Tesis sobre el tema "Metabolic syndrome"

Background: The metabolic syndrome is associated with an increased risk of diabetes and vascular disease. In order to understand the pathophysiological processes underlying such risk, it is necessary to develop a better understanding of normal fat metabolism and abnormalities associated with the syndrome. The hypothesis tested in this thesis is that specific abnormalities in adipose tissue and muscle fat metabolism characterise the metabolic syndrome. Methods: Fasting biochemical parameters were measured in a cohort of overweight men with and without the metabolic syndrome. Stable-isotope labeling and arterio-venous difference measurements were conducted in 18 men to elucidate pathways of exogenous and endogenous fat metabolism under fasting and postprandial conditions in adipose tissue and skeletal muscle. In addition, a pilot study of the effects of heat and electrical stimulation on adipose tissue metabolism was undertaken. Results: Cohort study - The prevalence of the metabolic syndrome depended on the definition used. Total cholesterol and apoB were greater in those with the metabolic syndrome than in those without. There was no difference in fasting NEFAs. Metabolic investigation - There was significant postprandial uptake of NEFA from the circulating NEFA pool by adipose tissue. Chylomicrons were confirmed as the preferred substrate of LPL. There was preferential uptake of FAs derived from chylomicron hydrolysis. There was release of NEFA across muscle. In the metabolic syndrome, adipose tissue NEFA output is lower during fasting and falls less following a meal than in the healthy obese. Clearance of dietary-derived TG is lower across both adipose tissue and muscle in the metabolic syndrome. Pilot study – Heat increased measures of lipolysis whereas electrical stimulation had no effect. Conclusions: Fat metabolism in individuals with the metabolic syndrome is characterised by metabolic inflexibility but not insulin resistance.

[Truncated abstract] Arachidonic acid is oxidised in vivo by non-enzymatic (free radical) or enzymatic pathways (cyclooxygenase, lipoxygenase, and cytochrome P450) to form a range of biologically active eicosanoids. Specifically, arachidonic acid is metabolised by cytochrome P450 -hydroxylase to produce vasoactive 20-hydroxyeicosatetraenoic acid (20-HETE), and by 5-lipoxygenase to produce proinflammatory leukotriene B4 (LTB4), which can further be metabolised by -hydroxylase to from 20-OH-LTB4 and 20-COOH-LTB4. F2-Isoprostanes (F2-IsoPs) are produced through free radical attack on arachidonic acid and have been recognised as the most reliable markers of lipid peroxidation in vivo. The metabolic syndrome (MetS) is characterised by abdominal obesity, hypertension, insulin resistance, glucose intolerance, and dyslipidemia. It is associated with low-grade inflammation and oxidative stress and an increased risk of developing cardiovascular diseases. Dietary weight loss is strongly recommended for the management of the MetS and can potentially minimise the risk of cardiovascular diseases and diabetes in individuals with the MetS. Little is known regarding the role of these arachidonic acid metabolites in the MetS and the effect of weight loss on their metabolism. Chapter three comprised of three in vitro studies aimed to examine 20-HETE synthesis in human blood cells. 20-HETE acts as a second messenger for vasoconstrictor actions of angiotensin II (Ang II) and endothelin-1 (ET-1) in renal and mesenteric beds. Human neutrophils and platelets are integral to the inflammatory process. ... Production of LTB4 and 20-OH-LTB4 was significantly lower compared with controls (P<0.005) and remained so after adjustment for neutrophil count (P<0.05).The weight loss intervention resulted in a 4.6kg reduction in body weight and a 6.6cm decrease in waist circumference and a significant increase in LTB4 and 20-OH- LTB4 in the weight loss group. Chapter Five continued to investigate the role of other arachidonic acid metabolites, 20-HETE and F2-IsoPs in the MetS and the effect of weight loss. In the case-control study (Human study 1), plasma and urinary 20-HETE and F2-IsoPs were significantly elevated in the MetS group, but no significant difference was found in stimulated-neutrophil 20-HETE. A significant gender x group interaction was observed in that women with the MetS had higher urinary 20-HETE and F2-IsoPs compared to controls (P<0.0001). In a randomised controlled trial (Human study 2), relative to the weight- maintenance group, a 4.6 kg loss in weight resulted in a 2 mmHg fall in blood pressure but did not alter the production of 20-HETE or F2-IsoPs. No significant differences were shown in 20-HETE released from stimulated-neutrophils before and after weight loss. 20-HETE and oxidative stress may be important mediators of cardiovascular disease risk in the MetS. Although a 4% reduction in body weight reduced BP, there were no changes in plasma or urinary 20-HETE or F2-IsoPs. In summary, in vitro studies show that human neutrophils and platelets can produce 20-HETE in response to Ang II and ET-1, and human studies demonstrate that the presence of MetS has a significant impact on arachidonic acid metabolism and effective weight loss can restore leukocyte synthesis of LTB4.

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 (χ² = 13.83, ns). Similarly, social support is not significantly related to metabolic syndrome when examined in cross-sectional (χ² = .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).

Recent studies support the association between metabolic syndrome (MetS), a cluster of cardiovascular risk factors, and diastolic dysfunction. Disproportionate collagen accumulation, particularly cross-linking of collagen, plays a key role in translating interstitial fibrosis into mechanical chamber stiffness and diastolic dysfunction. Characteristic changes in the expression and activity of myocardial lysyl oxidase (LOX), a matrix modifying enzyme that catalyzes cross-linked collagen, are unclear in MetS. We established a diet-induced MetS model to study diastolic dysfunction by treating male C57BL/6 mice a high-fat high-simple carbohydrate (HFHSC) diet for 6 months. Despite blunted gene expression of LOX isoforms, MetS mice demonstrated significant increase in the ratio of protein expression of mature to proenzyme LOX, enhanced LOX activity, and increased cardiac cross-linked collagen compared with controls. This fibrotic response coincided with marked increase in left ventricular end-diastolic pressure and stiffness and impaired diastolic filling pattern. Our data demonstrate that diet-induced MetS alters the remodeling enzyme LOX, thereby increasing the amount of crosslinking and inducing diastolic dysfunction.Furthermore we examined the role of T-lymphocytes in myocardial LOX regulation in diet-induced fibrotic hearts. Female SCID mice which are devoid of functional T-lymphocytes and C57BL/6 mice were treated with HFHSC diet for 12 months. Similar to male C67BL/6, female HFHSC-fed C57BL/6 mice demonstrated significant increase in maturation and catalytic activity of myocardial LOX, cross-linking, ventricular stiffness and diastolic dysfunction. Whereas induction of LOX protein was minimal in SCID mice compared with wild-type counterparts. Correspondingly fibrillar cross-linked collagen formation and diastolic dysfunction were less prominent in SCID mice. Our results suggest a potential role of T-lymphocytes in induction of myocardial stiffness and diastolic dysfunction through modulation of LOX-dependent collagen maturation.Moreover we studied the role of leptin, an adipokine over-produced in MetS with fibrotic effects in non-cardiac tissues, as a key mediator of profibrogenic responses in the heart by administrating leptin to C57BL/6 and leptin-deficient ob/ob mice. With exogenous leptin administration ob/ob mice displayed passive diastolic filling dysfunction that coincided with increase in myocardial collagen compared with ob/ob controls. Our findings suggest profibrotic effects of leptin in the heart, primarily through predominance of collagen synthesis over degradation.

