Page 19 - Human Bile Acid Metabolism: a Postprandial Perspective

Conclusion 1
Many preclinical studies have been performed since the initial discovery TGR5 to elucidate its physiology as a bile acid receptor and possible value as a therapeutic target in DM2, obesity and non-alcoholic steatohepatitis (NASH). However, the question remains whether the discovered pathways function similarly in human physiology, and if they do, whether they their effects are large enough to be relevant. In particular, profound interspecies differences in the biology of bile acids and bile acid receptors in multiple cells and tissues hamper translation to human patho- physiology. Therefore, we aimed to perform translational studies to uncover the relevance and biological importance of the postprandial bile acid response.
Outline
Part II – Variations in bile acid levels: Since it has been proposed that bile acids regulate lipid and carbohydrate metabolism, we set out in chapter 2 to describe postprandial plasma concentrations of 12 individual bile acid species in patients with DM2 and healthy controls using a 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat contents, respectively.
Because variation within, and between, subjects turned out to be considerable, we subsequently investigated portal bile acid concentrations and their increase after a meal, and compared these to peripheral plasma concentrations in a transorgan porcine model. In chapter 3 we describe this model that we used to investigate postprandial plasma concentrations in multiple compartments as well as transorgan fluxes of bile acids, glucose and insulin using the para-aminohippuric acid dilution method. Eleven pigs with multiple intravascular catheters received a standard mixed-meal. Additionally, we sampled fasted venous and portal blood from non-diabetic obese patients during gastric bypass surgery as a human reference point.
Part III - Intervention: To further examine regulating mechanisms in postprandial bile acid metabolism, we devised several interventions aiming to mimic the effect of physiological stimuli on insulin sensitivity. In chapter 4 we used a 2-week very-
Introduction
17