This thesis was to combine metabolomics and Chinese medicine (CM) diagnosis to search for biomakers or metabolic profiles to subtype of type 2 diabetes (T2DM). An explorative study of 50 males with... Show moreThis thesis was to combine metabolomics and Chinese medicine (CM) diagnosis to search for biomakers or metabolic profiles to subtype of type 2 diabetes (T2DM). An explorative study of 50 males with pre-diabetes was designed and two subtypes (A and B) could be identified by urine metabolomics. More metabolic disturbances were indicated in subtype B. The effects of rimonabant and a multi-component preparation (SUB885C), both with reported effects of regulating weight and the improvement on metabolic risks, were assessed by lipidomics on ApoE*3Leiden.CETP Mice. A 4-week rimonabant intervention brought a significant weight reduction, but moderate effects on lipid profile. SUB885C was able to produce multiple anti-atherogenic changes in lipids of the mice to improve metabolic parameters. A combined approach of lipidomics, biochemistry and herbal component profiling was used to evaluate the effects of the ginseng roots of 3__6 years on the regulation of dyslipidemia in diabetic Goto-Kakizaki rats. The more than 4 year ginseng proved to be valuable for drug development to regulate lipids. To conclude, the early metabolomics investigations performed in this thesis converged analytical bioscience, clinical approach and the diagnostic perspectives in other health system to provide the systems biology view on the pre-stage of T2DM. Show less
The introduction of systems biology in combination with the profiling of numerous biochemical components (e.g. lipid metabolites, herbal products) enables the study of living systems from a... Show moreThe introduction of systems biology in combination with the profiling of numerous biochemical components (e.g. lipid metabolites, herbal products) enables the study of living systems from a holistic perspective. In this thesis we explored systems biology-based platforms to investigate the therapeutic effects of chemical drugs and herbal medicines on animal models with high-fat diet-induced obesity and genetic manipulated diabetes. The aim of the work was to better understand the working mechanisms of both treatments on metabolic syndrome from a holistic point of view and to evaluate the potentials of __omics__ technologies to this effort. Our results showed that lipidomics approach with appropriate bioinformatics tools are essential to describe the global, dynamic metabolic response of living systems, e.g. from homeostasis via sub-optimal health and ultimately to dysfunction. These studies pointed hints to disco ver lipid biomarkers in relation to health promotion and disease prevention and facilitated the understanding of the complex regulatory mechanisms in humans or animals. Particularly, the introduction of the systems biology view will not only provide in-depth insights into the multi-target synergetic effects (which have hardly been used in modern drug discovery) but also can bridge Chinese Medicine (multi-target therapy) and Western Medicine (molecular pharmacology). Show less
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
Overgewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de... Show moreOvergewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de ontwikkeling van een chronische ontsteking in vetweefsel en lever. Met dit promotieonderzoek laten we met behulp van onderzoek in muizen zien dat ontsteking een belangrijke rol speelt in het metabolisme en transport van vetten. We bekijken ook welk effect dit heeft op de ontwikkeling van atherosclerose en type 2 diabetes. In het eerste deel van dit promotieonderzoek laten we zien dat ontsteking een belangrijke rol speelt in vetmetabolisme en atherosclerose. De ontstekingsremmer aspirine zorgde voor een verlaging van de hoeveelheid vet in het bloed. Activatie van een onsteking in de lever leidde juist tot een verhoging van vet in het bloed, wat de ontwikkeling van atherosclerose in de vaatwand verergerde. In het tweede deel van dit promotieonderzoek bestuderen we het belang van het inflammasoom/caspase-1 complex (betrokken bij ontstekingsprocessen) in obesitas, insulineresistentie en vetmetabolisme. We laten zien dat muizen die een deel van dit eiwit-complex missen, beschermt zijn tegen de ontwikkeling van obesitas en insulineresistentie. Het inflammasoom/caspase-1 complex lijkt daarmee een potentieel target voor de behandeling van obesitas, insulineresistentie en type 2 diabetes. Show less
