3 research outputs found
Studien zur Rolle von Trimethylamin-N-oxid in Lipid- und Glukosestoffwechsel
Hintergrund: Trimethylamin-N-oxid (TMAO) rückte aufgrund beobachteter Assoziationen mit kardiovaskulären Erkrankungen, Atherosklerose und Diabetes in letzter Zeit vermehrt in den Fokus explorativer Studien. TMAO besitzt proatherosklerotisches Potential, greift in den Cholesterolstoffwechsel ein und liegt bei Diabetikern im Vergleich zur gesunden Bevölkerung in höheren Plasmakonzentrationen vor. Schlüsselenzym der TMAO-Synthese in der menschlichen Leber ist die Flavin Monooxygenase 3, ein Enzym, das auch am Xenobiotika-Metabolismus beteiligt ist.
Gegenstand und Methoden: Diese Arbeit stellt drei Studien vor, in denen unterschiedliche Teilaspekte des TMAO- und Cholin-Stoffwechsels untersucht wurden. Eine Studie beschäftigte sich mit der Reaktion akuter Fett- und Glukosebelastung im TMAO- und C1-Stoffwechsel bei 18 Probanden. In einer zweiten Studie wurde anhand von 331 Blutplasmaproben analysiert, ob zwischen den Konzentrationen an proatherogenem TMAO und antiatherogenem HDL eine Korrelation besteht. Eine weitere Studie untersuchte den Einfluss des Xenobiotikums Abirateronazetat auf die Metabolitkonzentrationen des TMAO- und Cholin-Stoffwechsels im Plasma bei 34 Patienten mit progressiv Chemotherapie-naivem Kastrations-resistentem Prostatakarzinom.
Ergebnisse: Nach akuter Fett- und Glukosebelastung zeigten sich Konzentrationsänderungen mehrerer Metabolite des Cholin- und TMAO-Stoffwechsels im Plasma. Während nach Fettbelastung die Cholin-Konzentrationen abnahmen, stiegen sie nach Glukosebelastung an. Vier Stunden nach der Fettbelastung fanden sich zudem signifikante Änderungen in abfallenden Betain- und Glukosekonzentrationen sowie ansteigenden Triglyceridkonzentrationen. Durch die Glukosebelastung konnte ein Abfall der C1-Donoren Dimethylglycin und S-Adenosylmethionin sowie von TMAO und Taurin verzeichnet werden. Im Quintilvergleich waren TMAO- und HDL-Plasmaspiegel nicht signifikant assoziiert. Nach Applikation von Abirateronazetat stieg
die TMAO-Konzentration nur in Therapiegruppe A. In der prozentualen Konzentrationsänderung fanden sich unter Berücksichtigung der unterschiedlichen Ausgangskonzentrationen zwischen den Therapiegruppen keine Unterschiede.
Zusammenfassung: Nach akuter Fett- und Glukosebelastung wurden mehrere Parameter entdeckt, die als Marker für Fett- und Glukosestoffwechsel fungieren könnten. Eine Assoziation von antiatherogenen HDL- und proatherogenen TMAO-Plasmakonzentrationen konnte nicht nachgewiesen werden. Zwischen der Applikation von Abirateronazetat und den Konzentrationen an TMAO war kein eindeutiger Zusammenhang erkennbar.Background: In recent time, trimethylamine-N-oxide (TMAO) has been focussed increasingly by exploratory studies caused by observations that associated it to cardiovascular diseases, atherosclerosis and diabetes mellitus. TMAO has pro-atherosclerotic potential, has been linked to cholesterol metabolism and its plasma
concentrations are increased in diabetics compared to the healthy population. The key enzyme of TMAO synthesis in human liver is the flavin-monooxygenase 3, an enzyme that is also involved in the metabolism of xenobiotics.
Objectives and methods: This thesis presents three studies that analysed several aspects of TMAO and choline metabolism. One study examined the reaction of acute fat and glucose challenge in TMAO and C1 metabolism with 18 participants. Based on 331 blood plasma samples a second study analysed whether a correlation exists between pro-atherogenic TMAO and anti-atherogenic HDL. A third study investigated the influence of the xenobiotic abiraterone acetate to the plasma concentrations of metabolites in TMAO and choline metabolism with 34 patients with progressive chemotherapy-naı̈ve castration-resistant prostate cancer.
