In chapters 2, 3 and 4, novel biomarkers IGFPB7, TIMP-2 and long noncoding RNAs were studied in order to find new diagnostic possibilities for early recognition and diagnosis of injury in native... Show moreIn chapters 2, 3 and 4, novel biomarkers IGFPB7, TIMP-2 and long noncoding RNAs were studied in order to find new diagnostic possibilities for early recognition and diagnosis of injury in native and transplanted kidneys. In chapter 2, diabetic nephropathy was found to be associated with higher levels of circulating TIMP-2, which did not normalize after simultaneous pancreas-kidney transplantation. In chapter 3, we found that four circulating long noncoding RNAs associated with diabetic nephropathy and did normalize after simultaneous pancreas-kidney transplantation. In chapter 4, acute rejection in kidney transplant recipients resulted in higher circulating LNC-EPHA6 levels. In chapter 5, clinical parameters and single antigen bead assay for measurement of donor specific antibodies were evaluated in the context of antibody-mediated rejection. Female recipients who received a kidney transplant from their spouse were especially at risk for acute antibody-mediated rejection and a single antigen bead assay is more sensitive to detect antibodies in this group than the standard diagnostic strategy. In chapter 6, mesenchymal stromal cell therapy is studied in a randomized controlled trial to evaluate the potential for prevention of acute rejection and fibrosis in transplanted kidneys. MSC therapy resulted in similar fibrosis scores and rejection rates. Show less
Dit proeschrift beschrijft het ontstaan van ziekte in de kleine bloedvaatjes bij vrouwen en geeft een moleculaire uitleg van de synthese en het werkingsmechanisme van microRNAs (kleine RNA... Show moreDit proeschrift beschrijft het ontstaan van ziekte in de kleine bloedvaatjes bij vrouwen en geeft een moleculaire uitleg van de synthese en het werkingsmechanisme van microRNAs (kleine RNA moleculen die gen expressie reguleren) daarin. Specifieke aandacht wordt gegeven aan het mechanisme waarmee het vrouwelijk hormoon oestrogeen de functie van bloedvaatjes en het hart reguleert door een effect op deze miRs. Ook wordt de vraag beantwoord of expressie van miRs in plasma van vrouwen bruikbaar is als diagnostische marker voor ziekte van de kleine bloedvaatjes. Dit is onder andere aangetoond in een studie in vrouwen met boezemfibrilleren (een ritmestoornis in het hart). Ook is bestudeerd in transvrouwen (man-naar-vrouw transgenders) hoe oestrogeen toediening (voor de transitie operatie) een risico op het ontwikkelen van suiker ziekte. Specifieke microRNAs werden gevonden die hierin een doorslaggevende rol spelen. Deze microRNAs werden vervolgens in muizen geremd waardoor muizen een vorm van suikerziekte ontwikkelden. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
Diabetes mellitus type 2 (DM) is a major risk factor for developing active tuberculosis (TB) disease, yet the causal mechanisms driving this association remain largely elusive. As the incidence of... Show moreDiabetes mellitus type 2 (DM) is a major risk factor for developing active tuberculosis (TB) disease, yet the causal mechanisms driving this association remain largely elusive. As the incidence of DM is rising, especially in TB endemic countries, it is important to identify the relevant immunological and metabolic processes that underlie TB-DM comorbidity, because such insights will facilitate optimal treatment, diagnosis and prevention. In this thesis, we have started to unravel key factors underlying the association between TBand DM using two approaches. Firstly, we identified and analyzed human macrophage subsets and studied the interactions between these human cells and a major pathogen, Mycobacterium tuberculosis (Mtb), and the specific metabolic changes involved using well-controlled in vitro systems. Next, we employed metabolomics to determine the impact of concurrent TB-DM on circulating metabolites in patient cohorts ex vivo. In this thesis we present evidence derived from in vitro experiments and from ex vivo observational data which collectively suggest a pathogenic role of atherogenic lipid species during TB development. Show less
Obesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a... Show moreObesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a combination of known and unknown risk factors. Since effective long-term treatment strategies are currently lacking, the search for additional risk factors and development of targeted treatment strategies to combat these (cardio)metabolic diseases is warranted. An attractive approach seems to be activation of energy-combusting brown adipose tissue (BAT), which can result in increased energy expenditure and improvement in glucose and lipid metabolism. In this thesis, we aimed to address two key objectives: 1) unravelling the underlying mechanisms that could explain the increased predisposition for metabolic disease in the South Asian population, and 2) identifying novel pharmacological strategies that activate BAT and increase energy expenditure in risk populations, including South Asians and individuals with overweight and prediabetes. The studies described in this thesis have highlighted some novel factors, such as endocannabinoids and angiopoitein-like-protein-4, that might in part explain to unbeneficial metabolic phenotype of South Asians. In addition, novel potential therapeutic strategies were identified to combat metabolic disease, such as treatment with a β3-adrenergic receptor agonist and a dipeptidyl-peptidase-4 inhibitor. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
The glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this... Show moreThe glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this thesis we studied structural and compositional changes of the endothelial glycocalyx upon diabetes in mice and in vitro. In glomerular capillaries, the endothelial glycocalyx contributes to the filtration barrier in the glomeruli. In diabetes the glycocalyx is damaged but can be restored via several pharmacological compounds that subsequently results in a shift from inflammatory towards anti-inflammatory macrophage function (chapter 2-3). In our model this appeared not to a result of changes in nitric oxide availability, affirming the potential overruling role for glomerular macrophages in glycocalyx degradation in diabetic nephropathy (chapter 4). Enzymatic cleavage of heparan sulfates reduced the total amount of luminal glycosaminoglycan content, but increased inflammatory heparan sulfate epitopes in vitro and in zebrafish (chapter 5). In chapter 6 we demonstrate that endothelial-specific loss of hyaluronan, another glycocalyx constituent, results in loss of endothelial barrier function. Overall, this thesis provides evidence that inhibition of glycocalyx degrading enzymes is a potent treatment option in diabetic nephropathy and other vascular diseases. Show less
The worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease,... Show moreThe worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease, respectively. Inflammation is an important factor connecting obesity to these disorders, but the exact mechanisms connecting obesity, the immune system, type 2 diabetes and cardiovascular disease are still under investigation. The research described in this thesis was performed 1) to gain more insight into the role of the immune system in obesity, dyslipidemia, insulin resistance and atherosclerosis, 2) to study whether inflammation contributes to the disadvantageous metabolic phenotype of a human population with a particularly high risk to develop type 2 diabetes and cardiovascular disease, and 3) to study the therapeutic potential of decreasing inflammation by pharmacological strategies to reduce obesity and improve glucose and lipid metabolism in pre-clinical models. The studies described in this thesis have increased our understanding of the role of inflammation in adipose tissue function and lipid metabolism during the development of type 2 diabetes and cardiovascular disease. Moreover, novel potential therapeutic strategies were identified to combat obesity, metabolic inflammation and associated metabolic disorders, such as treatment with interferons, salsalate and GPR120 agonists. Show less
The main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of... Show moreThe main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of increasing urbanization in Indonesia. Our large-scale cluster-randomized controlled trial was performed in a rural area of Indonesia, which is endemic for soil-transmitted helminth (STH), and has been previously reported to have a low prevalence of IR and T2D. In STH-infected subjects, as assessed by microscopy, 12-month anthelmintic treatment increased IR, which was mediated by an increase in BMI and leptin to adiponectin ratio, as well as reduction in eosinophil count. Next, we also aimed to assess the different metabolic profile between populations living in rural and urban area, and to study the relative protective effect of rural environment to high-fat diet (HFD). In comparison to those living in rural area, individuals living in urban area had higher whole body IR, which was mainly mediated by the higher adiposity and leptin level, which were progressively increased with increased duration of time spent in urban area. Different environmental factors (including past or current exposure to STH) did not seem to affect the metabolic response to HFD intervention, independent from adiposity. Show less
The prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than... Show moreThe prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than half a billion adults worldwide are classed as obese. The fundamental cause of obesity is an imbalance between energy intake (excessive intake of energy-dense foods) and energy expenditure (reduced physical activity). People with obesity are at risk for a range of chronic conditions including cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Furthermore, obesity is a major risk factor for the development of type 2 diabetes, which is one of the most common chronic diseases in nearly all countries. According to the World Health Organization, the global prevalence of diabetes in 2014 was estimated to be 9%, of which 90% was comprised of type 2 diabetes. This thesis focuses on cardiovascular and cerebral dimensions and function in people with obesity and type 2 diabetes. State-of-the-art imaging techniques are used to investigate links between the heart, liver, abdominal fat, and brain to elucidate parts of the complex relationships between these organs. Show less
Type 1 Diabetes is caused by destruction of insulin producing beta-cells by autoimmune T-cells. Replacement of beta-cells through transplantation can supply new beta-cells, however these are at... Show moreType 1 Diabetes is caused by destruction of insulin producing beta-cells by autoimmune T-cells. Replacement of beta-cells through transplantation can supply new beta-cells, however these are at renewed peril of destruction through auto- and alloreactive immune responses. In this thesis, immune challenges, intervention strategies and biomarkers to guide treatment are investigated. Patient heterogeneity was identified as contributing factor to variations in efficacy of immune intervention therapies for type 1 diabetes. Immune infiltrations that matched with immune monitoring results were seen around islets transplanted to the liver of a patient. Cytokine and autoantibody immune markers were described that correlated with outcome of islet transplantation and combined kidney and pancreas transplantation. Immune consequences of tapering immune suppression after islet transplantation to minimize side effects were explicated. The immunological challenges that await beta-cells of alternative sources after transplantation, such as beta-cell lines and embryonic stem cells, were explored and pointed to need for immune protection and immune monitoring in early transplantation trials. These results support further investigation of immune intervention with disease specific immune modulation and beta-cell encapsulation strategies to achieve the desired drastic improvement in efficacy-risk balance for type 1 diabetes therapies. Show less
