title: 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: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: Stephen L
authors: SL
authors: Roesch
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: Amanda M
authors: AM
authors: Styer
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: G Craig
authors: GC
authors: Wood
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: Zachary
authors: Z
authors: Kosak
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: Jamie
authors: J
authors: Seiler
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: Peter
authors: P
authors: Benotti
authors: Department of Surgery, Geisinger Health System, Danville, PA, United States of America.
authors: Anthony T
authors: AT
authors: Petrick
authors: Department of Surgery, Geisinger Health System, Danville, PA, United States of America.
authors: Jon
authors: J
authors: Gabrielsen
authors: Department of Surgery, Geisinger Health System, Danville, PA, United States of America.
authors: William E
authors: WE
authors: Strodel
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America; Department of Biochemistry and Molecular Biology and Department of Pathology and Laboratory Medicine, Pennsylvania State University, Hershey, PA, United States of America.
authors: Glenn S
authors: GS
authors: Gerhard
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: Christopher D
authors: CD
authors: Still
authors: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.
authors: George
authors: G
authors: Argyropoulos
mesh_terms: D000328:Adult; D050110:Bariatric Surgery; D016022:Case-Control Studies; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006006:Glycogen Synthase / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009767:Obesity, Morbid / Q000150:complications / Q000601:surgery; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
chemical_list: C117476:FGF19 protein, human; C096916:FXR1 protein, human; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C538995:KLB protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C414620:fibroblast growth factor 21; C099713:nuclear receptor subfamily 0, group B, member 2; D005346:Fibroblast Growth Factors; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; D006006:Glycogen Synthase; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins