Thesis ((Ph.D. (Physiology))--North-West University, Potchefstroom Campus, 2010.

Širdies ir kraujagyslių ligos (ŠKL) yra pagrindinė mirčių priežastis Europoje, o taip pat ir Lietuvoje. Daugelyje išsivysčiusių Europos šalių mirtingumo nuo ŠKL tarp 1970 ir 1990 m. sumažėjo daugiau nei dvigubai, tačiau Lietuvoje jis išlieka didelis. Siekiant sumažinti mirtingumo nuo ŠKL riziką, būtina nuolatinė rizikos veiksnių stebėsena ir visuomenės informavimas apie rizikos veiksnių paplitimą bei kontrolės būdus. Naujausiais duomenimis, net 80 % mirčių nuo ŠKL galima išvengti koreguojant rizikos veiksnius. Šio darbo tikslas - nustatyti ŠKL rizikos veiksnių paplitimą Lietuvos darbingo amžiaus žmonių grupėje bei įvertinti taikomų prevencinių priemonių efektyvumą. Tyrime panaudoti atsitiktinai atrinktų 23 204 pacientų, kurie 2009–2011 m. ištirti pirminiuose sveikatos priežiūros centruose pagal asmenų, priskirtų ŠKL didelės rizikos grupei, atrankos ir prevencijos priemonių (LitHiR) programą, duomenys. LitHiR programoje dalyvauja 50–65 metų moterys ir 40–55 metų vyrai, nesergantys ŠKL. Lietuvoje tarp vidutinio amžiaus asmenų širdies ir kraujagyslių rizikos veiksniai yra labai paplitę ir dažnai viršija ne tik Vakarų, bet ir Rytų bei Vidurio Europos vidurkius. Daugiau nei pusei pacientų nustatyta arterinė hipertenzija, 9 iš 10 – dislipidemija, trečdaliui – metabolinis sindromas. / Cardiovascular disease (CVD) is still a major cause of premature death across Europe and in our country. Since seventies of the past century CVD mortality in the European Union (EU) countries declined more than twice, while in Lithuania, it even did not reach the level of the EU countries at the seventies of the twentieth century. In order to decrease morbidity from cardiovascular diseases, continuous risk factors, monitoring and informing the society about their prevalence and control methods are required. According to the latest data as much as 80% of deaths from cardiovascular diseases can be avoided when controlling risk factors. The goal of this research is to determine the cardiovascular risk profile in Lithuanian subjects of employable age without overt cardiovascular diseases and evaluate the effectiveness of preventive measures. This research describes the analysis of the cardiovascular risk profile in the group of 23,204 subjects enrolled into the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program on the primary level from 2009 to 2011. LitHiR program recruited men – at the age of 40–54 years and women – 50–64 years without overt cardiovascular disease. In the middle-aged subjects, participating in LitHiR programme, the prevalence of dyslipidemia, arterial hypertension, diabetes and metabolic syndrome was found to be high. We can roughly state that every second has established arterial hypertension, almost nine out of ten have established... [to full text]

Širdies ir kraujagyslių ligos (ŠKL) yra pagrindinė mirčių priežastis Europoje, o taip pat ir Lietuvoje. Daugelyje išsivysčiusių Europos šalių mirtingumo nuo ŠKL tarp 1970 ir 1990 m. sumažėjo daugiau nei dvigubai, tačiau Lietuvoje jis išlieka didelis. Siekiant sumažinti mirtingumo nuo ŠKL riziką, būtina nuolatinė rizikos veiksnių stebėsena ir visuomenės informavimas apie rizikos veiksnių paplitimą bei kontrolės būdus. Naujausiais duomenimis, net 80 % mirčių nuo ŠKL galima išvengti koreguojant rizikos veiksnius. Šio darbo tikslas - nustatyti ŠKL rizikos veiksnių paplitimą Lietuvos darbingo amžiaus žmonių grupėje bei įvertinti taikomų prevencinių priemonių efektyvumą. Tyrime panaudoti atsitiktinai atrinktų 23 204 pacientų, kurie 2009–2011 m. ištirti