Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2... Show more The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2 diabetes have a 2- to 3-fold increased risk of cardiovascular disease. We investigated whether insulin resistance and hyperglycemia are associated with atherosclerosis and incident cardiovascular disease before the onset of type 2 diabetes. Obesity can be considered as a common cause of both insulin resistance and atherosclerosis. Therefore, we investigated to what extent associations between insulin resistance, hyperglycemia and atherosclerosis were explained by body fat. We further aimed to study the specific role of visceral fat in the development of insulin resistance and atherosclerosis, and directly assessed abdominal subcutaneous and visceral adipose tissue depots. Show less
In today__s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin... Show moreIn today__s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin resistance. This thesis focuses on the differences in the energy and fatty acid metabolism that play a role in the susceptibility for metabolic complications. We have investigated certain existing associations between genetic clues and a disturbed energy metabolism, in order to construct a more refined mechanism of action for this genetic association. This knowledge could be used to more precisely target the causal proteins and pathways involved in the development of obesity. We have also investigated the role of fatty acid metabolism in the fat tissue of obese humans and mice. In this way, we have found a direct link in both humans and mice between fatty acids and inflammation, which is relevant for metabolic diseases such as obesity and insulin resistance. Show less
Nearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T... Show moreNearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells. In addition to their involvement in anti-helminth immunity, recent studies have shown that components of the type 2 immune responses can have additional functions. For example, recent evidence indicates that multiple facets of the type 2 immune response can regulate tissue-specific metabolic processes and whole-body nutrient homeostasis, and protect against insulin resistance. In this work we use omega-1, a glycosylated RNase excreted from Schistsoma mansoni eggs with strong Th2-inducing capacities, to study the requirements that equip DCs for Th2 skewing. In addition, we analyse the effect of chronic S. mansoni infection and administration of S. mansoni-derived egg antigens on metabolic homeostasis in diet-induced obese mice. Elucidating how helminths generate Th2 responses and contribute to metabolic homeostasis will not only shed light on the mechanisms that promote control of parasite infection, but may provide valuable leads for the development of pharmaceutical agents for the treatment of metabolic disorders. Show less
Overload of nutrients can lead to diet-induced inflammation, also called metabolic inflammation, which is thought to play an important role in many metabolic diseases, including the development of... Show moreOverload of nutrients can lead to diet-induced inflammation, also called metabolic inflammation, which is thought to play an important role in many metabolic diseases, including the development of nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of pathologies that range from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis. The pathogenesis of NAFLD, including the sequence of events in time and the underlying mechanisms that initiate the transition from a fatty liver to NASH and fibrosis, remain poorly understood. Effective and reliable therapeutic approaches that are based on the understanding of the pathogenesis of NASH are therefore still lacking. In order to gain more insight into the mechanisms of NASH pathogenesis, we started with comparison of human NASH and experimental NASH. Subsequently, we provided evidence that activation of AP-1 and associated neutrophil infiltration is important for NAFL progression towards NASH and this can be induced experimentally by __metabolic__ dietary triggers of inflammation.Furthermore, we explored novel nutritional and pharmacological agents as potential strategies to combat NASH. Finally, we investigated the effects of high fat diet-induced metabolic overload on the liver in relation to inflammation in white adipose tissue and kidney, and the dysfunction of these tissues. Show less
Insulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via... Show moreInsulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via increased _-cell function and/or increased _-cell mass. Inadequate _-cell adaptation leads to hyperglycemia and eventually diabetes mellitus. Therefore, it is critical to understand how the _-cell mass is regulated. We investigated _- and _-cell adaptation in response to different metabolic changes. We found that _-cell adaptation in response to insulin resistance in mice, rats, and deceased organ donors was regionally heterogeneous throughout the pancreas. We also observed that the glucagon-producing _-cell mass adapts to metabolic changes, resulting in the maintenance of the _- to _-cell ratio. Furthermore, we show that treatment of normoglycemic mice with a glucagon-like-peptide-1 receptor agonist improved _-cell function and that this is associated with a decrease in _-cell mass in order to maintain normoglycemia. In mice fed a high-fat, low-carbohydrate ketogenic diet beta-cell adaptation failed, resulting in symptoms that are associated with diabetes in humans. Finally, we developed three high-throughput culture platforms for human islets to assess _-cell function that can be used in future studies to identify novel mechanisms involved in _- and _-cell adaptation. Show less
People of South Asian origin have an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people of Western European descent. Not only is the prevalence... Show morePeople of South Asian origin have an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people of Western European descent. Not only is the prevalence of these diseases higher in South Asians, they also occur at a younger age and lower BMI, and have a more severe course. The high prevalence of T2D and CVD in South Asians, who comprise one fifth of the total world__s population, poses a major health and socioeconomic burden worldwide. The underlying cause of this excess risk is, however, still poorly understood. The studies described in this thesis were performed to gain more insight in the pathogenesis of T2D and CVD in South Asians and to provide new leads for preventive strategies and treatment options. For this purpose sophisticated techniques were used such as hyperinsulinemic-euglycemic clamp with stable isotopes, indirect calorimetry, skeletal muscle biopsies, MRI and spectroscopy, and brown fat quantification using PET-CT-imaging, combined with short-term dietary interventions, in healthy lean young adult men and overweight adult men. These studies have led to a number of promising areas for further research. It seems that not one, but multiple metabolic mechanisms have been affected, most likely due to gene-environment interactions. Show less
The studies performed in this thesis show that type 1 diabetes mellitus is characterized not only by insulin deficiency, but also by insulin resistance. Both hepatic and peripheral insulin... Show moreThe studies performed in this thesis show that type 1 diabetes mellitus is characterized not only by insulin deficiency, but also by insulin resistance. Both hepatic and peripheral insulin sensitivity were decreased in patients with type 1 diabetes mellitus, as well as inhibition of lipolysis. However, insulin resistance is not a fixed pathophysiological condition in type 1 diabetes. We demonstrated that a single night of partial sleep deprivation decreased insulin sensitivity by 14-20% in patients with type 1 diabetes and by 20-25% in healthy controls. These effects of partial sleep restriction could not be explained by a reduction of total slow wave sleep in patients with type 1 diabetes. Sleep duration is a determinant of insulin sensitivity, also in patients with diabetes. In addition, various aspects of diabetes could be linked to increased prevalence of sleep disturbances. Impaired sleep and type 1 diabetes might potentiate each other in some patients, thereby creating a negative vicious circle. Optimizing sleep duration and sleep quality could therefore be considered as a potential therapeutic target to improve metabolic control in patients with type 1 diabetes. Show less
This thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients.... Show moreThis thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients. Because of the increasing number of patients with obesity and T2DM, more research is needed to identify patients at risk of developing T2DM and to elucidate specific therapeutic targets to improve insulin resistance. For now, the prevention of overweight and obesity is the most essential step in the fight against the worldwide obesity and T2DM epidemic Show less
Sarcopenia in old age has been associated with a higher mortality, poor physical functioning, poor outcome of surgery and higher drug toxicity. There is no general consensus on the definition of... Show moreSarcopenia in old age has been associated with a higher mortality, poor physical functioning, poor outcome of surgery and higher drug toxicity. There is no general consensus on the definition of sarcopenia. The aim of the research presented in this thesis was to assess the implications of the use of different diagnostic criteria for sarcopenia, and to define the most accurate criteria for sarcopenia. Currently used diagnostic criteria for sarcopenia can be divided into criteria based on (1) low muscle mass, (2) low muscle strength, and (3) low walking speed. This thesis describes how muscle mass can be further divided into relative muscle mass and absolute muscle mass. A higher body or fat mass is associated with a lower relative muscle mass and with a higher absolute muscle mass. Higher relative muscle mass at old age is associated with better physical performance and with less insulin resistance. It is suggested to reserve the term sarcopenia to describe a low muscle mass and dynapenia to describe a low muscle strength. Most importantly, this research illustrates that it is impossible to compare studies about sarcopenia in scientific literature due to the use of different diagnostic criteria for sarcopenia. 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
