Page 180 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 10
Chapter 5 (van Nierop et al., 2019)
In this study, we investigated the postprandial bile acid response in peripheral plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response after a 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In experiment 1, we tested a 4-h mixed meal after an overnight fast and a 40-h fast. In experiment 2, we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In experiment 1, 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at various time points. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19. If this is due to increased enteral TGR5 and FXR activation due to exposure to bile acids, that would be counterintuitive, as enteral bile acid levels are usually linked to food intake. Alternatively, FGF19 could be upregulated through some other mechanism in order to suppress bile acid synthesis during starvation. In the second experiment, we observed increased postprandial GLP-1 levels after a meal in the fed state, indicating enteral TGR5 activation by orally administered bile acids. gDCA stimulation did not affect FGF19-levels, suggesting no enteral FXR-activation. Energy expenditure was not affected by gDCA administration. This experiment is a first step to explore the feasibility of bile acid supplementation in humans with metabolic disorders.
Chapter 6 (van Nierop et al., 2019)
Placement of the duodenal-jejunal bypass liner (DJBL), a bariatric device, in obese patients with type 2 diabetes leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement. To that end, we performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement. A weight loss 4.3 ± 0.6 kg was achieved at 1 week, which increased to 12.7 ± 1.3 kg after 6 months. Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation.
178