pirminiuose sveikatos priežiūros centruose pagal asmenų, priskirtų ŠKL didelės rizikos grupei, atrankos ir prevencijos priemonių (LitHiR) programą, duomenys. LitHiR programoje dalyvauja 50–65 metų moterys ir 40–55 metų vyrai, nesergantys ŠKL. Lietuvoje tarp vidutinio amžiaus asmenų širdies ir kraujagyslių rizikos veiksniai yra labai paplitę ir dažnai viršija ne tik Vakarų, bet ir Rytų bei Vidurio Europos vidurkius. Daugiau nei pusei pacientų nustatyta arterinė hipertenzija, 9 iš 10 – dislipidemija, trečdaliui – metabolinis sindromas. / Cardiovascular disease (CVD) is still a major cause of premature death across Europe and in our country. Since seventies of the past century CVD mortality in the European Union (EU) countries declined more than twice, while in Lithuania, it even did not reach the level of the EU countries at the seventies of the twentieth century. In order to decrease morbidity from cardiovascular diseases, continuous risk factors, monitoring and informing the society about their prevalence and control methods are required. According to the latest data as much as 80% of deaths from cardiovascular diseases can be avoided when controlling risk factors. The goal of this research is to determine the cardiovascular risk profile in Lithuanian subjects of employable age without overt cardiovascular diseases and evaluate the effectiveness of preventive measures. This research describes the analysis of the cardiovascular risk profile in the group of 23,204 subjects enrolled into the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program on the primary level from 2009 to 2011. LitHiR program recruited men – at the age of 40–54 years and women – 50–64 years without overt cardiovascular disease. In the middle-aged subjects, participating in LitHiR programme, the prevalence of dyslipidemia, arterial hypertension, diabetes and metabolic syndrome was found to be high. We can roughly state that every second has established arterial hypertension, almost nine out of ten have established... [to full text]

An der Spitze der Morbiditäts - und Mortalitätsstatistik steht weltweit das Metabolische Syndrom, bestehend aus androider Adipositas, pathologischer Glukosetoleranz, Dyslipidämie und arterieller Hypertonie, verbunden mit einer erhöhten Inzidenz atherosklerotischer Gefäßerkrankungen. Der Replikationsinitiator 1 (Repin1) wurde kürzlich als mögliches Kandidatengen für Adipositas sowie damit verbundene metabolische Funktionsstörungen in kongenen sowie subkongenen Rattenstämmen identifiziert. Ziel der Arbeit war es, den Einfluss von Repin1 auf den Fettzellstoffwechsel zu untersuchen. Hierfür wurde die Expression von Repin1 in 3T3– L1 Präadipozyten und differenzierten 3T3-L1 Adipozyten mittels siRNA Technologie stark vermindert, um so auf mögliche Funktionen des Proteins schließen zu können. Nachfolgend wurden Veränderungen des Zellstoffwechsels mittels Glukosetransport, Palmitataufnahme sowie Triglyceridgehalt der Adipozyten untersucht. Repin1 wird in der 3T3-L1 Zelllinie exprimiert und zeigt eine steigende Expression während der Adipogenese. Der Knockdown von Repin1 resultierte in kleineren Fettzellen mit geringerer basaler, jedoch verstärkter insulinstimulierter Glukoseaufnahme. Auch der Fettstoffwechsel zeigte sich alteriert: Neben einer reduzierten Palmitataufnahme war die Expression verschiedener Schlüsselgene der Fetttropfenfusion, des Glukose-sowie des Fetttransportes verändert. Fazit: Repin1 reguliert die Expression von Genen, die eine Rolle bei der Festlegung der Fettzellgröße und des basalen und Insulin-stimulierten Glukosetransports in Adipozyten spielen.

Abstract Metabolic Syndrome (MetSyn) is a medical condition prevalent in Australia. MetSyn is diagnosed with a varying combination of visceral obesity, insulin resistance/ impaired glucose tolerance/ Type 2 diabetes, dyslipidaemia and hypertension. Obesity is a central feature of this syndrome that is characterised by abnormalities in glucose and lipid metabolism. An understanding of the cause of the metabolic derangement that occurs in obesity, and that contributes to MetSyn, would allow effective treatment and prevention strategies to be formulated. This is a priority in the current environment of highly prevalent overweight and obesity in Australian children and adults. Lipotoxicity of insulin-dependent tissues and ectopic fat depots are emerging as fundamental processes in the pathogenesis of MetSyn. Lifestyle intervention, such as increased physical activity, show great promise as agents for disrupting the disease progression and may act via direct or indirect mechanisms on the underlying pathology of MetSyn. This study aimed to determine if diagnostic markers of MetSyn exist in obese, prepubertal, Australian children and to assess the contribution of lifestyle factors on components of MetSyn. Further, this study sought to investigate the relationship between body fat patterning (total body fat, abdominal adipose depots, skeletal intramyocellular lipids, intrahepatocellular lipids) and markers of MetSyn. An experimental intervention was then employed to examine the effect of physical activity on body fat distribution, insulin sensitivity, and haemodynamic and biochemical markers of MetSyn, and additionally to determine if the effect of exercise on parameters of MetSyn was mediated by a change in body fat patterning. Data were collected in a group of 15 obese (mean BMI Z-score 2.51 ± 0.49), prepubertal children (6 male, 9 female) aged 5.1 – 11.4 years (mean age 7.82 yrs ± 1.83). Measures included insulin sensitivity, blood biochemistry (lipid, haemostatic and adipocyte activity markers), blood pressure, two-compartment body composition by hydrometry, and nuclear magnetic resonance scanning for abdominal adipose depots, intrahepatic lipids and skeletal intramyocellular lipids. Each child’s habitual nutrition and physical activity were also ascertained using multiple-pass 24-hr diet recalls and accelerometry respectively. Data collection was conducted pre and post a 12-week physical activity intervention which consisted of cardiorespiratory activity during instructor led sessions (60 mins, twice weekly) and family led sessions (>10 mins, 4 days/wk). There is no universally accepted definition of MetSyn in childhood. The International Diabetes Federation suggests that MetSyn should not be diagnosed in children aged 6 to < 10 years. Children can be identified to be at risk of MetSyn, however, based on waist circumference ≥90th percentile and family history1,2; all subjects in this study were at risk according to these criteria. Four definitions of paediatric MetSyn previously applied to a group of young, overweight Australian children3 were used to calculate the prevalence of MetSyn in the current sample and it was found to be 27-89% at baseline and 13-80% after the experimental intervention depending upon the definition used. Acanthosis nigricans and impaired glucose tolerance (IGT) were present in one female child. Post-intervention, IGT had resolved and the child was glucose tolerant. Habitual dietary intake (energy intake and macronutrients) measured over a 3-day period pre-intervention displayed a significant positive association between fasting glucose and energy intake, as well as a significant negative association between fasting glucose and the protein component of the diet. Following the physical activity programme, energy intake was significantly positively correlated with body fat percentage (% BF). There was no difference found in dietary intake assessed prior to and following cessation of the physical activity intervention, in terms of energy or % energy from macronutrients. Habitual physical activity was not related to MetSyn diagnostic indicators. A higher level of physical fitness, estimated by predicted O2max (ml•kg-1•min-1), was significantly correlated with a lower level of diastolic blood pressure at baseline. A greater fitness level ( O2max) was moderately correlated with a lower BMI Z-score following the 12-week intervention. There was no difference between pre- and post-intervention habitual physical activity. A trend towards less sedentary time and increased light intensity activity was found, but these did not reach significance. Physical fitness level showed a trend for improvement following the intervention (P = 0.060). Anthropometrically determined body composition and body fat distribution did not change following the intervention. Radiologically determined abdominal adipose tissue depots were not significantly different post-intervention. % BF was not different when assessed with bioelectrical impedance analysis. However, % BF did reduce significantly over the 12-week intervention period when quantified by hydrometry (42.3% ± 5.0 vs 36.9% ± 8.6, P = 0.022). Adipokines, the secretory products of adipocytes displaying pleiotropic metabolic action, were investigated for their relation to lipid depots and additionally for change post-intervention. Cardiovascular (CV) disease risk was investigated by proatherogenic and protective blood lipids. When examined at baseline, fasting blood triacylglycerols (TAG) were inversely associated with basal and stimulated insulin sensitivity. Post-intervention, a higher level of HDL-C was found to be associated with greater insulin sensitivity, although this was not apparent at baseline. The relation between TAG and insulin sensitivity discovered pre-intervention was no longer evident. All