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

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) are at increased risk of the metabolic syndrome (MetS) and its complications. In the absence of published studies from sub-Saharan Africa, we investigated the prevalence and associations of the MetS amongst recent-onset SLE patients. METHODS: A cross-sectional study of recent onset (<5 years disease duration) patients with SLE meeting the SLICC SLE classification criteria. The MetS was defined by Joint Interim Statement criteria. Clinical and demographic data and a Functional Assessment of Chronic Illness Therapy score and the 36-Item Short-Form Healthy Survey were completed. RESULTS: Of 75 patients, the mean age was 37.1 (11.7) years, disease duration was 30.8 (23.6) months, 65 (86.7%) were female, 68.0% were of mixed ethnic ancestry and 29.3% were Black Africans. The mean SLEDAI score was 0.9 (1.6). The prevalence of MetS was 40.0%, and age and body mass index were the only significant features associated with MetS (p = 0.003 and 0.001 respectively). Increased waist circumference (WC) was the most frequently observed feature, present in 92.9% of MetS patients. Patients with an elevated WC were 32.5 times more likely to have MetS. CONCLUSION: This study shows a high prevalence of MetS amongst South Africans with recently diagnosed SLE. This calls for aggressive strategies to reduce the prevalence of Mets and atherosclerotic cardiovascular disease. Waist circumference is a useful and costeffective screening tool to identify SLE patients at risk of MetS.

This dissertation thesis is dedicated to the heart rate variability and methods of its evaluation. It mainly focuses on nonlinear methods and especially on the Poincaré plot. First it deals with the principle and nature of the heart rate variability, then the ways of its representation, linear and also nonlinear methods of its analysis and physiological and pathophysiological influence on heart rate variability changes. In particular, there is emphasis on the metabolic syndrome. In the next section of the thesis there are compared and evaluated different ways of representation of the heart rate variability and further are tested selected methods of heart rate variability analysis on unique data from patients with the metabolic syndrome and healthy subjects provided by the Institute of Scientific Instruments, Academy of Sciences of Czech Republic. In particular, they are used the Poincaré plot and its parameters SD1 and SD2, commonly used time domain and frequency domain parameters, parameters evaluating signal entropy and the Lyapunov exponent. SD1 and SD2 combining the advantages of time and frequency domain methods of heart rate variability analysis distinguish successfully between patients with the metabolic syndrome and healthy subjects.

