In this thesis, a number of observations are described in acromegaly patients with cured or biochemically well-controlled disease during long-term follow-up. These observations focus on the long... Show moreIn this thesis, a number of observations are described in acromegaly patients with cured or biochemically well-controlled disease during long-term follow-up. These observations focus on the long-term consequences of the disease on joints and bone. In addition, we investigated the role of the Growth Hormone (GH)/Insulin-like Growth Factor-1 (IGF-1) axis, including the possible effects of the exon 3 deleted GH receptor (d3-GHR) polymorphism, in patients with primary osteoarthritis (OA) that have serum IGF-1 levels within the normal range. Finally, we studied the long-term consequences of recombinant human GH (rhGH) replacement in GH Deficient (GHD) adults, focusing on the cardiovascular effects and the effects on bone in comparison to healthy controls. Show less
The studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell... Show moreThe studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell tumour (GCT) patients. We report a twofold increased prevalence of Metabolic Syndrome (MetS) in GCT patients who received chemotherapy compared to that in patients with stage 1 disease who did not receive chemotherapy, or to that in healthy controls. Thereafter, we describe disadvantageous metabolic changes and acute alterations in diastolic heart function in GCT patients treated with cisplatin-based chemotherapy. In the same group of patients we show that, during chemotherapy administrations, serum non-protein bound iron concentrations were inversely related to the latent iron-binding capacity and serum iron concentrations. This suggests that chemotherapy-associated iron overload may play a role in short and long-term chemotherapy induced toxicity in GCT patients. The study on bone metabolism shows an increased prevalence of vertebral fractures, independent of BMD and anticancer treatment, in newly diagnosed as well as long term survivors of testicular cancer. The last chapter reports on a significant decline in lumbar and femoral BMD in metastatic GCT patients one year after chemotherapeutic treatment. Show less
Osteoarthritis (OA) is a frequently occurring joint disorder with great impact on the quality of life. In general, OA is described as a heterogeneous disease with degeneration of articular... Show moreOsteoarthritis (OA) is a frequently occurring joint disorder with great impact on the quality of life. In general, OA is described as a heterogeneous disease with degeneration of articular cartilage as main outcome. Despite extensive research on the pathogenesis of OA, there is until now no cure and treatments are primarily aimed at reducing pain. Evidence starts to appear that mild inflammation and obesity-related biochemical changes are involved in OA pathology. It is uncertain what the relative contribution of these processes is and if they characterize a certain type of OA patients. We identified obesity, high cholesterol and systemic inflammation associated with these conditions as major players in OA development, which may activate joint tissues to secrete inflammatory mediators and contribute to the initiation and progression of OA. Our work suggests that a stratification of OA patients with (features of) the metabolic syndrome as underlying mechanism is recommendable, to optimize the efficacy of clinical trials. Approaching OA as a disease induced by whole body metabolism, and integrating knowledge about different potentially active tissues in the OA process, will provide new insights for possible pharmacological interventions. Show less
In this thesis we reported our investigations of the relationship between soil-transmitted helminths (STH) and a number of outcomes, in particular malaria, insulin resistance (a marker for type-2... Show moreIn this thesis we reported our investigations of the relationship between soil-transmitted helminths (STH) and a number of outcomes, in particular malaria, insulin resistance (a marker for type-2 diabetes (T2D)) and atherosclerosis (a marker for cardiovascular diseases (CVD)) on Flores island, Indonesia. In the study on Flores Island, the use of albendazole as a single dose at three monthly intervals decreased helminth infections significantly. However, this intensive deworming could not eliminate helminth infections. Despite no effect on malaria parasitemia and clinical symptoms was found, we noted that in vitro immune responses were improved after albendazole treatment and significant increases in malaria-specific and mitogen-induced tumor necrosis factor and interferon _ cytokine production were observed. We also reported that helminth infections are associated with improved insulin sensitivity and lower risk factors for CVD. A possible approach to confirm our results will be a long-term, well-powered, placebo controlled (adequate) anthelminthic trials to investigate asymptomatic malaria (in area where clinical malaria is highly prevalent); as well as to study whether alleviation of helminthic pressure is inversely correlated with anti-inflammation, lipid levels and insulin sensitivity, and therefore leads to an accelerated development of T2D and CVD. Show less
