The Association Of Serum Fibroblast Growth Factor 19 With Glucose Metabolism And Bile Acids

Fibroblast growth factor 19(FGF19), an ileum-derived hormone, can function as an endocrine hormone. Animal-based studies have suggested that FGF19 can play key roles in glucose homeostasis through insulin-independent pathways. Besides, it is also a regulator with important effects on bile acid biosynthesis. However, whether FGF19 is related to glucose metabolism and bile acids in humans remain unclear. This study investigated the relationship between FGF19 levels and glucose metabolism as well as bile acids by two parts.1. Association between serum fibroblast growth factor 19 and glucose metabolismOBJECTIVE This study investigated the kinetics of serum FGF19 after glucose challenge in differenglucometabolic status, and analyzed the association of serum FGF19 with glucose, insulinsecretion and sensitivity, as well as insulin independent glucose disposal(termed glucoseffectiveness, GE) in humans.RESEARCH DESIGN AND METHODS Serum FGF19 levels during oral glucose tolerance test(OGTT) were determined among 257 subjects including normal glucose tolerance(NGT), pre-diabetes and type 2 diabetes. The dynamic change of FGF19 and associations of FGF19 with glucose metabolism were investigated. Insulin secretion, insulin sensitivity were measured by hyperglycemic and hyperinsulinemic-euglycemic clamp in a subgroup of 14 NGT subjects. GE was measured by frequently sampled intravenous glucose tolerance test and Minimal Model in another subgroup of 18 NGT subjects. The association of FGF19 with GE was studied.RESULTS The kinetics of FGF19 during OGTT showed a peak at 120 min followed by a decline at 180 min in all subjects, and significant differences in FGF19 levels were found at 0, 30 and 60 min but not 120 min among them.The area under the curve of serum FGF19 from 0-60 min decreased from the NGT to pre-diabetes and diabetes and was negatively associated with 0-60 min AUC of plasma glucose. Interestingly, we found that serum FGF19 concentrations were positively associated with GE measured by FSIGTT but not insulin secretion and insulin sensitivity evaluated by glucose clamp. However, the association between FGF19 and GE was no longer significant after free fatty acid adjustment.CONCLUSIONS Our results showed the dynamic change of serum FGF19 after glucose challenge in different glucose tolerance status and demonstrated a positive correlation between serum FGF19 and insulin-independent glucose disposal in humans.2. Association between serum fibroblast growth factor 19 and bile acids OBJECTIVETo establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method for the analysis of nine kinds of bile acids in trace amount of serum. The method was applied to determine serum levels of bile acids in subjects with different glucose tolerance state after OGTT. The associations of bile acids with FGF19 were assessed.RESEARCH DESIGN AND METHODS Protein precipitation with acetonitrile was used for sample preparation. The analytes were eluted using methanol-water buffer(containing acetic acid) as mobile phase on a Waters Atlantis T3 column. And then mass spectrometric analysis of bile acids was performed by multiple reaction monitoring(MRM) mode. Serum bile acids levels during OGTT were determined among 12 healthy controls and 36 type 2 diabetes patients. The dynamic change of bile acids after OGTT and associations of bile acids with FGF19 were investigated.RESULTS The analytical linear range was 0.5-50 ?g/ml for bile acids. The detection limits was 0.01 ?g/ml. The recoveries were 80%-95%. The intra- and inter-assay variations were all less than 15%. In healthy subjects, free bile acids and glycine conjugated bile acids are the bile acid species with the highest serum levels. Compared with the normal, GCDCA [7.24(3.34, 10.83) vs 13.71(10.39, 27.12) ?g/ml, P<0.05]?GCA [0.81(0.36, 1.88) vs 2.38(1.50, 3.45) ?g/ml, P < 0.05] concentrations in patients with type 2 diabetes were significantly higher, and CDCA [6.89(3.17, 8.37) vs 4.05(1.99, 6.26) ?g/ml, P < 0.05]?CA [1.39(1.15, 2.63) vs 0.82(0.39, 3.16) ?g/ml, P < 0.05] concentrations were significantly lower. However, no significant difference in fasting serum GDCA and DCA levels were observed between the normal controls and diabetic subjects. After OGTT, serum bile acids levels showed a peak at 30 min with a decline in the following 150 min in most subjects. Fasting CDCA, CA and total free bile acids were positively associated with FGF19.CONCLUSIONS The UHPLC-MS/MS method can efficiently differentiate and quantify nine bile acids. The concentrations of serum bile acids were different in diabetic and normal healthy subjects, serum free bile acids were positively associated with serum FGF19.