Early identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for... Show moreEarly identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for risk stratification and optimizing individual prevention and treatment strategies in patients with metabolic syndrome. This thesis evaluates MR and CT imaging techniques for identifying risk factors and subclinical disease in metabolic syndrome. Show less
Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as... Show more Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as diabetes mellitus. In the first part of this thesis, the epidemiology of insulin resistance has been described. Since there is no clear definition for insulin resistance, the prevalence of IR remains unclear. In addition, the use of IR in the screening for diabetes mellitus in obese children was evaluated. In the second part of the thesis, treatment of obese children with insulin resistance is discussed. In a randomized controlled trial of 18 months, children were treated with either metformin or placebo in addition to lifestyle intervention. Body mass index in children treated with metformin remained stable during the 18 months, whereas placebo-treated children had an increase in body mass index. Finally, the treatment with metformin under the strict circumstances of the clinical trial was compared to treatment with metformin in daily practice during 18 months. Both groups showed similar results regarding body mass index during metformin treatment. Show less
This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several... Show more This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease. Show less
Paans, N.P.G.; Bot, M.; Gibson-Smith, D.; Does, W. van der; Spinhoven, P.; Brouwer, I.; ... ; Penninx, B.W.J.H. 2016
Conclusion: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the... Show moreConclusion: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the presence of sex differences in the pathogenesis of hand OA. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
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
