The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN... Show moreThe studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM. Show less
Obesity and insulin resistance (IR) are multifactorial pathologies, characterized by a complex etiology. In addition to genetics, age and sex, environmental factors such as dietary composition and... Show moreObesity and insulin resistance (IR) are multifactorial pathologies, characterized by a complex etiology. In addition to genetics, age and sex, environmental factors such as dietary composition and lifestyle have profound effects on the development of both pathologies. Excess dietary energy intake (EI) per se has effects on energy homeostasis through physiological systems involved in maintenance of substrate balances. Moreover, the composition of the diet itself may contribute and aggravate the phenotype in time by acting as a second hit. In particular, high levels of saturated long chain fatty acids have been associated with the development of obesity and IR. In this thesis, we have addressed a number of important aspects that play a role in the development of diet-induced obesity and insulin resistance. Show less
Assessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to... Show moreAssessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to completely reverse once patients reach dialysis. b) Specific additional problems related to chronic kidney disease, in particular protein-energy wasting, may act as “competing risk”, overshadow effects and interfere in various hormonal regulations. c) In advanced chronic kidney disease, the pattern and composition of risk is changing. The aim of this thesis is to 1) Detect specific effects of metabolic alterations in dialysis patients 2) Provide explanations for conflicting results in the literature 3) Provide a rationale for novel interventions. In this thesis, the metabolic status of dialysis patients is adressed and its consequences for the decline in residual kidney function, cardiovascular events and survival. The metabolic status includes alterations in nutritional and hormonal status, focussing on: lipid metabolism, diabetes mellitus type 2, obesity, the role of adipokines, specific effects of protein-energy wasting, and Vitamin D status with the clinical consequences. The investigations are performed in two large cohorts of dialysis patients, the 4D and NECOSAD studies (The German Diabetes and Dialysis Study and The Netherlands Cooperative Study on the Adequacy of Dialysis). Show less
The nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include... Show moreThe nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include unintended weight loss, sleep and circadian rhythm disturbances, as well as autonomic nervous system dysfunction. However, the pathogenesis of these less well-known features of HD is poorly understood and currently no effective treatment options are available. It is thus of paramount importance to elucidate the pathological basis of these symptoms and signs in order to design and apply more effective therapeutic interventions. Recently, substantial dysfunction of the hypothalamus was reported in both human studies and various knock-in and transgenic animal models of HD. The hypothalamus consists of groups of interconnected neuronal nuclei located at the base of the brain that regulate a broad array of physiologic, homeostatic and behavioural activities. Therefore, in this thesis we attempt to substantiate the premise that hypothalamic dysfunction per se, as well as secondary (neuro)endocrine and metabolic alterations could contribute to the pathogenesis of several non-motor symptoms and signs of HD. Show less
The first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington... Show moreThe first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington__s Disease. To determine whether the hypocretin system is affected in these disorders, the total number of hypocretin neurons was determined using quantitative techniques in post-mortem human hypothalami. The reason why hypocretin neurons disappear in narcolepsy is still a mystery. A putative autoimmune aetiology has been hypothesized, but a screening for autoantibodies and a n=1 trial with intravenous immunoglobulins yielded no unequivocal results in favor of this hypothesis. In the second part, the consequences of hypocretin deficiency in narcoleptic patients are explored, focussing on vigilance, metabolism and the autonomic nervous system and skin temperature regulation. The ability of a specific neuropsychological test to measure vigilance as a severity indicator for narcolepsy is explored. Two possible causes for the obesity commonly seen in narcolepsy are a decreased basal metabolic rate and a changed autonomic tone. To assess the influence of hypocretin deficiency on skin temperature regulation, thermoregulatory profiles of the proximal and distal skin of narcoleptic subjects were compared to profiles of healthy controls during a daytime sleep registration. Show less
There is a fundamental difference between mammals and fish in how hypoxia affects the lipid metabolism by means of the stress hormone noradrenaline. In mammals, hypoxia induces an increase in lipid... Show moreThere is a fundamental difference between mammals and fish in how hypoxia affects the lipid metabolism by means of the stress hormone noradrenaline. In mammals, hypoxia induces an increase in lipid metabolism, which can eventually lead to tissue damage due to elevated plasma fatty acid levels, e.g. in case of a heart attack. However, hypoxia is not a normally occurring situation in healthy mammals as opposed to many fish species, because water is a relative poor source of oxygen. In hypoxic fish therefore, noradrenaline mediates a decrease in lipid metabolism, and we believe that this is a general protection mechanism in fish against lipid poisoning. There is a clear difference in the mode of breathing between mammals and fish, namely air- vs. water-breathing. Hence, we hypothesise that this difference is the cause for the opposing effects of noradrenaline. Therefore, we studied the effects of hypoxia on an air-breathing fish, the African catfish. However, physiologically this species reacted the same as other water-breathing fish, namely by means of a reduced lipid metabolism. Additionally, we demonstrated that, despite the opposing effects on the lipid metabolism, the transduction pathways in fish and mammals are very alike, and thus only a minor change has occurred in the course of evolution. This research has aided in a better understanding of the evolutionary changes in lipid metabolism.|Er is een fundamenteel verschil tussen zoogdieren en vissen in hoe het vetmetabolisme onder hypoxie (=zuurstoftekort) wordt veranderd door het stresshormoon noradrenaline. In zoogdieren leidt hypoxie tot een verhoogd vetmetabolisme, wat uiteindelijk zelfs weefselschade kan veroorzaken door te hoge vetzuurgehaltes, b.v. bij een hartaanval. Gezonde zoogdieren komen normaliter niet in zuurstofnood, in tegenstelling tot veel vissoorten, omdat water een relatief arme zuurstofbron is. In hypoxische vissen daalt dan ook het vetmetabolisme door noradrenaline, en wij denken dat dit een beschermingsmechanisme is tegen een vetzuurvergiftiging. Er is een duidelijk verschil in de manier van ademhalen van zoogdieren en vissen, respectievelijk lucht- en waterademhaling, en dit verschil ligt mogelijkerwijs ten grondslag aan deze verschillende effecten van noradrenaline; dit is de centrale hypothese van het onderzoek. Daarom is gekeken naar het effect van zuurstoftekort bij een luchtademhalende vissoort, de Afrikaanse meerval. Deze vis bleek echter fysiologisch hetzelfde te reageren als waterademhalende vissen, namelijk een verlaagd vetmetabolisme. Daarnaast is aangetoond dat, ondanks tegenovergestelde effecten op het vetmetabolisme, de aansturingmechanismen in vissen en zoogdieren vergelijkbaar zijn, en dat er dus maar een minimale verandering in de evolutie heeft plaatsgevonden. Dit onderzoek heeft bijgedragen tot een beter begrip van de evolutionaire veranderingen in het vetmetabolisme. Show less
