Differential effects of a 40 hour fast and bile acid supplementation on human GLP-1 and FGF19 responses (original) (raw)
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The Journal of clinical endocrinology and metabolism, 2016
Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Bile acid and FGF-19 concentrations. Postprandial total bile acid concentrations increased with increasing meal fat content (P < .05), peaked after 1-2 hours, and were higher in T2D patie...
Bile acid signaling after an oral glucose tolerance test
Chemistry and Physics of Lipids, 2011
Monitoring bile acids as signal molecules in combination with a bile acid synthesis marker and the FXR regulator fibroblast growth factor 19 (FGF19), this study addresses significant postprandial changes. The efficacy of the different pathways to regulate bile acid synthesis through short heterodimer partner (SHP) dependent FXR modulation in liver, and SHP independent activation via FGF19 is demonstrated. Characteristic changes of the bile acid profile during an oral glucose tolerance test (oGTT) were investigated in 73 individuals. 15 bile acid species including conjugated and unconjugated forms were quantitatively determined with LC-MS/MS in serum samples collected at three time points during the oGTT. All conjugated bile acid species showed the same time course, a significant increase at 60 min after the glucose intake and an incline at 120 min. In contrast, a consistent decline of all unconjugated bile acids was monitored. 7␣-Hydroxy-4-cholesten-3-one, an early bile acid synthesis marker, showed an inverse response with a significant decrease at 60 min which proves the efficient and rapid downregulation of CYP7A1 via FXR activation through bile acid signaling. Significantly higher levels of FGF19 were observed 120 min after glucose intake and 60 min after bile acid excursion.
Determinants of postprandial plasma bile acid kinetics in human volunteers
American journal of physiology. Gastrointestinal and liver physiology, 2017
Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate ana...
Postprandial plasma bile acid responses in normal weight and obese subjects
Annals of Clinical Biochemistry, 2010
Background Bile acids can act as signalling molecules via various receptors including the nuclear farnesoid X receptor (FXR) and pregnane X receptor (PXR), and the cell surface G-protein-coupled receptor TGR5. The signalling has been implicated in the release of peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), which improves glycaemic control and energy expenditure. We investigated whether morbidly obese subjects have altered postprandial bile acid responses in comparison to normal weight subjects. Method Blood samples were taken every 30 min from 0 to 180 min following a 400 kcal test meal. Samples were taken from 12 normal weight subjects with a body mass index (BMI) of 23.2 (2.8) kg/m2 (median [interquartile range (IQR)]) and seven obese patients with a BMI of 47.2 (7.2) kg/m2. Fractionated bile acids were measured on these samples using high-performance liquid chromatography tandem mass spectrometry. Results The obese subjects showed a lower postprandial response in total b...
Alimentary Pharmacology & Therapeutics
Background Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. Aim To explore if an impaired FGF19 response identifies primary bile acid diarrhoea. Methods Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme-linked immunosorbent assay and bile acids including 7a-hydroxy-4-cholesten-3-one by liquid chromatography-tandem mass spectrometry. Results Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41-138] to 99 pg/mL (IQR: 67-147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54-512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42-79); 90 min: 48 pg/mL [IQR: 37-63); 150 min: 57 pg/mL (48-198)]. Receiver operating characteristics (ROC AUC) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROC AUC 1.0; P = 0.001). 7a-hydroxy-4cholesten-3-one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation. Conclusions The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.
An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers
Gastroenterology, 2018
Interfering with bile acids (BAs) signaling within the enterohepatic circulation (EHC) has recently emerged as an important way of controlling human metabolic homeostasis. This is highly relevant to a number of frequent disease entities such as dyslipidemia, fatty liver disease, insulin resistance, obesity, type 2 diabetes, gallstone disease and BA-induced diarrhea. The studies presented in this thesis focus on exploring how changes in the fluxes of BAs in the EHC may influence the synthesis and turnover of BAs and cholesterol, the metabolic signaling by endocrine fibroblast growth factors (FGFs) 19 and 21, and the modulation of lipid and carbohydrate metabolism. LIST OF SCIENTIFIC PAPERS I. Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism.
Higher circulating bile acid concentrations in obese patients with type 2 diabetes
Annals of Clinical Biochemistry
BACKGROUND: Bile acids (BAs) play an important role in releasing incretin hormones via the enteroendocrine L-cell surface TGR5 receptors. The aim of this study was to investigate the difference in BA concentration at baseline and in response to a meal stimulus between type 2 diabetes mellitus (T2DM) and a matched normoglycaemic group. MATERIALS AND METHODS: A cross-sectional study of 12 patients with known T2DM and 12 matched normoglycaemic controls compared BA fractions after an overnight fast and following a standard meal. RESULTS: The T2DM group had higher baseline glucose (P < 0.001), but baseline total BA, total glycine conjugated BAs (GCBA) and total taurine conjugated BA (TCBA) were similar between both groups. The T2DM group compared to the normoglycaemic group had a higher post-prandial peak change in total BAs 4.28 (3.51-5.38) µmol/L vs. 0.88 (0.60-1.57) µmol/L (P < 0.001) and peak total GCBA 2.77 (1.07-4.19) µmol/L vs. 0.94 (0.34-1.15) µmol/L (P < 0.0001), but si...
Metabolism: clinical and experimental, 2019
BACKGROUND AND AIMS Placement of the duodenal-jejunal bypass liner (DJBL) 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. METHODS 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. RESULTS Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile acid species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandi...