Subjects with the Ala12Ala genotype of PPARγ2 had significantly higher levels of serum adiponectin compared with subjects with the Pro12Ala and Pro12Pro genotypes. Subjects having the X12Ala genotype of PPARγ2 with > 10% weight reduction showed a significant increase in serum adiponectin compared to other groups during the follow up. Those having the Ala12Ala genotype of PPARγ2 + Gly972Gly genotype of IRS-1 combination had significantly higher adiponectin compared with subjects with the Pro12Pro + Gly972Gly and Pro12Ala + Gly972Gly genotype combinations. Adiponectin levels were significantly higher in men with the T276T genotype compared with subjects with the G276T or G276G genotypes of SNP+276 of the APM1 gene. In conclusion, this study shows a possible impact of a military lifestyle as well as, candidate gene variations, and their interactions upon the regulation of serum adiponectin levels as a marker of MetS. This study could serve as a pilot for the further extensive studies with longer follow up periods as well as more accurate information on specific lifestyle factors.

Background: Alcohol, marijuana and tobacco are the most common recreationally used substances in United States (US). However, unlike alcohol and tobacco, marijuana is an illicit substance. The increasing support for reclassification of marijuana as legal substance necessitates investigating its effect on health. These studies seek to examine the relationship of marijuana and tobacco with metabolic syndrome (a precursor of cardiovascular diseases - the primary cause of morbidities and mortalities). Method: Data from 2011 public-use linked mortality file of the National Center for Health Statistics, Centers for Disease Control and Prevention, and 2005-2006 & 2011-2012 US National Health and Nutrition Examination Survey was used to estimate the effect of marijuana and tobacco on metabolic syndrome. Odds ratios from logistic regression analyses were determined using four main diagnostic criteria for metabolic syndrome. Odds ratios were compared using: National Cholesterol Education Program Adult Treatment Panel III, World Health Organization, European Group for the study of Insulin Resistance and International Diabetes Federation definitions of metabolic syndrome. Hazard ratios (HRs) for cardiovascular mortality were estimated using cox proportional hazard regression. Results: Each year of marijuana use was associated with increased odds of metabolic syndrome [OR=1.05 (95% CI: 1.01, 1.09)] and hypertension [OR=1.04 (95% CI: 1.01, 1.07)]. Each additional year of cigarette smoking was associated with increased odds of hypertension [OR=1.03 (95% CI: 1.00, 1.06)] and hyperglycemia [OR=1.03 (95% CI: 1.01, 1.05)]. Adjusted HR for hypertension mortality for marijuana users compared to non-marijuana users was 3.42 (95% CI: 1.20, 9.79) and 1.04 (95% CI: 1.00, 1.07) for each year of marijuana use. Conclusion: Prolonged years of marijuana use was associated with increased odds of metabolic syndrome and hypertension irrespective of the criteria used to define metabolic syndrome. Our results also indicate that marijuana use is associated with increased risk for hypertension mortality. The association between prolonged use of marijuana and risk of cardiovascular morbidities and mortalities requires further investigation whilst developing global public health policies regarding legalization of marijuana use.

The global number of obese people has reached pandemic proportions. High caloric diets and reduced physical exercise are to blame for this growing epidemic. Obesity has a very complex association with several other metabolic disorders, such as insulin resistance (IR), diabetes mellitus type 2 (DMT2) and cardiovascular disease. This puts a huge burden on health care systems world wide and claims many lives. Sutherlandia frutescens is a traditionally used herb, which is known to have anti-diabetic properties. However, the direct mode of action of S. frutescens still remains to be elucidated. The aim of this study was to investigate the developmental stages of high fat diet (HFD)-induced IR, to illuminate the pathogenesis of IR with a focal point on modifications in the lipid metabolism. Furthermore, the effects of S. frutescens as a treatment or prevention drug for IR and associated metabolic changes were examined. Two sets of experiments were conducted on male Wistar rats. In the first experiment rats, one week post weaning received a low fat diet (LFD), high fat diet (HFD) or HFD supplemented with S. frutescens (50mg/kg BW/d). Rats were sacrificed at week 0, 1, 2, 4, 8 and 12 in the feeding regime. In a second experiment rats were fed with a LFD or a HFD for 12 weeks and treated thereafter with S. frutescens (50mg/kg BW/d), metformin (13mg/kg BW/d) or water (control) for 28 days. Rats in the second experiment were sacrificed at week 12 to confirm IR while concurrently run rats were sacrificed after 28 days of treatment. For all the experiments rats were anaesthetized, blood was removed and rats were dissected. Plasma samples were analyzed for insulin, glucose, blood lipid parameters and cytokines. Liver, muscle and adipose tissue were analyzed for glucose uptake, total lipid content, lipid profile and fatty acid profile. It was shown that the intake of HFD caused IR and hyperinsulinaemia. The developmental stages in experiment one confirmed that an increase in plasma free fatty acids preceeded the onset of IR. Plasma and tissue lipid parameters (free fatty acid-, triglyceride- and cholesterol concentrations) showed pathological modifications in the HFD group. An ectopic accumulation of fat was observed in muscle and liver, as well as a change in membrane fatty acid profile. The results for circulating cytokines were somewhat inconclusive. Rats supplemented with S. frutescens did not develop HFD-induced IR (study one) or IR was reversed (study two). S. frutescens treatment also resulted in positive changes in plasma and tissue lipid parameters. In summary, an animal model for HFD-induced IR was established and the detrimental effect of elevated plasma FFA on glucose and lipid metabolism was observed. A novel discovery suggests that the anti-diabetic mode of action of S. frutescens is through modulation of lipid metabolism. It was also established that S. frutescens has the potential to prevent IR in vivo.