Today__s Western society and work promotes a sedentary lifestyle. This, coupled with high caloric food availability has increased obesity followed by an increased prevalence of the metabolic... Show moreToday__s Western society and work promotes a sedentary lifestyle. This, coupled with high caloric food availability has increased obesity followed by an increased prevalence of the metabolic syndrome (MetS), type 2 diabetes (T2D) and cardiovascular diseases (CVD). Epidemiological data show a clear association between increased cortisol plasma levels, CVD and obesity, but animal models of the MetS are inconclusive with respect to whether the hypothalamus-pituitary-adrenal (HPA) axis is activated or not. It has remained unknown if, and to what extent HPA axis activity plays a pathogenic role in MetS development, and if the development of MetS changes it. In this thesis, we investigate high fat diet (HFD)-effect on the basal HPA axis activity and the effect of chronically elevated, exogenuously administered, corticosterone on MetS features as well as atherosclerosis development in spesific mouse models. From these studies we concluded that HFD reduces HPA axis activity where supraphysiological corticosterone levels worsen the features of MetS and the metabolic adaptations to a period of corticosterone excess in mice are long-lasting and may not completely recover to restore homeostasis. Futher more corticosteroid excess has both beneficial and harmful effects on cardiovascular risk factors that can be explained by their immunosuppressive and metabolic properties. Show less
The metabolic syndrome is a multi-component condition that includes obesity hypertriglyceridemia and insulin resistance. The prevalence of the metabolic syndrome is rising world-wide and is... Show moreThe metabolic syndrome is a multi-component condition that includes obesity hypertriglyceridemia and insulin resistance. The prevalence of the metabolic syndrome is rising world-wide and is associated with an increased risk for the development of cardiovascular diseases and type 2 diabetes. In the past decades it has been discovered that obese persons have slightly elevated markers of inflammation in their plasma. This low-grade chronic inflammation, also called metabolic inflammation, is hypothesized to function as the link between the various components of the metabolic syndrome. In this thesis, it is evaluated how alterations in triglyceride (TG) and fatty acid (FA) metabolism and inflammatory pathways interact in the development of obesity and insulin resistance, which are both primary risk factors for the development of type 2 diabetes Show less
The aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our... Show moreThe aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our findings indicate that people with more severe symptoms of depression and anxiety are at particular risk of progressive dyslipidemia and (abdominal) obesity. The higher rates of smoking and systemic inflammation among people with depression or anxiety partially accounted for their adverse metabolic profile. Dysregulations of the autonomic nervous system partly explained why users of tricyclic antidepressants displayed an increased risk of dyslipidemia and (abdominal) obesity as well, and also of hypertension. These important findings shed light on useful avenues for future research, and on preventive and therapeutic insights and directions. Show less
This thesis discusses the metabolic and endocrine characteristics of long-lived Dutch families. We found that familial longevity is marked by low thyroid function and preserved insulin senitivity.... Show moreThis thesis discusses the metabolic and endocrine characteristics of long-lived Dutch families. We found that familial longevity is marked by low thyroid function and preserved insulin senitivity. The second part of this thesis adresses the Gompertz law of mortality as an estimate of the rate of senescence Show less
The general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity... Show moreThe general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity compared to standard care. The main findings from these studies are a modest long-term reduction of both total and abdominal adiposity accompanied by improved physical fitness, while unchanged adiposity in the untreated controls led to decreased physical fitness and deteriorating insulin sensitivity. In addition, we found significantly impaired health related quality of life in the obese children compared to their normal weight peers. We showed that our multidisciplinary lifestyle treatment improved health related quality of life of the obese children after 1 year. We observed a significantly increased postprandial ghrelin response after the multidisciplinary treatment, but no effect on inflammatory markers, nor on gut hormones PYY and GLP-1. Finally, we propose an alternative for the definition of the metabolic syndrome in children, since the usefulness of its current dichotomous form is questionable. We show that a multivariate prediction model based on the individual components of the metabolic syndrome expressed as standard deviation scores (SDS) has a good predictive value regarding increased HOMA-IR SDS. Show less
Obesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public... Show moreObesity is characterized by excessive fat storage and is associated with various diseases like cardiovascular disease (CVD) and type 2 diabetes (DM2), thereby being a serious problem of public health. Excessive energy intake is an important cause of obesity since excess energy is primarily stored as fat. The stored fat is mobilized again during fasting in the form of fatty acids (FA). These FA are re-esterified in the liver in triglycerides (TG) that are secreted in VLDL particles to deliver FA to peripheral tissues where they can be used for energy. One of the current views of the cause of diseases related to obesity is the (mis)handling of TG derived FA. Therefore it is important to understand pathways involved in the uptake, distribution, oxidation and storage of TG. In this thesis we have evaluated the effect of different interventions on VLDL-TG metabolism to gain a better understanding of its complex regulation. For these studies we used APOE*3-Leiden (E3L) and E3L.CETP transgenic mice that have a human-like lipoprotein metabolism and respond to lipid-modifying drugs in a ways similar to humans. Show less
