Page 40 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 2
suggests a positive effect of FXR antagonism on glucose homeostasis, which is also evidenced by the success of bile acid sequestering therapy for the treatment of T2D (3, 6). However, reduced FGF19 concentrations, achieved with bile acid sequestration (FXR inactivation), is not likely to explain the beneficial effect of bile acid sequestering agents. Indeed, animal studies have shown that FGF19 has insulin-like effects in the liver (9). Thus, FGF19 promotes protein and glycogen synthesis in the liver without promoting lipogenesis—in fact, FGF19 may even reduce triglycerides and cholesterol through currently unknown mechanisms (35, 36). A physiologically important difference is the temporal relationship between postprandial insulin and FGF19 secretion. As has been shown in other human studies and is confirmed in our study, FGF19 peak concentrations are segregated from insulin (~3 hours vs ~1 hour). Mice studies suggest that FGF19 —similar to insulin—is responsible for curbing postprandial endogenous glucose production, which is augmented in T2D (9). Specifically, FGF19 may be responsible for a delayed repression of gluconeogenesis, whereas postprandial insulin works in the early postprandial phase (37). Because gluconeogenesis accounts for approximately half of the endogenous glucose production (EGP), being low for up to approximately 4 hours after a meal (38), such a temporal relationship of postprandial insulin and FGF19 could physiologically make sense. However, our finding of very small FGF19 perturbations (in both T2D patients and NGT subjects) after a 75-g OGTT prompts questions about the idea that FGF19 is an important inhibitor of postprandial EGP by suppression of hepatic gluconeogenesis. However, EGP could be stimulated via bile acid-induced glucagon release from the intestine (39).
In summary, we find that T2D patients exhibit marked changes in fasting and postprandial bile acid concentrations compared to matched NGT subjects. These differences were dominated by increased unconjugated and glycine-conjugated secondary bile acids in T2D patients compared to NGT subjects, whereas primary bile acids were comparable among the two groups. In contrast, FGF19 concentrations tended to be lower in T2D patients vs NGT subjects. Most likely, these changes arise secondary to the T2D disease, as suggested by recent studies. Theoretically, this “T2D-bile acid-FGF19” phenotype results in altered FXR/ FGF19 signaling in the small intestine and the liver, which could potentially add to the deterioration of postprandial glycemic homeostasis inT2D.
38