Page 169 - Human Bile Acid Metabolism: a Postprandial Perspective

cells through TGR5, but the timing argues against it: GLP-1 levels rapidly increased in the first hour after administration of gDCA. On the whole, it does fit our assumed idea of bile acids as metabolic signals, stimulating downstream GLP- 1 effects: increasing pancreatic beta cell mass, glucose-dependent insulin release and sensation of satiety. In our study, the increased GLP-1 levels did not translate into higher insulin or lower glucose levels, which may be explained by well-tuned compensatory mechanisms in these healthy individuals, which are absent in metabolically deranged patients.
In obese insulin resistant patients with type 2 diabetes (DM2), the relative contribution of DCA, a strong TGR5 agonist, to the total bile acid pool is increased (Brufau et al., 2010; Glicksman et al., 2010; Haeusler et al., 2013; Vincent et al., 2013). We speculate that this may be an adaptive response to hyperglycemia, analogous to the increase in insulin seen in these patients when they develop insulin resistance. In this view, decreased insulin signaling increases bile acid synthesis through decreased activation of FOXO1, which normally suppresses CYP8B1 transcription. Increased enteral bile acid signaling through TGR5 could then lead to an increase in circulating GLP-1, which in turn stimulates glucose- dependent insulin release from the pancreatic beta cell.
Natural variation in bile acid pool composition
Recurring themes in this thesis are the large intra- and interindividual variations
in both human and porcine postprandial bile acid profiles. We have demonstrated
this in healthy subjects (Chapters 2, 3 and 5) as well as in subjects with metabolic
disturbances (Chapters 2, 5 and 6). This is in line with data reported by others.
Already in 1978, LaRusso et al found intra-individual variations in postprandial
peak-time and peak levels (LaRusso et al., 1978; Schalm et al., 1978). This 9 has been repeated in more detail by Steiner et al., who describe considerable interindividual variations in bile acid levels over the course of a 24-hour study
day (Steiner et al., 2011).
We speculate that the variability in the data can arise from multiple sources. Firstly, we are measuring peripheral plasma concentrations in a system where there is flow through different compartments, as evidenced by our catheter study in a porcine model (Chapter 3). This means that more robust signals that are contained in the enterohepatic cycle may remain out of sight, bypassing the sampled compartment.
Discussion and future perspectives
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