Results: Acute fat and glucose challenge changed plasma concentrations of several metabolites in TMAO and choline metabolism. While choline concentrations decreased after fat challenge, they increased after glucose challenge. Furthermore, four hours after fat challenge significant changes have been noticed in decreased betaine and glucose concentrations and increased triglyceride concentrations. Glucose challenge caused a decrease in C1 donors Dimethylglycin and S-adenosylmethionin as well as TMAO and taurine. A quintile comparison showed no significant association between TMAO and HDL plasma concentrations. After application of abiraterone acetate the TMAO concentration increased only in therapy group A. There were no differences in the percental concentration change between the therapy groups in consideration of the different baseline concentrations.
Conclusions: After acute fat and glucose challenge several metabolites were identified that could function as a marker in fat and glucose metabolism. An association between anti-atherogenic HDL and pro-atherogenic TMAO plasma concentrations could not be proved. A definite association could not be observed between the application of abiraterone acetate and the TMAO concentrations
Glucose and Fat Tolerance Tests Induce Differential Responses in Plasma Choline Metabolites in Healthy Subjects
Plasma choline shows associations with plasma glucose and lipids. We studied changes of choline metabolites after oral glucose tolerance test (OGTT) and fat tolerance test (OFTT). Eighteen healthy subjects (mean age 54.3 years; BMI 26.8 kg/m2) underwent 2 tests. First, OFTT (80 g fat) was applied and blood was collected at baseline and 4 h after OFTT. Seven days later, 75 g glucose was applied and blood was collected at baseline and 2 h after OGTT. Plasma concentrations of choline, betaine, trimethylamine N-oxide (TMAO), dimethylglycine, S-adenosylmethionine (SAM), lipids and glucose were measured. After OFTT, plasma choline declined (10.6 to 9.2 µmol/L; p = 0.004), betaine declined (33.4 to 31.7 µmol/L; p = 0.003), TMAO slightly increased (4.1 to 5.6 µmol/L; p = 0.105), glucose declined (5.39 to 4.98 mmol/L; p < 0.001), and triglycerides increased (1.27 to 2.53 mmol/L; p < 0.001). After OGTT, plasma choline increased (10.1 to 11.1 µmol/L; p < 0.001), TMAO declined (4.0 to 3.5 µmol/L; p = 0.029), dimethylglycine declined (2.0 to 1.7 µmol/L; p = 0.005), SAM declined (103 to 96 nmol/L; p = 0.041), but betaine, glucose, and SAM were unchanged. In conclusion, OFTT lowered plasma betaine and choline and caused heterogeneous changes in plasma TMAO. OGTT reduced the flow of methyl groups and plasma TMAO
Glucose and Fat Tolerance Tests Induce Differential Responses in Plasma Choline Metabolites in Healthy Subjects
Plasma choline shows associations with plasma glucose and lipids. We studied changes of choline metabolites after oral glucose tolerance test (OGTT) and fat tolerance test (OFTT). Eighteen healthy subjects (mean age 54.3 years; BMI 26.8 kg/m2) underwent 2 tests. First, OFTT (80 g fat) was applied and blood was collected at baseline and 4 h after OFTT. Seven days later, 75 g glucose was applied and blood was collected at baseline and 2 h after OGTT. Plasma concentrations of choline, betaine, trimethylamine N-oxide (TMAO), dimethylglycine, S-adenosylmethionine (SAM), lipids and glucose were measured. After OFTT, plasma choline declined (10.6 to 9.2 µmol/L; p = 0.004), betaine declined (33.4 to 31.7 µmol/L; p = 0.003), TMAO slightly increased (4.1 to 5.6 µmol/L; p = 0.105), glucose declined (5.39 to 4.98 mmol/L; p < 0.001), and triglycerides increased (1.27 to 2.53 mmol/L; p < 0.001). After OGTT, plasma choline increased (10.1 to 11.1 µmol/L; p < 0.001), TMAO declined (4.0 to 3.5 µmol/L; p = 0.029), dimethylglycine declined (2.0 to 1.7 µmol/L; p = 0.005), SAM declined (103 to 96 nmol/L; p = 0.041), but betaine, glucose, and SAM were unchanged. In conclusion, OFTT lowered plasma betaine and choline and caused heterogeneous changes in plasma TMAO. OGTT reduced the flow of methyl groups and plasma TMAO