The rate of obesity throughout Europe has more than doubled over the past 20 years. It was hypothesised that certain patterns of adiposity and associated co-morbidity metabolic parameters were related to certain psychological traits and neurochemical markers. The study aim was to measure associations between adiposity, metabolic markers, psychological traits and the neurochemicals whole blood serotonin and salivary cortisol, in a single study. Participants were healthy (n=102), males (n=35) and females (n=67), aged 20-65 years (mean 39.7 years). The literature review found that some patterns of adiposity were associated with metabolic risk factors more strongly than were others. Gynoid fat may be a healthier state of adiposity in terms of cardiovascular health. Negative emotional traits, such as anxiety were associated with greater risk for metabolic syndrome/obesity, whilst positive measures such as optimism were linked with lower risk. Experimental findings showed optimism being linked with lower adiposity and life satisfaction associated with greater high density lipoprotein (HDL) cholesterol. Associations between whole blood (WB) serotonin and anthropometric measures found lower WB serotonin being associated with greater adiposity, and that this may be sex-linked. The theory that adiposity may be linked to salivary cortisol and certain psychological factors showed positive associations between gynoid fat, BMI and resilience. Higher salivary cortisol was also correlated with greater perceived stress, and with lower trait mood. These data imply a link between cortisol, adiposity and psychological factors. There are few studies in the literature linking these cross-disciplinary fields. Results suggest that serotonin could be an antecedent and/or a consequence of obesity. Data also suggest that psychometric and salivary cortisol factors, particularly resilience, may interplay together to contribute towards adiposity. This study also implies that the positive traits of optimism, resilience and life satisfaction are related to better metabolic health and more “healthy” patterns of fat deposition.

The metabolic syndrome, a clinical condition linked to diabetes and cardiovascular disease is a powerful predictor for overall mortality, and is present in more than 20% of the US. population (Ford, Giles, & Dietz, 2002). This study examines gender differences as well as other factors associated with metabolic syndrome as defined by the Adult Treatment Panel III of the National Cholesterol Education Program. A sample of 10,134 adults between 20-64 years of age was selected from the Third National Health and Nutrition Survey. Metabolic syndrome was present in 19.6 % of this sample. An ecological model of health services was used to analyze metabolic syndrome. The four model domains include population characteristics, environmental factors, health behaviors, and utilization of health care services. The descriptive results showed statistically significant differences in individuals with metabolic syndrome and without metabolic syndrome. Those with metabolic syndrome were proportionately more older, reported a past medical history of cardiovascular disease and family history of diabetes, had lower levels of education and a lower annual household income. There were no differences between men and women in age, geographic residence, education or health insurance coverage. However, there were higher proportions of women with metabolic syndrome in all race categories when compared to men with metabolic syndrome with the exception of Caucasians. A family history of diabetes, a family history of cardiovascular disease, a past personal history of cardiovascular disease, level of income, habitual activity and having a usual source of health care were found to be statistically significant between men and women with metabolic syndrome. Results of the logistic regression analysis revealed that overall, women were 30% less likely to have metabolic syndrome, yet African American women and Hispanic American women were nearly twice as likely to have metabolic syndrome than Caucasian women. Further research on gender differences for shared medical conditions is needed.

Metabolic functions are one of the principal determinants of energy expenditure and are exquisitely susceptible to the effects of circulating hormones and chemical changes. Consequently, clinical experiments based on energy expenditure and metabolic functions were considered to be valid approaches to the present research. Significant abnormalities were found in the proton magnetic resonance spectroscopy of basal ganglia in CFS patients. Automatic cardiovascular responses to exercise are also impaired in a subset of CFS patients. Finally, plasma membrane injury appears to be a possible explanation for a range of observations made in this research. Subjective fatigue is a complex symptom. It is the outcome of a variable combination of physiological and neuropsychological changes induced by the primary disease process. Downstream links between brain, neuromuscular and the cardiorespiratory functions are implicated in the neural control of force output during exercises in health and disease. Higher perceived fatigue in CFS is probably caused by the central mechanisms while the sensory input to these neural regulatory mechanisms may limit endurance to maximal and submaximal exercises. Based on these findings and more indirect evidence from other studies, changes in cell membrane properties affecting neuronal signalling in the basal ganglia seem to emerge as one of the likely pathophysiological mechanisms in CFS. There is also evidence of an imbalance of the central autonomic tone in a subset of CFS patients. Surely, research in CFS has the potential to unravel the biology of central fatigue and may bridge the gap that exists between the borderland of neurology and psychiatry.

