Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes.

Abstract

Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have been implicated, independently, in type 2 diabetes (T2D) but it is not known if their circulating levels correlate with each other or whether the associated hepatic signaling mechanisms that play a role in glucose metabolism are dysregulated in diabetes. We used a cross-sectional, case/control, experimental design involving Class III obese patients undergoing Roux-en-Y bariatric surgery (RYGB), and measured FGF19 and FGF21 serum levels and hepatic gene expression (mRNA) in perioperative liver wedge biopsies. We found that T2D patients had lower FGF19 and higher FGF21 serum levels. The latter was corroborated transcriptionally, whereby, FGF21, as well as CYP7A1, β-Klotho, FGFR4, HNF4α, and glycogen synthase, but not of SHP or FXR mRNA levels in liver biopsies were higher in T2D patients that did not remit diabetes after RYGB surgery, compared to T2D patients that remitted diabetes after RYGB surgery or did not have diabetes. In a Phenome-wide association analysis using 205 clinical variables, higher FGF21 serum levels were associated with higher glucose levels and various cardiometabolic disease phenotypes. When serum levels of FGF19 were < 200 mg/mL and FGF21 > 500 mg/mL, 91% of patients had diabetes. These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.

• Authors: Stephen L Roesch, Amanda M Styer, G Craig Wood, Zachary Kosak, Jamie Seiler, Peter Benotti, Anthony T Petrick, Jon Gabrielsen, William E Strodel, Glenn S Gerhard, Christopher D Still, George Argyropoulos
• Journal: PloS one (PLoS One) Vol. 10 Issue 2 Pg. e0116928 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25664662 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• FGF19 protein, human
• FXR1 protein, human
• HNF4A protein, human
• Hepatocyte Nuclear Factor 4
• KLB protein, human
• Membrane Proteins
• RNA, Messenger
• RNA-Binding Proteins
• Receptors, Cytoplasmic and Nuclear
• fibroblast growth factor 21
• nuclear receptor subfamily 0, group B, member 2
• Fibroblast Growth Factors
• CYP7A1 protein, human
• Cholesterol 7-alpha-Hydroxylase
• Glycogen Synthase
• FGFR4 protein, human
• Receptor, Fibroblast Growth Factor, Type 4
• Klotho Proteins

Topics

• Adult
• Bariatric Surgery
• Case-Control Studies
• Cholesterol 7-alpha-Hydroxylase (genetics)
• Cross-Sectional Studies
• Diabetes Mellitus, Type 2 (blood, complications, genetics, metabolism)
• Female
• Fibroblast Growth Factors (blood, genetics, metabolism)
• Gene Expression
• Glycogen Synthase (genetics)
• Hepatocyte Nuclear Factor 4 (genetics)
• Humans
• Klotho Proteins
• Liver (metabolism)
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Obesity, Morbid (complications, surgery)
• RNA, Messenger (metabolism)
• RNA-Binding Proteins (genetics)
• Receptor, Fibroblast Growth Factor, Type 4 (genetics)
• Receptors, Cytoplasmic and Nuclear (genetics)