Introducción. A nivel mundial el 27,5% de la población adulta tienen sobrepeso u obesidad. Convertirse en una persona obesa, aumenta el riesgo de presentar Síndrome Metabólico (SM); sin embargo, también existen personas obesas que no presentan SM y se les conoces como Obesos Metabólicamente Normales (OMN). En el presente estudio, consideramos definir a los pacientes OMN como pacientes obesos (IMC≥30 kg/m2) sin SM. A su vez, el SM se define como la presencia de tres o más de los siguientes parámetros por fuera de los límites normales: perímetro abdominal, niveles de triglicéridos, niveles de HDL-c, presión arterial y niveles de glucosa. Objetivos. El presente estudio tiene como finalidad conocer la prevalencia e identificar algunos factores asociados a ser OMN. Métodos. Se realizó un estudio observacional analítico de corte transversal recolectando datos de forma retrospectiva de las historias clínicas, en la Clínica Internacional – Sede Lima (CI) y en el Hospital Nacional Dos de Mayo (HNDM), con una muestra de 675 participantes. Resultados. La prevalencia total de OMN en ambos establecimientos de salud (EESS), fue de 35.11%. La población estudiada en ambos EESS, fue en su mayoría mujeres (65.19%), con una mediana de edad de 51 años. Respecto a la dieta, se encontró que el 81.66% de los pacientes que acuden al HNDM y 89.61% de los que acuden a la CI, no poseen una dieta balanceada (p=0.004). Además, el 53.88% de los obesos con SM y el 38.82% de los OMN presentan valores elevados de colesterol (>200mg/dL) (p<0.001). En el análisis ajustado, encontramos que, por cada año de vida del paciente, la probabilidad de ser OMN disminuye en un 2% (PR=0.98; 95%IC: 0.97-0.99). Conclusiones. En nuestra población, se encontró una prevalencia de OMN de 35.11%, siendo esta mayor a lo reportado anteriormente en el país. Esta diferencia en la prevalencia de OMN puede ser debida a que diversos autores definen a OMN de distintas maneras, las cuales están explicadas en el presente estudio. Además, encontramos que el factor más importante que influye para ser OMN es la edad. / Introduction. Globally, the 27,5% of adult population is overweight or obese. Becoming an obese person increases the risk of developing Metabolic Syndrome (MS); however, there are obese people who do not have MS and are known as Metabolically Normal Obese (MNO). In this study, we consider to define MNO patients as obese patients (IMC≥30 kg/m2) without MS. On the other hand, MS is defined as the presence of three or more of the following parameters outside of their normal limits: abdominal circumference, triglyceride levels, HDL-c levels, blood pressure and glucose levels. Objectives. The aim of this study is to know the prevalence and to identify some factors associated to being MNO. Methods. A cross sectional, analytical observational study was conducted, collecting data retrospectively from medical records at the “Clinica Internacional” –Lima (CI) and at the “Hospital Nacional Dos de Mayo” (HNDM), with a sample of 675 participants. Results. The prevalence of MNO in both health facilities (HFs) was 35,11%. The participants in both HFs were mostly women (65,19%), with an average of 51 years. Regarding the diet, it was found that 81,66% of the patients who go to the HNDM, and 89,61% of those who go to the CI, do not have a balanced diet (p=0.004). Furthermore, 53,88% of obese people with MS and 38,82% of MNOs have high cholesterol values (>200mg/dL) (p<0.001). In the adjusted analysis, we found that for extra year of the patient’s life, the probability of being MNO decreases by 2% (PR=0.98; p<0.000; 95%CI: 0.97-0.99). Conclusion. In our population, we found a MNO prevalence of 35,11%, which is higher than previously reported in the country. This difference in the prevalence of MNO may be due to different authors defining MNO in different ways. Moreover, we found out that the most important factor influencing the presence of MNO is age. / Tesis

Magister Curationis / Undiagnosed and untreated medical illnesses are more predominant in patients with mental illnesses, compared to the general population. Concerns have risen about the observed lack of regular screening for Metabolic Syndrome potentially increasing the prevalence rate of the disease especially in young adolescents on anti-psychotics. Recognizing the recurrent co-morbidity between mental and physical health conditions, specific commendations addressing the physical conditions causing the increased morbidity and mortality of people with severe mental illness are needed. In some instances, treatment recommendations for the general population may need to be modified for people with SMI.

The leading cause of death among women is coronary heart disease (CHD), a multifactorial disease with polygenic heritability estimated at 50%. Polymorphisms in the family with sequence similarity 5, member C' (FAM5C) gene have been associated with myocardial infarction (MI), and one single-nucleotide polymorphism (SNP) has partially accounted for linkage in an acute coronary syndrome subset. The linkage peak on FAM5C corresponds directly with a quantitative trait locus for the inflammatory biomarker monocyte chemoattractant protein 1, as well as a linkage peak to metabolic syndrome (MetS). Metabolic syndrome increases the risk of developing CHD, and MI has been positively associated with elevated inflammatory biomarkers. This study was designed as a descriptive pilot gene association study. The purpose was to investigate the variability of the FAM5C SNP (rs10920501) in a cohort of women with documented CHD. It also examined the association between the variability of the FAM5C SNP (rs10920501), MetS, inflammatory markers, and the association with early onset CHD in the presence or absence of MI. A subset of 91 women was derived from an earlier study of women randomized to either a gender-tailored or traditional cardiac rehabilitation program. The results indicated the T allele of FAM5C SNP rs10920501 has a strong protective effect in women with a history of MI. Women with a history of MI and the heterozygous (AT) genotype had a mean age of onset of CHD at 62 years, compared to the homozygous wild type (AA) with a mean age of onset at 55 years, (F (3, 34) = 5.00, p < .01). No women in this study with the homozygous variant (TT) had an MI, further demonstrating the protective effective of the T allele. The genotype of FAM5C SNP rs10920501 explains approximately seven percent of the variability of age of onset of CHD in women who have had an MI, while holding body mass index (BMI) and smoking history constant. There was no significant relationship between FAM5C SNP (rs109320501) and MetS or any inflammatory biomarkers in this sample. In conclusion, FAM5C remains a gene of interest in a complex disease process.