Purpose: The overall objective of this prospective study was to quantify the prevalence of insulin resistance (IR), metabolic syndrome (MetS) and type 2 diabetes (T2D) in women at high risk for breast cancer, stratified by menopausal status. We also aimed to calculate the sample size required for a future case-control study comparing these prevalences to those of the general population. Methods: Participants consisted of 100 Caucasian women above the age of 35 with an estimated 5yr risk of breast cancer ≥1.7%. A comprehensive metabolic profile was obtained for each participant based on a questionnaire, fasting blood sample and biophysical measurements. Results: In comparison to published prevalence’s of IR, MetS and T2D in the general population, the prevalence of IR and MetS is higher in our study sample. High risk postmenopausal women have a higher prevalence of body mass index, waist circumference, MetS and hypertension than premenopausal women. We have shown a significant correlation between Gail score and high-density lipoprotein cholesterol. Conclusions: The sample size calculation, based on the prevalence’s obtained in the present study, support the significance and feasibility of a future case control study comparing the prevalence of IR and MetS in women at high risk and average risk for breast cancer. Further studies are needed to clarify the underlying mechanisms for the association between IR, MetS, T2D and breast cancer risk.

Metabolic syndrome is a constellation of risk factors, including abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high fasting glucose, that commonly cluster together and can result in cardiovascular disease. The prevalence of metabolic syndrome and the components that comprise the syndrome vary by age and by racial/ethnic group. In addition, previous research has indicated that the risk factors contributing to metabolic syndrome may be exacerbated by exposure to perceived stress. This study utilized data from the 2002, 2004, and 2006 Health and Retirement Study (HRS) and National Health and Nutrition Examination Survey (NHANES) data sets. It was hypothesized that depression and anxiety (conceptualized as stress in this study) increase the risk of presenting with metabolic syndrome while social support decreases the risk of metabolic syndrome. While results of cross-sectional analysis do not indicate a significant relationship between depression and metabolic syndrome (t = -.84, ns), longitudinal analysis does indicate a significant relationship between depression and metabolic syndrome over time (t = -5.20, p <.001). However, anxiety is not significantly related to metabolic syndrome when the relationship is examined through cross-sectional analysis (t = -1.51, ns) and longitudinal analysis (&#967;² = 13.83, ns). Similarly, social support is not significantly related to metabolic syndrome when examined in cross-sectional (&#967;² = .63, ns) and longitudinal (t = 1.53, ns) analysis. Although level of stress is not significantly related to metabolic syndrome as a whole, there is a significant relationship between stress and both triglyceride level (t = -2.94, p = .003) and blood glucose level (t = -3.26, p = .001).

Over the past forty years, there has been an increase in obesity, diabetes, and heart disease, collectively known as metabolic syndrome (MetS), in which fructose has been implicated. In addition to MetS, hereditary fructose intolerance (HFI) has no known treatment aside from the difficult removal of fructose from the diet. Ketohexokinase (KHK) is the first enzyme in the fructose metabolic pathway and catalyzes an ATP-dependent reaction that phosphorylates fructose to fructose 1-phosphate. For effective inhibitor development, it is key to understand the KHK-catalytic mechanism. To that end, the research described in this thesis focuses on two goals: 1) understanding how KHK functions in its role as a metabolic enzyme, using structure-function analysis to inform the development of KHK inhibitors, and 2) investigating how these findings can be used to make KHK a prime therapeutic target for alleviating diseases such as HFI and MetS. The X-ray crystal structure of the mouse-liver isozyme, KHK-C (mKHK-C), was determined at a resolution of 1.79 Å. The mKHK-C structure is in complex with the substrate fructose and the product of catalysis, ADP, forming a ground-state complex. The mKHK-C structure has nearly identical secondary structure to its human homolog and has similar steady-state kinetic parameters validating the use of mouse models for exploring the pre-clinical efficacy of KHK-C inhibitors. Furthermore, six structures of human KHK-C in complex with inhibitors and ligands are presented. These structures support the kinetic analyses showing these inhibitors are all competitive with ATP and reveal the shape and polarity of the ATP-binding pocket to achieve inhibition constants (Ki) as low as 50 nM. Lastly, comparison of all KHK structures demonstrate that the β-sheet domain of KHK is capable of 30.3° rotation of the β-sheet domain towards the active site of the opposing dimer subunit. Kinetic experiments using site-directed mutants of human KHK-C and various viscogens confirmed that a conformational change is linked to KHK’s catalytic function. This research provides a foundation for further development of more specific KHK inhibitors aimed at HFI and MetS therapies. / 2022-10-30T00:00:00Z