Le syndrome métabolique est caractérisé par un regroupement de facteurs de risque présents chez un même individu et augmentant ainsi ses chances de développer le diabète de type 2 et les maladies cardiovasculaires. Il est donc important de comprendre l’étiologie génétique de ce trait. Dans cette thèse, une multitude d’approches génétiques ont été utilisées afin d’apporter un brin de connaissance sur l’architecture génétique du syndrome métabolique et de ses composantes individuelles. Trois gènes candidats ont été testés incluant le récepteur activé par les proliférateurs de péroxisomes (PPAR) α et PPARγ ainsi que la protéine de transfert des phospholipides (PLTP). Les gènes PPARα et PLTP ont tous deux été associés significativement avec plusieurs variables d’adiposité. Des effets significatifs d’interaction entre les gènes PPARα et PPARγ ont été obtenus pour les paramètres de glucose et d’insuline. Il a aussi été démontré que le polymorphisme PPARα L162V influence les changements de cholestérol-HDL2 suite à un traitement au gemfibrozil. Par la suite, des criblages génomiques ont été effectués sur les concentrations de lipides et de lipoprotéines plasmatiques. Plusieurs régions chromosomiques ont été identifiées incluant 1q43, 11q13 q24, 15q26.1, et 19q13.32 pour le cholestérol-LDL, 12q14.1 pour le cholestérol-HDL, 2p14, 11p13, et 11q24.1 pour les triglycérides, 18q21.32 pour l’apolipoprotéine (apo) B-LDL, et 3p25.2 pour l’apoAI. La contribution génétique à la variation du diamètre principal des particules LDL (DP-LDL) a aussi été étudiée. Les résultats démontrent une forte ressemblance familiale avec des coefficients d’héritabilité de plus de 50%, la présence d’un gène à effet majeur, et une forte évidence de liaison sur le chromosome 17q. Le gène de l’apoH, localisé à cet endroit, a par la suite été significativement associé au DP-LDL, suggérant que ce gène est responsable du signal de liaison observé sur le chromosome 17. Finalement, une variable quantitative du syndrome métabolique a été construite à l’aide d’une analyse factorielle. Un criblage génomique effectué sur cette variable a démontré une évidence de liaison sur le chromosome 15q, suggérant la présence d’un gène à cet endroit contribuant au regroupement des facteurs de risques caractérisant le syndrome métabolique. Plusieurs de ces résultats devront être répliqués, alors que d’autres méritent d’être suivis.
The metabolic syndrome is a cluster of interrelated cardiovascular risk factors co-occurring in the same individual. People with this syndrome are at increased risk for developing diabetes mellitus and cardiovascular diseases. Accordingly, it is important to elucidate the genetic aetiology governing this trait in order to better comprehend its pathogenesis. In the present thesis, heritability and complex segregation analyses as well as candidate gene and genome-wide scan approaches have been applied to shed some lights on the genetic architecture of the metabolic syndrome and its individual components. A total of three candidate genes have been investigated including peroxisome proliferator-activated receptor (PPAR) α and PPARγ as well as phospholipid transfer protein (PLTP). It has been shown that polymorphisms in both PPARα and PLTP genes are significantly associated with several indices of adiposity. In addition, significant gene-gene interactions have been observed between PPARα and PPARγ on glucose/insulin parameters. It has also been shown that the HDL2-cholesterol response to gemfibrozil therapy is modulated by the PPARα L162V polymorphism. Genome-wide linkage scans have been performed on lipid and lipoprotein concentrations. Many chromosome regions harbouring lipoprotein/lipid genes have been identified including 1q43, 11q13 q24, 15q26.1, and 19q13.32 for LDL-cholesterol, 12q14.1 for HDL-cholesterol, 2p14, 11p13, and 11q24.1 for triglycerides, 18q21.32 for LDL-apolipoprotein (apo) B, and 3p25.2 for apoAI. The genetic contribution of the variation in LDL peak particle diameter (LDL-PPD) has been also investigated. Overall, the results indicate: 1) that LDL-PPD strongly aggregates within families with heritability estimate above 50%; 2) the existence of a major gene effect affecting the phenotype; and 3) the presence of a major quantitative trait locus located on chromosome 17q. The apo H gene, a positional candidate gene, was then significantly associated with LDL-PPD, suggesting that this gene is responsible for the linkage signal observed on 17q. Finally, factor analyses have been used to construct a quantitative metabolic syndrome variable and a genome-wide linkage scan has been conducted to identify the genomic regions underlying this trait. A major quantitative trait locus has been observed on chromosome 15q suggesting a gene within this region contributing to the clustering of the metabolic syndrome-related phenotypes. Many of these findings must go through independent replication, while others produced new leads that deserve follow-up.
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Rising levels of metabolic syndrome across Europe and India, and scant research on psychosocial determinants prompted these studies. Stress, depression and physical inactivity were hypothesized to predict obesity and metabolic syndrome; constant mood and increased resilience to confer protection. Abundant vegetable/fruit intake; lower saturated fat intake from dairy, meat and olive oil, and low/moderate wine intake were predicted determinants of health. Secondary modelling of representative data from GB and Portugal (Lipgene study) assessed psycho-social, dietary and lifestyle predictors of metabolic syndrome. Cultural adaptation of the Lipgene questionnaire was informed by qualitative research incorporating 24hr dietary recall for use in India (ChurpE). Qualitative themes suggested that urbanisation negatively impacted upon social structure, food choice, physical activity and health. Stress arising from the changing role of women was perceived to have affected familial wellbeing. Healthy eating referenced freshness, convenience, meal skipping, high fat/sugary foods, and nostalgia for tradition and rural lifestyle. Latent class analyses of the Indian and both European samples indicated three classes: 'healthier' lacking metabolic syndrome symptoms; 'metabolic syndrome' with comorbidities; and, 'obese/high blood pressure'. Additionally, an 'overweight' group in Europe was distinguished. In both studies older age, less sedentary behaviour and stress distinguished the 'healthier' from all other classes. Compared with the 'healthier', 'metabolic syndrome' members were more likely Portuguese experienced lower resilience and smoking cessation; and more British, younger and stressed members typified 'overweight' among Europeans. The 'obese' class were predominantly female with high BP. Among Indians, 'happier' mood characterised 'high BP' membership. That comorbidities varied between classes suggests disease progression from overweight/obesity to metabolic syndrome. Among Indians, alcohol, smoking, higher earnings, chatting to relax and dietary habits predicted obesity and comorbidities. Developing public health policy to prevent and treat obesity and metabolic syndrome should intervene to reduce sedentary behaviour, tackle stress, promote resilience and healthy eating.