Extensive literature links the dopamine receptor D2 to insulin resistance and diabetes mellitus type 2. However, many aspects of the functional relationship remain unclear. In this thesis we... Show moreExtensive literature links the dopamine receptor D2 to insulin resistance and diabetes mellitus type 2. However, many aspects of the functional relationship remain unclear. In this thesis we focused on unraveling the characteristics of the interplay between dopamine D2 receptors and glucose metabolism as well as understanding the underlying mechanism(s). We evaluated the impact of DRD2 agonistic and antagonistic drugs on glucose and insulin metabolism in healthy volunteers, mice and INS-1E cells and we assessed dopaminergic parameters under different metabolic conditions. Our results show that altered dopaminergic parameters associated with obesity are due to mechanisms other than diet composition. But, changes in dopaminergic signaling may set the stage for metabolic corollaries of high fat feeding and may be involved in the beneficial impact of calorie restriction. We also demonstrate that inhibiting DRD2 activation may affect glucose homeostasis independent of body weight alterations. The underlying mechanisms include a reduction in physical activity and a direct effect on insulin sensitivity. In addition we provide evidence that inhibition of insulin secretion may, paradoxically, underlie the beneficial impact of DRD2 activation on glucose metabolism. We believe these findings may offer new ideas for strategies to prevent of treat diabetes mellitus type 2. Show less
This thesis shows the results of a 16-week very low calorie diet on insulin resistance, Quality of Life, low-grade inflammation and ectopic fat depositions
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
Type 2 diabetes mellitus has now become a global epidemic. The past decade hormones from the gastrointestinal tract have gained much interest as potential new therapeutic drugs in the battle... Show moreType 2 diabetes mellitus has now become a global epidemic. The past decade hormones from the gastrointestinal tract have gained much interest as potential new therapeutic drugs in the battle against this disease. Gut peptides play an important role in regulating food intake and energy homeostasis. In addition, they are able to impact on insulin sensitivity. In the present thesis we focused on modulation of insulin sensitivity by different gut hormones or their analogues. By means of the hyperinsulinemic euglycemic clamp technique we show that these gut hormones beneficially impact on insulin resistance. In addition, we show that these gut hormones can decrease body weight and inhibit lipid production, which are promising results since insulin resistance is a complex disease and is associated with obesity and cardiac disease. Also, we show that the hormone GLP-1 reduces endogenous insulin resistance via the brain. Over the past decade a growing amount of evidence indicates that the gut-brain axis is a key player in the control of glucose homeostasis. Elucidating more precisely the molecular events in the brain that underlie the effects of these hormones could lead to the identification of new (or improved) therapeutic agents. Show less
We have identified ATF2 as a component of the cellular and in vivo insulin signaling systems. Insulin induced ATF2-phosphorylation in A14 fibroblasts, 3T3L1-adipocytes and several mouse tissues in... Show moreWe have identified ATF2 as a component of the cellular and in vivo insulin signaling systems. Insulin induced ATF2-phosphorylation in A14 fibroblasts, 3T3L1-adipocytes and several mouse tissues in vivo. In cell lines, the insulin-induced ATF2-phosphorylation was dependent on cooperation between two Ras-dependent MAPK-pathways: ERK and p38/JNK. Analysis of several described ATF2-target genes identified insulin-induced expression of Egr1, ATF3, c-jun and SREBP1c as being ATF2-dependent in cell lines. These genes encode transcription factors whose targets have been postulated to be involved in several aspects of normal insulin action, like control of hepatic fat and glucose metabolism and proliferation and differentiation of beta-cells. Quantitative PCR analysis showed increased mRNA expression of these genes in mouse livers correlating with hepatic ATF2-phosphorylation induced by insulin, but also in response to HFD-induced insulin resistance. In addition, the known ATF2 target genes, the inflammatory cytokines IL1-beta and TNF-alpha were also significantly induced by the HFD in liver. Although the elucidation of the exact role of ATF2 activation under these conditions needs further experimentation, the data presented in this thesis suggest a potential dual function for ATF2 as a mediator of insulin action on the one hand and a putative regulator of the development or maintenance of insulin resistance and/or diabetes-associated complications on the other. 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