other biomarkers of CV risk were not associated with body composition, glucose homeostasis, and lifestyle factors pre- and post-intervention. The effect of the physical activity intervention on indicators of haemostasis, physical fitness, blood lipids and lipoproteins, systemic inflammation, and fibrinolytic activity were analysed for change. Both systolic and diastolic blood pressure were significantly reduced following the physical activity programme. There was no significant difference found in any other measured parameter of CV risk. Log[HOMA], a surrogate index of insulin resistance, was significantly decreased post-intervention indicating reduced insulin resistance. QUICKI, a surrogate index of insulin sensitivity, was significantly improved post-intervention. The remaining indicators of insulin resistance, insulin sensitivity and β-cell function based on fasting surrogates did not significantly change over the 12-week experimental period. Dynamic insulin sensitivity and β-cell function were investigated pre- and post-intervention using paired samples t-tests. Glucose and insulin area under the curve of the OGTT were significantly reduced and whole-body insulin sensitivity index (WBISI) was significantly increased hence showing an improvement in stimulated insulin sensitivity. AUCCP/AUCglu significantly declined also indicating an improved response to oral glucose stimulation. IGI and ΔCP30/ΔG30, as markers of β-cell insulin secretion, did not change. Disposition index, the interrelationship of insulin secretion (IGI) and insulin sensitivity (WBISI), was not changed pre- and post-intervention. Hepatic insulin extraction was increased post-intervention (4.3 ± 1.2 vs 4.8 ± 1.1, P = 0.022) possibly due to greater hepatic and/or peripheral insulin sensitivity. General linear modeling (GLM) showed the improvement in whole-body insulin sensitivity discovered following the intervention was independent of % BF, abdominal adipose tissue depots, and ectopic lipid depots. Intrahepatocellular lipids (IHCL) significantly decreased after the 12-week intervention (6.99% ± 9.41 vs 5.83% ± 8.54) whilst there was no significant change in the serum markers of liver inflammation. IHCL was positively and strongly associated with total abdominal adipose tissue, intra-abdominal adipose tissue and subcutaneous abdominal adipose tissue both before and after the intervention. IHCL was positively associated with %BF measured post-intervention; this relationship almost reached significance when measured pre-intervention (P = 0.060). IHCL was not associated with insulin sensitivity either pre- or post-intervention nor with circulating lipids at either timepoint. The change in IHCL was independent of % BF and abdominal adipose tissue tested by GLM. However, there was no significant difference found in IHCL post-intervention after adjustment for insulin sensitivity (WBISI) by GLM. Prior to intervention, 10 of 15 subjects had hepatic steatosis diagnostic of non-alcoholic fatty liver disease. Eight of the 10 subjects with clinically significant hepatic steatosis had reduction of fatty infiltrate following the exercise intervention. In the whole group it was demonstrated that physical activity attenuates lipid infiltration of the liver independent of body fat. To further investigate the pathophysiology of ectopic lipid depots, biomarkers of oxidative stress and anti-oxidant status were examined in relation to IHCL. Pre-intervention, there was no association found between pro-oxidative or anti-oxidative activity and IHCL. Post-intervention, an inverse association of plasma carotenoid:cholesterol ratio with IHCL was found. Skeletal intramyocellular lipids (IMCL) measured in the right soleus were significantly increased post-intervention (2.4 ± 1.1 vs 2.6 ± 1.2, P = 0.035). There was no association between IMCL and % BF when measured pre- or post-intervention. Abdominal adipose depots were associated with IMCL at baseline and following the intervention. IMCL was not related to IHCL at either timepoint. Pre-intervention, there was a trend for a relationship between IMCL and insulin. Post-intervention, IMCL was tightly and inversely correlated with insulin sensitivity (r = -0.85 P = 0.000). Linear regression between IMCL and WBISI run pre-intervention and post-intervention found the slopes were not significantly different whereas the intercepts were highly significantly different (P = 0.001), thus, as IMCL increased there was a corresponding decrease in insulin sensitivity. GLM found the increase in IMCL was independent of % BF and abdominal adipose tissue, but was not independent of WBISI. These data indicate the greater IMCL level found post-intervention was a non-pathologic training adaptation. To further investigate the pathophysiology of ectopic lipid depots, biomarkers of oxidative stress and anti-oxidant status were examined in relation to IMCL. Pre-intervention, there was a positive association between malondialdehyde and IMCL. Post-intervention, an inverse association was found between IMCL and both plasma total carotenoids and total carotenoid:free cholesterol ratio. In summation, this study found improved metabolic health in obese, prepubertal children following a 12-week physical activity intervention without dietary intervention or intentional weight loss. Body fat and fat distribution were not prime mediators for the effect of the intervention on parameters of the Metabolic Syndrome; whereas insulin sensitivity was discovered to be a mediator of the change shown in ectopic fat depots. Causality and directionality of these fascinating relationships cannot be determined from the present study, and further research is encouraged. This thesis offers an insight into the pathogenesis of MetSyn and the use of physical activity to improve MetSyn in the setting of paediatric obesity.