1n NMR spectroscopy and gas chromatography (GC) based metabolimics approaches were used to characterize the metabolic profiles of a selection of mouse models of atherosclerosis, including the wildtype C57BL/6 mice, the low-density lipoprotein receptor null (LDLR^-/-) mice, and the Apolipoprotein E null (ApoE^-/-) mice. The LDLR^-/- mice demonstrated a profound perturbation in lipid and choline metabolism, notably the choline oxidation pathway, which results in reduced concentrations of choline derivatives in urine. A consistent change in this pathway was also observed in the ApoE^-/- mice. The ApoE^-/- mice exhibited significant changes in energy metabolism, favouring the utilisation of fatty acids for energy production. These findings were also compared with the ApoE^-/- mice that are haplodeficient for the Ataxia telangiectasia mutated (ATM) gene. The ATM^+/-/ApoE^-/- mice demonstrated accelerated atherosclerosis and more severe abnormalities in energy metabolism, as compared with the ATM^+/+/ApoE^-/- mice. Finally, a metabolomic study on an inducible Akt1 transgenic mouse model was conducted. These mice exhibit inducible muscle hypertrophy, as well as a significant reduction in fat mass. The muscle-specific Akt1 activation caused increased glycolysis in gastronemius muscle, as well as increased gluconeogenesis, glycogenolysis and ketogenesis in the liver of the mice. These data demonstrate how hypertrophic muscle affects systemic metabolism, and influences distant organs to feed its active cell growth. The studies demonstrated the impact of a muscle-specific Akt1 activation on systemic metabolism, which leads to a reduction in risks associated with cardiovascular disease.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of childbearing age and is associated with a number of metabolic disturbances. It has been hypothesised these women carry an increased risk of developing cardiovascular diseases (CVD) with advancing age. The first aim of this thesis was to establish the prevalence of PCOS-related symptoms in Northern Sweden. The Northern part of the WHO MONICA project was used for this purpose. Based on self-reported menstrual disturbances and hirsutism together with biochemical analyses of free androgen index, the estimated prevalence of PCOS in Northern Sweden was 4.8%, which corresponded with previous prevalence studies. Disturbances in the fibrinolytic system are predictors of future cardiovascular events and measurements of plasminogen activator inhibitor 1 (PAI-1) activity and tissue plasminogen activator (tPA) mass concentration may be used to assess fibrinolytic activity in women with PCOS. From the findings, over-weight women with PCOS had impaired fibrinolysis, especially if they displayed objective biochemical markers of hyperandrogenism. Conversely, lean women with PCOS, displayed no signs of disturbed fibrinolysis. The adipose tissue is an active endocrine organ that produces and releases hormones, pro- and anti-inflammatory cytokines, and chemoattractant cytokines. Proinflammatory molecules produced by adipose tissue can be active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. The findings suggested being overweight, rather than the PCOS diagnosis per se, was the main explanatory variable for elevated adipose tissue inflammation in PCOS patients. Weight reduction is the primary target for intervention in overweight and obese women with PCOS. When this thesis was planned, no placebo-controlled trials on anti-obesity drugs in women with PCOS had been conducted. Sibutramine in combination with lifestyle intervention resulted in significant weight reduction in overweight women with PCOS. In addition to the weight loss, sibutramine appeared to have a beneficial effect on metabolic and cardiovascular risk factors.

The polycystic ovary syndrome (PCOS) is a heterogeneous disorder in women characterised by chronic ovulatory failure, hyperandrogenaemia, and insulin resistance. Some women are completely asymptomatic and others present with extreme menstrual disturbance, severe hirsutism, infertility and recurrent miscarriage. The pathophysiology of PCOS is not completely understood, but it is thought that insulin resistance plays a central role. In normal subjects, non-diabetic obese patients and patients with non-insulin dependent diabetes, insulin resistance is associated with elevated plasminogen activator inhibitor-1 (PAI-1) levels. PAI-1 is a glycoprotein, which inhibits the formation of plasmin (a proteolytic enzyme). Plasmin aids fibrinolysis and extracellular proteolysis. High PAI-1 and low plasmin levels increase the risk of thrombosis and impair extracellular proteolysis required in ovarian follicle growth, ovulation and embryo implantation. This study was designed to determine whether elevated plasminogen activator inhibitor-1 (PAI-1) was associated with the insulin resistance present in PCOS, investigate its possible role in the causation of anovulation and recurrent pregnancy loss in these women and ascertain whether it was an additional thrombotic risk factor so that clinicians and patients could take appropriate measures to reduce this risk In a pilot study, systemic PAI-1 activity was significantly elevated in oligomenorrhoiec women with PCOS. A larger study supported these findings, but demonstrated that obesity was a significant confounding factor, as the increase in PAI-1activity disappeared when standardised for weight. Activated Protein-C (APC) resistance was subsequently tested in these women because of the unexpected finding of an increased prevalence of a positive family history of thrombosis in women with PCOS compared with controls, but there was no increase in the prevalence of APC-resistance in PCOS. In another project, the cellular distribution of PAI-1 protein in human ovaries was described for the first time using immunohistochemistry. It was localised to the granulosa and theca cell compartments in both polycystic and normal ovaries, however there was no significant difference in the intensity of PAI-l staining between both groups on image analysis. PAI-1 messenger RNA expression was also evaluated in these biopsies by in-situ hybridisation, but no signal was detected suggesting that there was either a low overall RNA preservation in the tissues, or an insufficient sensitivity of the cocktail of oligonucleotide probes used. This study did not support the hypothesis that elevated PAI-1 was a feature of PCOS, however the in-situ location of PAI-1 protein was demonstrated for the first time in the human ovary and consistent with a previously suspected role in ovulation. The results did not support a role for PAI-1 in anovulation, recurrent miscarriage or increased thrombosis in PCOS.

Next to age, obesity is one of the main predictors of the development of osteoarthritis. The link between obesity and osteoarthritis is a multi-unit. Definitely it was considered that excess weight leads to wear and tear seam. In fact, excessive load leads to cartilage degradation and subchondral bone shows that weight plays an important role in the initiation and development of osteoarthritis. However, the weight is correlated with obesity, osteoarthritis no weight-bearing joints.