Children born small-for-gestational-age (SGA) are at risk for short stature, and cardiovascular disease and type 2 diabetes in later life. There is some preliminary evidence for a similar phenotype... Show moreChildren born small-for-gestational-age (SGA) are at risk for short stature, and cardiovascular disease and type 2 diabetes in later life. There is some preliminary evidence for a similar phenotype in survivors of preterm birth. In contrast to children born SGA, preterm infants born appropriate-for-gestational-age who experienced neonatal growth retardation, resulting in a small size at term, are excluded from growth hormone therapy if they fail to catch up in height subsequently. We tested in 19-year-olds born before 32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants cohort the effect of early growth on the growth pattern and adult metabolic health. Childhood growth and adult height were similar in preterm infants born SGA and those with neonatal growth retardation (weight and/or length at 3 months <-2 SD score). Young adults born preterm had a waist circumference and a waist-to-hip ratio much greater than the population reference mean, especially women. In addition, they showed a tendency towards insulin resistance and a high prevalence of hypertension. These findings were not explained by antenatal glucocorticoid treatment. Carriers of the 23K variant of the R23K polymorphism in the glucocorticoid receptor, associated with a mild glucocorticoid resistance, were less insulin-resistant and showed complete catch-up growth early in infancy and attained height was similar to the population reference mean, whereas stature in non-carriers was on average 0.5 SD below this mean Show less
In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between... Show moreIn this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism underlying this association remains unclear. Recently, attention has focused on the role of excessive accumulation of triglycerides (TG) in the liver (hepatic steatosis) in this association. Hepatic steatosis was considered a benign condition until it was discovered that a nonalcoholic fatty liver is associated with many cardiovascular risk factors. Subsequently, many studies have shown a strong association between hepatic TG content and hepatic insulin resistance. The studies in this thesis show that hepatic steatosis is actively and passively involved in the metabolic disturbances in the glucose and lipid metabolism. The prevalence of hepatic steatosis in western countries is high and will certainly increase with the epidemics of obesity and diabetes. This will put an increasing number of subjects at risk for disturbances in the glucose and lipid metabolism and concomitantly for cardiovascular disease. Show less
The metabolic syndrome is an increasing problem in our Western society. Many of the features of the metabolic syndrome, like obesity, insulin resistance, dyslipidemia, and hepatic steatosis are... Show moreThe metabolic syndrome is an increasing problem in our Western society. Many of the features of the metabolic syndrome, like obesity, insulin resistance, dyslipidemia, and hepatic steatosis are established risk factors for cardiovascular disease. Growing evidence supports the important role of body free fatty acid handling and/or body distribution of triglycerides in the pathogenesis of the metabolic syndrome-associated problems. We used several different approaches to study the development of obesity, insulin resistance, dyslipidemia, and liver steatosis. In chapter 2 we found that absence of apoC3, a natural LPL inhibitor, enhances FA uptake from plasma triglycerides in adipose tissue leading to increased susceptibility to diet-induced obesity, followed by more severe development of insulin resistance. Therefore, we have shown that regulation of body distribution of triglycerides, in a LPL-dependent process, plays an important role in obesity development. In chapter 3 we found that acute inhibition of the β-oxidation of FA indeed increases hepatic lipid content, but neither stimulates hepatic VLDL secretion nor reduces insulin sensitivity. In chapter 4 we showed that the combination of proteomics with relevant physiological parameters in a sensitive animal model, is a powerful tool, which will aid in identifying workingmechanisms of various dietary FA. In chapter 5 we found that sphingolipids protect the liver from fat and cholesterol-induced steatosis. Since sphingolipids are nutritional compounds present in several daily foods, such as milk and meat, addition of sphingolipids to the diet may decrease traditional cardiovascular risk factors, such as plasma cholesterol and triglycerides. Show less