Adipose tissue secretes many important biologically active proteins called adipokines. A subset of adipokines, called C1q tumor necrosis factor (TNF) related proteins (CTRPs), play a key role in metabolism, inflammation, and cell signaling. C1q TNF Related Protein 3 (CTRP3) increases hepatic fatty acid oxidation, decreases inflammation, and aids in cardiovascular recovery following a myocardial infarction. However, the mechanisms behind CTRP3’s protective effects on organ systems are unknown. This exploratory study aims to analyze the circulating oligomeric state of CTRP3 and the circadian regulation of CTRP3 to help understand the role of CTRP3 in preventing disease. METHODS: For analysis of the oligomeric state of CTRP3 non-fasting mouse serum was collected from high fat fed hyper-glycemic mice or low fat fed normoglycemic mice and was separated by size exclusion filtration. For analysis of the circadian regulation of CTRP3 serum samples were collected from mice at 4 different time points (2 dark cycle and 2 light cycle) throughout the day and circulating CTRP3 levels were analyzed by immunoblot analysis. RESULTS: In both high fat and low fat fed mice CTRP3 was found to circulate in both >300 kDa oligomers and >100kDa oligomers, with no detectable amount of CTRP3 less 100 kDa. Interestingly, although there was no difference in the total amount of CTRP3 between the high fat and low fat fed mice there was a higher abundance of CTRP3 >300 kDa in the high fat fed and a greater abundance of CTRP3 found 100-300 kDa. Additionally, we found that serum CTRP3 levels vary greatly throughout a 24-hour time-period within each mouse, but no consensus circadian pattern was observed. CONCLUSION: In vitro mammalian produced recombinant CTRP3 protein was found to exist as trimer, hexamer, and high molecule weight. This is the first study to indicate that CTRP3 circulates in different oligomeric states in vivo, and this is also the first study to observe a difference in the oligomeric state of CTRP3 related to metabolic state. Combined these findings indicate that oligomeric state of CTRP3 may be more metabolically relevant than total amount of circulating CTRP3. In addition, our finding of a high variability of CTRP3 within the same mouse at different times throughout the day indicates that is not regulated by circadian rhythms but is susceptible to variability due to some unknown regulatory factor. These findings have identified novel unknown aspects of CTRP3, which require further research to understand the role of CTRP3 in human health and disease.

Background Both depression and metabolic syndrome (MetS) confer an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease. Accumulating evidence suggests healthy behaviors are crucial to maintain, improve and manage chronical disease and mental health; and unhealthy diet and sedentary behavior were found two major risk factors of MetS. The objective of this study was to investigate whether health behaviors (alcohol consumption, smoking, diet and recreational physical activity) are associated with depression and metabolic syndrome simultaneously. Methods This study included 1300 participants aged 20 years and over who had answered mental health-depression screener questions (PHQ-9) and finished examinations and laboratory tests related to five risk factors of MetS during the U.S. National Health and Nutrition Examination Survey (NHANES) 2007–2014. A set of series of weighted logistic regression models were used to investigate the aforementioned relationship. Results The prevalence of depression among U.S. adults is 15.08%. The two most often reported depression symptoms were “Trouble sleeping or sleeping too much” and “Feeling tired or having little energy”, with rates of14.68% and 13.09%, respectively. Participants who engaged in only light physical activity were more likely to have been identified as experiencing depression and MetS than those who engaged in vigorous physical activity with odd ratios 3.18 (95% CI: 1.59, 6.37) and 3.50 (95%CI: 2.17, 5.63), respectively. Individuals in the study having poor diets were more likely to suffer from depression than those eating good diets (OR=2.17, 95%CI: 1.47, 3.22). Conclusion Physical activity is strongly and inversely associated with depression and MetS. Diet is significantly associated with depression rather than MetS in this study.