The metabolic syndrome is a constellation of vascular risk factors including abdominal obesity, hypertension, diabetes, hypertriglyceridaemia and low high density lipoprotein cholesterol. The aim of the study was to explore the link between the metabolic syndrome and its components, and psychosis in Alzheimer’s disease. The participants were selected from the Human Serum Metabolome Project. 246 participants with Alzheimer’s disease were assessed at baseline and 151 were followed up a year later. The neuropsychiatric inventory was used to capture information about psychiatric symptoms including delusions and hallucinations. The vascular risk factors were determined from the history from the participant and carer; abdominal obesity however was measured during the study. Hypertriglyceridaemia and high density lipoprotein cholesterol data were unavailable and so the study focuses on the link between the metabolic syndrome components of obesity, hypertension and diabetes, and psychosis in Alzheimer’s disease. Although not part of the metabolic syndrome criteria, a history of hypercholesterolaemia was used in conjunction with the available metabolic syndrome components and the link between the resulting vascular syndrome and psychosis in Alzheimer’s disease was studied. Two measure of psychosis were used for the research. First of all, a factor representing psychosis was derived by factor analysis of the neuropsychiatric inventory data. Secondly, a direct measure of psychosis using the delusions and hallucinations items from the neuropsychiatric inventory was used. Cross-sectional and longitudinal analyses were conducted. The majority of the analyses conducted failed to find a significant link between the measures. Male sex, a lower Mini Mental State Examination score as well as the use of antipsychotics and memantine were found to be significantly associated with psychosis at baseline. Overall this study does not support the link between the metabolic syndrome or its components and psychosis in Alzheimer’s disease. Future research looking at subsets of Alzheimer’s patients with more clearly defined lipid triglyceride and high density lipoprotein cholesterol data will be useful.

Obesity, especially if associated with metabolic syndrome, promotes oxidative stress, a low grade chronic inflammatory state, and modify the composition and function of plasma lipoproteins. Oxidative damage to lipoproteins not only make LDL atherogenic but can also alter HDL reducing their anti-atherogenic properties. The possibility of monitoring the lipid peroxidation of the individual regions of LDL and HDL could lead to more detailed information on the molecular mechanisms that are the basis of the increased risk of cardiovascular diseases observed in obesity and metabolic syndrome. The object of this study was to investigate the susceptibility to peroxidation of plasma and of the hydrophobic core and the surrounding envelope of LDL and HDL in obese male (BMI between 25 and 35 Kg mq) with (SM, n=20)) or without (OB, n =40) metabolic syndrome. The susceptibility of plasma to peroxidation was higher in SM and OB than in normo-weight controls (CT, n=60), but not significant differences were observed between these two obese groups. Also the susceptibility to peroxidation of isolated LDL and HDL was higher in both obese groups than in CT. LDL and HDL in SM presented an higher content of triacylglicerols than the corresponding HDL of OB. Moreover, the hydrophobic core of HDL showed a risk of peroxidation significantly higher in SM than in OB. This last parameter was inversely correlated with the waist to hip ratio, an index of visceral obesity. This last evidence seems to indicate that the increase of inflammation typical of the visceral adipose tissue could be one of the major causes of the higher susceptibility to peroxidation found in the hydrophobic core of HDL. The evaluation of the susceptibility to peroxidation of the core and the envelope of LDL and HDL might contribute to the identification of a subset of patients at increased risk of metabolic and cardiovascular complications. Future “ad hoc” randomized clinical trials should be designed to address the effects of weight reduction and /or different diet and/or nutritional supplementation on these parameters.

The metabolic syndrome is a cluster of metabolic risk factors such as diabetes type II, dyslipidemia, hypertension, obesity, microalbuminurea and insulin resistance, which in the recent years has increased greatly in many parts of the world. In this thesis decision trees were applied to the BioExpress database, including both clinical data about donors and gene expression data, to investigate nuclear receptors ability to serve as markers for the metabolic syndrome. Decision trees were created and the classification performance for each individual risk factor were then analysed. The rules generated from the risk factor trees were compared in order to search for similarities and dissimilarities. The comparisons of rules were performed in pairs of risk factors, in groups of three and on all risk factors and they resulted in the discovery of a set of genes where the most interesting were the Peroxisome Proliferator Activated Receptor - Alpha, the Peroxisome Proliferator Activated Receptor - Gamma and the Glucocorticoid Receptor. These genes existed in pathways associated with the metabolic syndrome and in the recent scientific literature.

The association between cardiovascular reactivity and the metabolic syndrome, as well as individual metabolic syndrome criterion variables, was investigated in adolescents. Cardiovascular reactivity has been examined as a risk marker or factor in the pathogenesis of hypertension or cardiovascular disease, but few studies have looked at its relationship with the metabolic syndrome. Blood pressure (BP) and heart rate (HR) cardiovascular reactivity to three tasks, evaluated speaking, mirror star tracing, and cold pressor, were assessed in 148 adolescents. Using the American Heart Association (AHA) adult definitional criteria, individuals were classified into metabolic syndrome groups (presence vs. absence of metabolic syndrome), and 16% of individuals met criteria for the metabolic syndrome. In logistic regression analyses, the occurrence of the metabolic syndrome was negatively associated with HR reactivity to the cold pressor (OR = 0.920, 95% CI = 0.873, 0.969), and positively associated with diastolic blood pressure (DBP) reactivity to the star tracing task (OR = 1.089, 95% CI = 1.008, 1.177). Results of multiple regression analyses that included individual metabolic syndrome risk variables indicated that cold pressor reactivity explained 7% of the variance in casual BP, while star tracing reactivity accounted for 7% of the variance waist circumference and 6% of the variance triglycerides (ps < .05). The findings indicate that cardiovascular reactivity to physical or behavioral challenge is associated with the metabolic syndrome in a sample of adolescents. Cardiovascular reactivity may be an important clinical tool for identifying individuals at risk of the metabolic syndrome and cardiovascular disease.

