Page 127 - Human Bile Acid Metabolism: a Postprandial Perspective

Introduction
Bile acids (BAs) are secreted into the gut after every meal in order to emulsify lipid droplets. After reabsorption into the portal circulation, a fraction of BAs escapes the enterohepatic cycle and enters the systemic circulation in a pattern of postprandial peaks. Experimental and observational data suggest that these circulating BAs affect lipid and glucose metabolism (1). By binding to the nuclear Farnesoid X Receptor (FXR), circulating BAs decrease hepatic glucose production and increase muscle insulin sensitivity (2) and possibly increase pancreatic insulin secretion (3). Additionally, activation of the G-protein-coupled BA receptor (GPBAR1/TGR5) increases energy expenditure in brown adipose tissue (4) and intestinal incretin secretion (5).
In clinical studies, the BA sequestrants cholestyramine (6) and colesevelam
(reviewed in (7; 8)) effectively reduce plasma glucose levels in patients with type
2 diabetes, indicating that interventions in the BA pool affect glucose metabolism.
In human observational studies, obese patients with type 2 diabetes showed
exaggerated postprandial BA responses (9; 10) and patients with type 2 diabetes
(11) and insulin resistance (12) show an altered composition of the fasting BA pool.
Since individual BA subtypes show different receptor binding affinities in vitro (13; 7 14) and in mice (15), changes in pool composition may affect glucose metabolism.
There is evidence suggesting a circadian rhythm in hepatic BA synthesis (16-19). This rhythm is likely to be driven by the mammalian circadian (~24hr) timing system based on the molecular transcriptional-translational clock cycle (20; 21). However, the question whether postprandial BA excursions change over the day remains to be answered, since most studies investigating the diurnal patterns in postprandial BA excursions used varying meal sizes (22; 23) or varying intervals between meals (24-26). The only study that used identical and equidistant meals stems from the 70s, measured only glycine conjugates using a non-specific radioimmunoassay method, and detected no diurnal rhythm in glycine conjugate excursions (27). Since then, more specific mass spectrometric methods have been developed to detect BA concentrations.
In a recent study we demonstrated that obese patients with type 2 diabetes show attenuated diurnal rhythms of plasma glucose tolerance in response to
Diurnal rythm of bile acids
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