In this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that... Show moreIn this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that obesity is the most important trigger of metabolic impairment, the MetS definition in this thesis was chosen to include the obesity measure waist circumference as an essential component. In the study described in chapter 2, the heritability of the metabolic syndrome was addressed and compared to the heritability of its individual components. Since the individual components of MetS were shown to be more heritable than MetS itself, the studies described in chapter 3 and 4 focused on the genetics of the individual MetS component plasma TG. For this purpose, a candidate gene approach was employed using HTG patients and healthy controls. The involvement of a series of candidate genes was confirmed. The study described in chapter 5 followed a similar approach to that used in the studies described in chapter 3 and 4. Several candidate genes were studied in patients suffering from hyperlipoproteinemia (HLP) type III, which is characterized by elevated levels of total plasma cholesterol and plasma TG. HLP type III is characterized by APOE2 homozygosity. Contributing genetic factors in the (metabolically stressed) APOE2/2 environment were confirmed. Plasma adiponectin, an adipose tissue secreted hormone (adipokine), has been suggested to be a biomarker for MetS. In chapter 6 we describe a study which particularly aimed to determine the effect of menopause on the discriminating accuracy of adiponectin to predict MetS. Especially low levels of plasma adiponectin in postmenopausal women were found to be a risk for MetS. However, the discriminating accuracy of adiponectin for the presence of MetS was exceeded by BMI in men and pre __and post menopausal women. Since plasma adiponectin levels are very well correlated with MetS components or related traits, the study described in chapter 7 addressed the question whether these correlations are caused by a genetic overlap (genetic correlation). The genetic correlation was mono-laterally validated with regard to the adiponectin gene (ADIPOQ). Chapter 8 describes a study towards finding novel loci associated with adiponectin or loci that are possibly involved in the genetic overlap between adiponectin and MetS components or related traits. This study followed a genome-wide association (GWA) approach. The results of this GWA were used in a joined analysis with two other cohorts in a meta-analysis. In addition, a selected proportion of SNPs was submitted for replication in several cohorts. Chapter 9 provides a general discussion by reviewing all previous chapters in the thesis. Furthermore, chapter 9 includes suggestions and proposals for future analyses towards unraveling genetic and environmental factors involved in the expression and manifestation of metabolic risk factors. Show less
The content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other... Show moreThe content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other part. The thesis starts with a systematic review of the literature about the growth of infants born preterm. Next, three specific methodological issues related to early origins of adult disease studies are addressed. A: the most favorable regression model for analyzing and interpreting the effect of both prenatal and subsequent postnatal growth on adult health outcomes. B: the efficiency of reliability studies in the context of a multi-centre study. And C: the correct and clear assessment of reliability in case of log transformed outcomes. These methods are used ind the second part, in which three topics about the effects of prenatal and early postnatal growth on adult health outcomes are addressed, namely: A the association between birth weight and adult renal function in non-premature subjects. B: The association between birth weight and the adult metabolic syndrome, and its separate components in the same population. And finally, C: the association between early growth and adult body composition in subjects born very preterm. Show less
This thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East... Show moreThis thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East India. Due to the former colonial bounds with the Netherlands, a relatively young South Asian migrant population settled in the Netherlands. South Asians have a high prevalence of central obesity and an eight-fold higher prevalence for type 2 diabetes mellitus. We found the following conclusions: 1.Surinamese South Asian persons have a nearly 40-fold higher risk for end-stage diabetic nephropathy in comparison to Dutch European persons. 2.There was no familial predisposition for diabetic nephropathy among South Asian families. 3.South Asian type 2 diabetic patients have a three-fold higher risk for diabetic nephropathy and faster progression of renal insufficiency in comparison to Dutch European patients. 4.Central obesity is an early and independent risk factor for increased albuminuria in normoglycemic South Asian subjects. We assume that the nearly 40-fold higher risk of end-stage diabetic nephropathy in South Asian migrants is primarily caused by central obesity which leads to: a. Early renal injury in the pre-diabetic state. b. Eight-times higher prevalence of type 2 diabetes mellitus. b. More diabetic nephropathy and faster decline in renal function. Show less