This thesis aims to highlight molecular mechanisms that have been altered by prenatal undernutrition and may be involved in the metabolic syndrome. Two separate studies were conducted both using a rat model developed through manipulation of the maternal diet to provoke the key features of the metabolic syndrome in adult offspring. Microarray technology was used to detect changes in gene expression in target tissues between offspring of control (normally fed, AD) and undernourished (UN) mothers to obtain a broader picture of the cellular functions and genetic pathways that may be implicated in the metabolic syndrome. The rst study compared gene expression differences in liver, skeletal muscle, and white adipose tissue between 55 day old male offspring of AD and UN mothers. No significant changes were found in muscle or adipose tissue; however, the differences in the liver suggested the UN animals had been metabolically programmed to favour fat as an energy source. To investigate whether DNA methylation might be responsible for the observed transcriptional changes, pooled liver samples from the rat study were used with the McrBC restriction enzyme assay to determine full, partial, incomplete, or no methylation between AD and UN. Two differentially expressed genes (Zfand2a and Mapk4) showed methylation changes. The same liver samples were hybridised to a miRNA array. Two miRNAs showed a nearly 2-fold upregulation in the UN livers. Both were found to be either directly or indirectly associated with the metabolic syndrome. MiR-335 has been shown to be upregulated in the livers of obese/diabetic mice. By association with miR-27a, miR-451 might be involved in aspects of lipid metabolism in adipose tissue. A second study used microarray to analyse the liver tissues of day 170 female offspring of the same rat model with additional insults (neonatal leptin treatment and post-weaning high-fat (HF) diet). Leptin has been shown to reverse the programming effects of the restricted maternal diet and this study aimed to highlight mechanisms that could be involved in this reversal. The results revealed the importance of the interaction between treatments. Significant gene expression changes were only present when two or more treatments were combined. This study revealed significantly, differentially expressed genes involved in immune function, regulation of the circadian rhythm, and metabolism. These findings provide a number of interesting genes and pathways for further studies and also highlight the need to conduct a thorough study in multiple tissues at different time-points to pinpoint the window of developmental plasticity.

The overall aim of this master thesis was to get an overview on how milk and dairy consumption affect development of the metabolic syndrome, and from this review to formulate a milk product with potentially beneficial effects. A cluster of metabolic abnormalities such as insulin resistance and type 2 diabetes, hypertension, obesity and dyslipidaemia are known as the metabolic syndrome. Epidemiological studies performed to investigate the relation between milk and dairy intake and the metabolic syndrome, suggests that low-fat milk and dairy intake have a positive effect in the prevention of the disease. Many dairy components might contribute to this effect. There are promising effects seen by whey amino acids on the glucose and insulin control, but the long-term effects are warranted. Low-fat milk and dairy as part of a diet rich in fruits and vegetables have the most blood pressure reducing effect. This beneficial effect is in part believed to be due to the calcium content of milk and dairy products. In addition, it is also hypothesised that calcium plays an important roll in weight management. However, the evidence up to date is contradictorily. Weight control, on the other hand, can be improved by affecting satiety. Acute intervention studies show that whey, in particular, alfa-lactalbumin, is more satiating than other proteins, resulting in a lower energy intake in a subsequent meal. It is of interest to the dairy industry to provide milk and dairy consumers with milk products that have beneficial effects on wellness and health. Therefore, based on the literatured reviewed on milk and dairy intake and the metabolic syndrome, a milk product with beneficial effects on weight was formulated and developed.

Metabolic Syndrome (MetS) may be defined as a clustering of risk factors for diabetes mellitus (T2DM) and cardiovascular disease (CVD) which puts individuals at increased risk of developing these conditions and consequently leads to a reduction in life expectancy and increased morbidity. Although there are a number of definitions of MetS, essentially having any three of the following five risk factors confers a diagnosis of MetS; (i) impaired fasting glucose levels, (ii) raised blood pressure, (iii) raised triglycerides, (iv) low levels of high-density lipoprotein cholesterol (HDLC), and (v) increased waist circumference. A comprehensive decision model has been developed to combine different levels of evidence in a Markov model. This model is based in the behavior of MetS and its possible progression to T2DM and CVD, in order to evaluate the potential impact of a MetS based intervention at population level. Evidence synthesis methods are going to be incorporated in the model to integrate different levels of information. Firstly, a Mixed Treatment Analysis (MTC) of Randomized Controlled Trials (RCTs), which have evaluated a number of lifestyle and pharmacological interventions in individuals with MetS was undertaken. This information also assessed the possibility of reversing a diagnosis of MetS. Secondly, a systematic review of published literature was conducted to assess the evidence related with the association between the MetS and development of T2DM and/or CVD. A Bayesian approach to the problem has also been advocated which enables flexibility to develop a Markov model of this complexity. WinBugs offers a comfortable solution for the evaluation of a Markov model, given its Gibbs sampler. Main findings of this thesis are related with large amount of uncertainty, presuming a difficulty to provide a clear decision related to the application of MetS for prevention of T2DM and CVD.

Cardiovascular disease (CVD) is the number one cause of death worldwide. The clustering of metabolic risk factors, defined as metabolic syndrome (MetS), and aging are two separate factors that significantly increase the risk of CVD. Both aging and MetS influence CVD by impairing heart tissue (myocardial) function. However, the exact understanding of mechanisms and evolution of these impairments are incomplete in MetS and aging populations. One of the most accessible and utilised techniques for assessing myocardial function is conventional transthoracic echocardiography, and more recently speckle tracking echocardiography (STE); a robust and sensitive modality of echocardiography, capable of assessing myocardial function in both the longitudinal and circumferential axes.

Statistics show a high prevalence of metabolic syndrome (MetS) in patients with mental illness receiving second-generation antipsychotic medications. MetS is associated with elevation of obesity, truncal obesity, blood pressure, cholesterol, and fasting glucose. The purpose of this project was to educate psychiatric providers about the importance of MetS screening, early detection, management, and referral for better treatment and management. The project was guided by Lewin's theory of change model. The project inquired if educational intervention on MetS improved providers' knowledge and intent to adopt MetS guidelines. A literature review and established guidelines of the American Psychiatric Association and American Diabetic Association about MetS in psychiatric patients directed the educational content. Five expert panelists with over 10 years of experience in psychiatric mental health reviewed the educational content using a Likert-type questionnaire. Findings resulted in the acceptance of the educational content without further recommendation. Twelve staff attended the educational session presented on MetS. Comparison of the pretest and posttest questionnaires that has 5 multiple choice questions indicated some positive effects. The good knowledge of MetS, how to screen for MetS, health promotion activities with consumers, metabolic profile of different neuroleptic medications, providers' roles in MetS. The participants' overall knowledge about MetS screening improved from 8.3% pretest to 83.3% after receiving the educational program. The educational project for MetS screening might foster positive social change by improving continuity and quality of care, which will lead to better patient outcomes, reduce healthcare cost, and impact positive patient outcomes.

The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on September 16, 2009). Thesis advisor: Dr. John Thyfault, Dr. Tom Thomas. Includes bibliographical references.

