Conclusions/interpretation This study shows that type 2 diabetes is characterised by increased fasting and postprandial plasma alpha-dicarbonyl stress, which can be reduced by improving glucose... Show moreConclusions/interpretation This study shows that type 2 diabetes is characterised by increased fasting and postprandial plasma alpha-dicarbonyl stress, which can be reduced by improving glucose metabolism through a VLCD or RYGB. These data highlight the potential to reduce reactive alpha-dicarbonyls in obese individuals with type 2 diabetes. Trial registration: ClinicalTrials.gov NCT01167959 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 modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the... Show moreIn modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the central clock in the suprachiasmatic nuclei (SCN) in the brain. In mice, a complete abolishment of central clock-driven rhythms resulted in obesity and severe hepatic insulin resistance. An attenuation of rhythms resulted in decreased muscle strength, osteoporosis-like bone changes and transient changes in the immune system. In humans, short sleeping obese individuals with a preference for evening activities ("evening chronotypes") had increased cardiovascular risk factors. Their neurocognitive function was often impaired and could be improved with sleep extension. Insufficient sleep was also associated with an increased risk for osteopenia and sarcopenia. Taken together, disrupted circadian rhythms and insufficient sleep associate with a spectrum of unfavorable health outcomes. Studies described in the thesis provide insight in potential strategies to improve rhythms and sleep: by appropriately timed behavior (active behavior during the active phase; rest during the rest phase), light exposure (light during the subjective day; darkness at night) as well as caffeine intake. 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
Depression and cardiovascular disease (CVD) are among the most prevalent health problems worldwide, with a significant burden of disease. Both conditions are associated and thought to be mediated... Show moreDepression and cardiovascular disease (CVD) are among the most prevalent health problems worldwide, with a significant burden of disease. Both conditions are associated and thought to be mediated by the metabolic syndrome (MetSyn), a cluster of cardiovascular risk factors (waist circumference, blood sugar, cholesterol, triglycerides, blood pressure) and related parameters (BMI, waist-hip-ratio and LDL-cholesterol). Better insights in this association are important in order to better prevent and treat both conditions. This thesis focuses on the association between depression and metabolic disturbances. The results show that there is a significant and longitudinal and bidirectional association between depression and obesity, which is most pronounced among those with a clinical diagnosis depression. When subjects are approached not based on the presence or absence of the diagnosis, but based on the most prevalent symptoms, results show that only __Somatic Arousal__ symptoms (palpitations, dizziness, tension, shortness of breath) are associated with most MetSyn components. Comparing depressed inpatients to depressed outpatients, inpatients show more adverse metabolic disturbances in the lipid-spectrum, while blood pressure is more favorable. Further, inpatients show higher cortisol levels, which are considered to be a measure of the HPA-axis, an important stress-system in the onset and natural course of depression. Show less
Gast, K.B.; Heijer, M. den; Smit, J.W.A.; Widya, R.L.; Lamb, H.J.; Roos, A. de; ... ; NEO Study Grp 2015
In this thesis we examined several effects of fasting in lean and obese individuals. As expected, both the hormonal response as well as the metabolic shift from glucose towards lipid oxidation was... Show moreIn this thesis we examined several effects of fasting in lean and obese individuals. As expected, both the hormonal response as well as the metabolic shift from glucose towards lipid oxidation was impaired in obese individuals. At baseline, mitochondrial protein content in skeletal muscle of obese subjects was significantly reduced compared to lean individuals. We assessed the neuronal response to fasting by fMRI scanning. We found a different neuronal response to fasting between lean and obese individuals in terms of functional connectivity between the hypothalamus and respectively the dACC and insula. Since these regions are part of the saliency network, these differences may reflect distinct perception of calorie imbalance between lean and obese subjects. The effects of fasting on sympathetic tone (estimated by heart rate variability) were studied. Our data suggests that fasting decreases sympathetic tone in lean subjects, whereas it increases sympathetic activity in obese individuals. Weight loss in obese individuals increased HRV parameters that reflect the postprandial sympathetic tone. Finally, we studied the effects of fasting in the presence and absence of food-odors since this has been shown to reduce the fasting-induced increase in life span in fruit flies __ no differences were found in our human subjects. Show less
In this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic... Show moreIn this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic surgical procedure Roux-en-Y gastric bypass. Moreover, we found differences between NGT and T2DM subjects at baseline, which enable us to better be able to dissect the subsequent effects of the procedures. To our surprise, and in contrast to previous studies, we observed no additional effect of the RYGB as compared to calorie restriction, on our main outcome parameters: postprandial glucose, insulin and the gut peptide levels three weeks after surgery. Furthermore, both restrictive and RYGB induced weight loss resulted in comparable effects on the lipidome, circulating thyroid hormone levels and the autonomic nervous system. For these outcome parameters, it seems that calorie restriction is the common denominator of the effect of the different weight loss strategies on the short term. Clearly distinct effects of RYGB, however, were seen on bile salt, FGF21 and glucagon levels in response to food intake. Although neither the exact mechanisms, nor the eventual metabolic effect are as yet clear, the gut-liver-pancreas axis may be an important mediator of the effect of the RYGB Show less
This thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of... Show moreThis thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of circulating adiponectin can predict radiographic progression in patients with early RA. In contrast, in patients with hand OA, this association appears protective. Therefore, to obtain insight into the mechanisms underlying these associations, we investigated the high-molecular-weight isoform of adiponectin (hmwAPN), which is one of the most biologically active isoforms of adiponectin. We show that the associations of total adiponectin with radiographic progression are not mediated by hmwAPN, in either RA or HOA. In the second part, we present the immunological characterization of the infrapatellar fat pad (IFP), a joint associated adipose tissue, in patients with advanced knee OA. We observed profound differences in secreted inflammatory factors and immune cell composition between the IFP and paired subcutaneous adipose tissue samples. Interestingly, we observed obesity-related changes in the IFP phenotype, and in macrophages and adipocytes, Therefore, we investigated the modulatory effects of adipocytes on the phenotype of human macrophages in vitro and we observed that adipocyte-derived lipids can mediate the obesity-related changes in the phenotype of adipose tissue macrophages in humans Show less