Diss. (sammanfattning) Umeå : Umeå universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 6 uppsatser. På omslag felaktigt: Fat mass, adipokines and clinical complications of chronic kidney disease.

Thesis (M.S.)--Mississippi State University. Department of Biological Sciences. / Title from title screen. Includes bibliographical references.

Bipolar disorders and recurrent depressions are two common psychiatric disorders with a life time prevalence of approximately 1% and 8%, respectively. Despite treatment these patients suffer from affective symptoms up to 50% of the time, resulting in lower well-being. The average life length is also reduced with 10-15 years, mainly attributable to suicide and cardiovascular disease. Increased stress is one of many factors that have been shown to be linked to an increased risk for developing affective disorders and some comorbid somatic conditions such as metabolic disturbances and cardiovascular disease. An increased stress level is known to cause hyperactivity of the hypothalamic-pituitary-adrenal-axis (HPA-axis) with increased cortisol secretion. Hyperactivity of the HPA-axis (or hypercortisolism) is one of the most replicated neurobiological finding in depression. In other stress related disorders it has however been shown that prolonged stress over long periods of time can lead to a state of low HPA-axis activity, hypocortisolism. Since persons with recurrent affective disorders such as bipolar disorder and recurrent depression are exposed to a high degree of recurrent and chronic stress it could be expected that in addition to hypercortisolism, a state of hypocortisolism could also develop in these disorders, potentially exerting an influence upon the psychological and somatic wellbeing among these patients. The major aim of this thesis was to evaluate whether hypocortisolism is related to relevant psychiatric and somatic phenotypes in recurrent affective disorders. In bipolar disorder, individuals with hypocortisolism exhibited a higher degree of depression and low quality of life compared to patients with normal HPA-axis activity. In recurrent depression, individuals with hypocortisolism exhibited shorter leukocyte telomere length than patients with normal or high HPA-axis activity, which is an indication of an accelerated aging process. In a sample of both bipolar and recurrent depression patients, hypocortisolism was associated with an increased proportion of obesity, dyslipidemia and metabolic syndrome compared with patients with normal or high HPA-axis activity. Patients with recurrent depression showed a higher occurrence of hypocortisolism than the control sample representative of the general population. Patients with bipolar disorder showed a similar occurrence of hypocortisolism as the control sample. Among bipolar disorder patients with a low degree of lifetime with lithium prophylaxis, there was an inverse correlation between age and HPA-axis activity. In contrast, among patients with a higher degree of lifetime with lithium prophylaxis as well as among the controls, there was no correlation between age and HPA-axis activity. Accordingly, hypocortisolism was most common among older patients with a low degree of lifetime with lithium prophylaxis. In conclusion, hypocortisolism in both recurrent depression and bipolar disorder was associated with multiple clinically-relevant phenotypes. Additionally it was shown for bipolar disorder patients that increasing age was a risk factor for hypocortisolism and that prophylactic lithium treatment was a protective factor. It is argued that the protective effect of lithium towards the HPA-axis is attributable to its mood-stabilizing effect, which in turn reduces the chronic stress level. These results provide new insight into the role of hypocortisolism and chronic stress in recurrent affective disorders warranting further studies and hopefully providing clues to improved treatment strategies.