Metabolic syndrome (MetS) is a condition that is linked to the increased risk of developing chronic diseases, including type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). The association between MetS and chronic disease development lies in the cardiometabolic risk factors that comprise MetS: abdominal obesity, hypertension, hyperglycaemia and dyslipidaemia [1]. The development of MetS is also associated with the dysregulation of many different body systems, such as the immune system [2] and gut microbiome [3]. Due to its multifactorial nature, research in MetS requires the simultaneous analysis of multiple biomarkers across different body systems. As most research thus far have utilised univariate analysis, no biomarker profile has been identified to characterise individuals more at risk of MetS and related diseases. The current study has therefore implemented the use of correlationbased network analysis (CNA) and multiple classification models to identify the biomarkers that collectively link to increased MetS development. Four variable groups comprising of multiple different measurements were obtained from 117 healthy weight controls and 35 obese with MetS individuals. The four variable groups consisted of: anthropometric measures, haematological measures, gene expression levels and gut microbial counts. The use of CNA allowed a better understanding of the relationships between biomarkers affected by MetS. As expected, the obese with MetS network was denser than the healthy weight control network, demonstrating the complex nature of MetS. The results found molecular interactions supporting the findings of previous literature, particularly correlations that demonstrated the development of anaemia of inflammation in the obese with MetS network. There were also three key hubs identified using gene expression levels, involving transcription factor EB (TFEB), lipocalin 2 (LCN2), and cluster of differentiation- (CD-) 68. The three genes are associated with regulatory T cells and neutrophils, two prominent cells in regulating the inflammatory state. As obesity and MetS are often described as a state of chronic low-grade inflammation, the findings of CNA correspond with that of previous studies. Classification models are another type of analytical tool that have demonstrated high predictive ability in many diseases, including T2DM and CVD. The use of classification models for the prediction of diseases allows the risk of disease development to be evaluated. The current study applied classification models for the prediction of MetS using three of the four variable groups measured: haematological measures, gene expression levels and gut microbial counts. Classification models are not only able to assess the relevance of these variable groups to MetS but also identify the specific variables that contributed the most to MetS development. There are a range of classification models that can be used and due to MetS being a relatively new area of research, the most appropriate model for MetS prediction has yet to be determined. As such, the current study predicted MetS using four different types of classification models and compared the predictive abilities of each model. The four models that were used in the current study were: logistic regression (LR), decision tree (DT), support vector machine (SVM) and artificial neural network (ANN). The performance of each classification model was evaluated using 10-fold cross-validation, which splits the dataset into 10 training and testing sets. Each model is then built using the training sets and evaluated using the testing sets to ensure that the model was not fit too closely to the training data. The model with the highest performance when predicting MetS using haematological measures and gut microbial counts was ANN, while SVM had the highest performance when using gene expression levels. However, ANN was also able to attain a high area under the curve (AUC) value of 0.804 when predicting MetS using gene expression levels. As such, the prediction model that had the highest performance overall was ANN. Each model has their own strengths and limitations dealing with specific types of data and the most appropriate model depends on the research question being asked. Although SVM and ANN are both very powerful algorithms, capable of handling high-dimensional data, both models have difficulty producing clinically significant results. On the other hand, LR and DT models are both able to identify specific biomarkers that should be further investigated for links to diseases development, deeming them more suitable for clinical applications. For each of the 10 LR and DT models, constructed using the 10 training sets, the haematological measurement that was found to be most important was triglycerides (TG). Additionally, the best performing LR model, out of the 10 constructed models, found measurements of TG, platelets (PLT), erythrocyte sedimentation rate (ESR), fasting plasma glucose (FPG), haemoglobin (HG) and glycated haemoglobin A1c (HbA1c) to be associated with MetS development. At the same time, high-density lipoprotein-cholesterol (HDL-C) was linked to a reduced risk of MetS development. Using DT, the important measurements in MetS development were TG, PLT, HDL-C, age, HG, C-reactive protein (CRP) and white cell counts. Each variable identified has been found to be linked to either a cardiometabolic risk factor or inflammation and thus the results of the current study are supportive of previous literature on obesity and MetS. Logistic regression also found the expression of AKT serine/threonine kinase 3 (AKT3), Fc fragment of IgE receptor II (FCER2), cathelicidin antimicrobial peptide (CAMP), interleukin- 11 receptor subunit alpha (IL11RA) and granzyme H (GZMH) to increase the odds of developing MetS while C-X-C motif chemokine receptor 6 (CXCR6), C-C motif chemokine ligand- (CCL-)3, suppressor of cytokine signalling 1 (SOCS1) and killer cell lectin like receptor C2 (KLRC2) expression reduces these odds. Consistent with these findings, DTs also predicted individuals with high AKT3, FCER2 and CAMP expression to be obese with MetS while healthy weight controls had higher CXCR6, CCL3 and KLRC2 expression. The findings of the current study were partially supportive of previous literature, with FCER2 and CAMP expression being associated with obesity and inflammation [4, 5] and KLRC2 expression being inversely associated with obesity and inflammation [6, 7]. On the other hand, AKT3 is associated with glucose and lipid metabolism [8] with evidence of its expression leading to the protection against insulin resistance. As such, the high AKT3 expression found in the obese with MetS cohort was not consistent with current literature. Similarly, the association between the expression of CXCR6 and CCL3 with a healthy weight control classification could not be explained as both genes are typically linked to inflammation [9, 10]. Finally, LR and DT found microbial species belonging to the Firmicutes and Bacteroidetes phyla to both be associated with the increased and reduced risk of developing obesity with MetS. Obesity with MetS is largely characterised by a high Firmicutes-to-Bacteroidetes ratio, particularly when compared to healthy weight controls [11]. While this pattern was not clearly evident in the current study, the cause of discrepancy with previous literature may be due to gut microbial studies in obesity and MetS not being typically reported at the species level. While LR and DT are both able to identify the variables that are likely to contribute to MetS development in a clinical setting, the performances of either model were not able to compete with that of ANN or SVM. At the same time, despite having the highest performance overall, ANN is unable to produce easily interpretable results with clinical significance. As such, its high predictive ability is not enough to convince researchers to choose ANN for clinical use. To overcome this issue, many researchers combine ANN with a feature selection technique, such as genetic algorithm (GA). Feature selection techniques are able to identify the best combination of biomarkers for the prediction of diseases. In the current study, the variables that were recognised to be significant by the hybrid model supported the findings of LR and DT. The haematological biomarkers that were consistently recognised as important by all three prediction models were measures of TG and HG. Additionally, CCL3 and CXCR6 expression, as well as three gut microbial species belonging to the Firmicutes and Bacteroidetes phyla, were also found to be important for MetS development. Other than the identification of important variables, the hybrid model was also able to improve the performance of ANN when predicting MetS using gene expression levels and gut microbial counts. Consequently, the current study concluded that the hybrid GA with ANN model was considered to be the most appropriate for MetS prediction. Another analytical method that was used by the current study was weighted majority voting, which combines the final predicted outcomes of the other classification models to determine whether the performance could be further improved. The weighted majority voting method was able to achieve the highest AUC value for the prediction of MetS using gut microbial counts as well as the second highest AUC when using haematological measures and gene expression levels. However, the dependency of the weighted majority voting method on the performance of individual classification models used was demonstrated in the study. The low sensitivity values attained by DT in the testing set of all three variable groups is likely what prevented the weighted majority voting method from outperforming all the other classification models in the prediction of MetS. In spite of the limitation caused by DT, however, the method was still able to achieve a high performance. As such, the combination of the results from different classification models into a weighted majority voting method to increase the overall predictive ability was found to be a viable choice. The classification model that was found to be most suitable for the prediction of MetS was the hybrid GA with ANN model. Not only was the model able to achieve high predictive ability due to the ANN portion of the model, it was also able to reveal the optimal combination of variables that contributed the most to an accurate MetS prediction. The variables that were identified were also supportive of the findings of both LR and DT. The measurements used by the current study (haematological measures, gene expression levels and gut microbial counts) were all found to be suitable for the prediction of MetS. Future studies may consider the use of other biomarkers, including measurements from adipose tissue, for the prediction of MetS using the hybrid GA with ANN model.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
Full Text

