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
Diabetes is taking on epidemic proportions, not only in western society. Via the blood, glucose is transported to the organs in the human body. When a meal is consumed, blood glucose levels rise.... Show moreDiabetes is taking on epidemic proportions, not only in western society. Via the blood, glucose is transported to the organs in the human body. When a meal is consumed, blood glucose levels rise. Insulin is secreted from the pancreas in response to the increased blood glucose levels and lowers blood glucose by increasing glucose uptake in insulin-sensitive tissues. Under conditions of insulin resistance, insulin does not have its full effect resulting in increased blood glucose levels, which left untreated will result in diabetes. Also at the signal transduction level insulin resistance is evident. An important signaling intermediate is protein kinase B (PKB/Akt). Its activity is decreased under conditions of insulin resistance. However PKB/Akt phosphorylates many targets and not all phosphorylation targets have been linked to a specific function. Therefore the aim of the research conducted in the thesis was to examine the role of PKB/Akt phosphorylation target PRAS40 in insulin action. PRAS40 is expressed in insulin sensitive tissues and is phosphorylated in response to insulin. PRAS40 interacts with another component of the insulin signaling cascade: mammalian target of rapamycin. Under conditions of insulin resistance, PRAS40 phosphorylation is decreased and higher expression of PRAS40 has a protective role in insulin resistance. Show less
The aim of the thesis was to provide more insight into the influence of myocardial steatosis on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus.... Show moreThe aim of the thesis was to provide more insight into the influence of myocardial steatosis on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus. Therefore we developed a reproducible proton magnetic resonance (MR) spectroscopic technique with respiratory motion compensation to study myocardial steatosis. Using these technique, combined with MR imaging to study myocardial function, correlations between myocardial steatosis and left ventricular function were shown in several (patho)physiological conditions. Furthermore, we showed that myocardial triglyceride content is increased in patients with type 2 diabetes mellitus and is an independent predictor of left ventricular diastolic dysfunction. In addition, differential, tissue-specific partitioning of triglycerides and/or fatty acids among non-adipose organs during various diets was shown. Given the obesity and type 2 diabetes mellitus pandemic and the increasing evidence indicating that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, therapeutic strategies that target reduction of cardiac lipid overexposure might be beneficial to prevent diabetic cardiomyopathy. Show less
Using newly developed single cell A3243G mutation load assays a novel mechanism of mtDNA segregation was identified in which the multi-copy mtDNA nucleoid takes a central position. Furthermore,... Show moreUsing newly developed single cell A3243G mutation load assays a novel mechanism of mtDNA segregation was identified in which the multi-copy mtDNA nucleoid takes a central position. Furthermore, likely due to low level changes in gene expression, no genes or gene sets could be identified with gene wide expression analysis that would hint to the molecular pathways that are altered upon loss of mitochondrial ATP production as a consequence of A3243G mtDNA mutation. Extensive post-transcriptional adaptation in the form of global translation repression, was however apparent. A comparison between two mtDNA haplotypes indicated, that these presumably neutral sequence variants can affect the nuclear expression program, which tentatively indicates that mtDNA haplotype can affect phenotype. Show less
Nowadays, obesity has reached epidemic proportions globally. It can lead to several chronic diseases, including insulin resistance/type 2 diabetes mellitus. Feeding behaviour is regulated in the... Show moreNowadays, obesity has reached epidemic proportions globally. It can lead to several chronic diseases, including insulin resistance/type 2 diabetes mellitus. Feeding behaviour is regulated in the hypothalamus of the brain by two opposing pathways: NPY/AgRP neurons vs. POMC/CART neurons. In addition, there are numerous peripheral signals, deriving from stomach, gut, pancreas and adipose tissue, that act on the hypothalamus and thereby contribute to the regulation of food intake. The aim of the studies we have performed, was to investigate the effects of some of these neuropeptides and peripheral signals that affect these neuropeptides, on insulin action. Our experiments showed, that NPY can cause insulin resistance, specifically in the liver. The POMC pathway can improve insulin-mediated glucose disposal and does not affect hepatic insulin sensitivity. Therefore, both pathways are not completely opposing each other’s effects, but seem to have a different tissue-specific effect. Experiments with gut hormones like PYY and ghrelin showed that these hormones affect insulin sensitivity as well. Also leptin, and specifically leptin signalling in the brain, was found to be important for insulin sensitivity. In conclusion, this work showed that neuropeptides/hormones that are involved in the regulation of food intake also affect insulin sensitivity. Show less
The scope of the current thesis is to obtain insight in immunological aspects of transplantation and diabetes. This thesis underscores the current concept of collaboration between the innate and... Show moreThe scope of the current thesis is to obtain insight in immunological aspects of transplantation and diabetes. This thesis underscores the current concept of collaboration between the innate and adaptive immune system by showing close interactions between both immune systems. Mannose binding lectin as a major recognition molecule of the lectin pathway and as a key protein of the immune system was studied in relation to its functional characteristics. Appreciating the Jekyll-and-Hyde character of MBL and the fact that MBL serum levels and functionality are under strict genetic control, MBL was studied under distinct pathological conditions. Chapter 2 describes molecular and biological aspects of mannose binding lectin and the interaction of MBL with the adaptive immune system. Chapter 3 focuses on the involvement of MBL in autoimmunity, by studying juvenile type 1 diabetic patients at disease onset. Chapter 4 addresses the role of the liver in production of serum MBL and evaluates the effect of MBL variant alleles on the susceptibility to infection after liver transplantation. Chapter 5 focuses on the effect of the adaptive immune system on islet transplantation, a novel treatment of type 1 diabetes. Show less
Pancreatic islet transplantation by a new method is introduced here : the isolation of islets in an organ preservation solution, the University of Wisconsin solution. A new concept allowing for the... Show morePancreatic islet transplantation by a new method is introduced here : the isolation of islets in an organ preservation solution, the University of Wisconsin solution. A new concept allowing for the first time large-scale isolation and transplantation of consistently near 100% pure islets of Langerhans in a preclinical dog model with fasting normoglycemia up to 3 years posttransplant. Detailed metabolic studies demonstrated normal insulin levels after meals with preservation of gut hormone action stimulating insulin secretion at the mild hyperglycemia after meals. The introduction of the University of Wisconsin solution organ preservation solution for islet isolation at the start of these studies in 1989 is a new concept … and has been shown by now in 2022 , world-wide , to make the future of islet isolation and transplantation methods for insulin-dependent diabetes mellitus (IDDM). Show less