Thesis (Ph. D.) -- University of Maryland, College Park, 2009.
Thesis research directed by: Dept. of Sociology. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

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.

Polycystic ovary syndrome (PCOS) is a complex clinical condition characterized by hyperandrogenism and chronic oligo/anovulation. Infrequent ovulation and metabolic alterations in women with PCOS are associated with subfertility and probably increased miscarriage rates compared with normal fertile women. The overall risk of developing type 2 diabetes and impaired glucose tolerance (IGT) is three- to sevenfold higher in PCOS women, and the onset of glucose intolerance seems to occur at an earlier age than in healthy controls. Women with PCOS also have several risk factors for cardiovascular disease, although it is unclear whether they actually experience more cardiovascular events than other women. Very few studies assessing the long-term reproductive and metabolic consequences in older women with previously confirmed PCOS have been conducted. In this long-term follow-up of women with PCOS, 84 women with a diagnosis of PCOS between 1987 and 1995 and age at the follow-up > 35 years and an age-matched population-based group of control women participated. Data on reproductive outcome, ovarian reserve, endothelial function, insulin sensitivity and beta-cell function were collected. According to our results most women with PCOS had given birth and the rate of spontaneous pregnancies was relatively high. The rate of miscarriages was not increased in PCOS patients and the ultrasound findings together with increased levels of anti-müllerian hormone suggested that their ovarian reserve is superior to women of similar age. PCOS women displayed signs of endothelial dysfunction, but this was largely due to the increased prevalence of independent risk factors for cardiovascular disease such as increased BMI, triglycerides and blood pressures. IGT and type 2 diabetes occurred more often in PCOS women. Free androgen levels and beta-cell function decreased over time whereas insulin sensitivity remained unchanged. Obesity at young age and progressive weight-gain rendered them more prone to be insulin resistant at the follow-up. Beta-cell function was increased in PCOS women in comparison with control subjects but declined over time. Independent of PCOS phenotype at the index assessment and persistence of PCOS symptoms at the follow-up investigation, premenopausal women with PCOS had lower insulin sensitivity and increased beta cell function in comparison with control subjects. Conclusion: The long-term reproductive outcomes of PCOS are similar compared to women with normal ovaries. Although symptoms and androgen levels are normalized over time, women with PCOS continue to display reduced insulin sensitivity and increased beta-cell function and they also have an increased risk of IGT and type 2 diabetes.

Polycystic Ovary Syndrome (PCOS) is the most common reproductive and endocrine disorder in females during their reproductive life. The syndrome is characterized by a constellation of symptoms and signs including menstrual disturbance, hyperandrogenism and polycystic ovaries. Other features of PCOS include obesity, metabolic syndrome, insulin resistance and an increased risk of developing diabetes mellitus and cardiovascular disease. Recently, PCOS has been recognized as a low grade inflammatory condition. Several inflammatory markers have been found to be raised in PCOS, such as interleukin-6, tumour necrosis factor-alpha and Interleukin-18. Low grade inflammation may potentially produce an insulin resistant state and promote the development of atherosclerosis. Insulin sensitzers such as metformin and pioglitazone have been shown to have a favourable effect not only on the symptoms of PCOS, but also on the hormonal and metabolic parameters in those subjects. In my thesis I primarily focussed on IL-18, B cells activating factor (BAFF), and the hepatokine, Fetuin-A, all linked to insulin resistance. IL-18 has a strong affinity towards its natural inhibitor, IL-18 binding protein (BP) and binding of IL-18 to IL-18 BP results in neutralization of IL-18, and consequently reduced free IL-18; the active form of the molecule. I have shown that PCOS women have a higher free IL-18, with hyperinsulinaemia the main factor that determines IL-18 in vitro. Furthermore, I have shown that Pioglitazone treatment for 12 weeks decreased both the total and free IL-18 in PCOS women. The reduction of IL-18 was accompanied by an improvement in IR. On the other hand, metformin treatment for six months failed to improve insulin sensitivity and did not influence IL-18 levels. BAFF, a novel adipokine, was studied in PCOS subjects, and I found lower BAFF levels in this cohort of patients. In vivo, BAFF correlated negatively with androgens, and in vitro work revealed that androstenedione as a negative regulatory factor for BAFF production Fetuin-A also known human protein α2-Heremans-Schmid glycoprotein, is a known natural inhibitor for insulin and abundantly expressed and secreted by the liver; fetuin-A has been suggested to act as a link between obesity, insulin resistance and MS. The circulating levels of Fetuin A are increased in women with PCOS, which is more pronounced when associated with MS. Metformin decreases Fetuin A in vivo, and also decreases both the expression and secretion of Fetuin A from HepG2 cells.