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

Roesch SL, Styer AM, Wood GC, Kosak Z, Seiler J, Benotti P, Petrick AT, Gabrielsen J, Strodel WE, Gerhard GS, Still CD, Argyropoulos G - PLoS ONE (2015)

Bottom Line: We found that T2D patients had lower FGF19 and higher FGF21 serum levels.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.These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.

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.

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Comparison of hepatic gene expression between non-diabetic (No-T2D) and diabetic (T2D) patients.Gene expression levels (mRNA determined by real time qPCR) for genes modulating the bile acids-FGF19-FGF21 pathway in the liver were compared between non diabetic and diabetic patients. mRNA levels of FGF21 (A), CYP7A1 (C), and β-Klotho (E) were significantly higher in diabetic patients. There were no significant differences between diabetic and non-diabetic patients for HNF4α (B), SHP (D), GS (F), FGFR4 (G), and FXR (H). Statistical analysis was performed by using the Student’s T-test (*: P-value < 0.05). NS: not statistically significant.
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pone.0116928.g002: Comparison of hepatic gene expression between non-diabetic (No-T2D) and diabetic (T2D) patients.Gene expression levels (mRNA determined by real time qPCR) for genes modulating the bile acids-FGF19-FGF21 pathway in the liver were compared between non diabetic and diabetic patients. mRNA levels of FGF21 (A), CYP7A1 (C), and β-Klotho (E) were significantly higher in diabetic patients. There were no significant differences between diabetic and non-diabetic patients for HNF4α (B), SHP (D), GS (F), FGFR4 (G), and FXR (H). Statistical analysis was performed by using the Student’s T-test (*: P-value < 0.05). NS: not statistically significant.

Mentions: To test further the hypothesis that hepatic gene expression in the FGF19-FGF21 axis is dysregulated in diabetes, we compared gene expression levels (mRNA determined by real time qPCR) between T2D and No-T2D patients (Table A in S1 File). We found that mRNA levels of FGF21 (Fig. 2A), CYP7A1 (Fig. 2C), and β-Klotho (Fig. 2E) were significantly higher in diabetic patients. There were no significant differences between diabetic and non-diabetic patients for HNF4α (Fig. 2B), SHP (Fig. 2D), glycogen synthase (GS) (Fig. 2F), FGFR4 (Fig. 2G), and FXR (Fig. 2H).


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

Roesch SL, Styer AM, Wood GC, Kosak Z, Seiler J, Benotti P, Petrick AT, Gabrielsen J, Strodel WE, Gerhard GS, Still CD, Argyropoulos G - PLoS ONE (2015)

Comparison of hepatic gene expression between non-diabetic (No-T2D) and diabetic (T2D) patients.Gene expression levels (mRNA determined by real time qPCR) for genes modulating the bile acids-FGF19-FGF21 pathway in the liver were compared between non diabetic and diabetic patients. mRNA levels of FGF21 (A), CYP7A1 (C), and β-Klotho (E) were significantly higher in diabetic patients. There were no significant differences between diabetic and non-diabetic patients for HNF4α (B), SHP (D), GS (F), FGFR4 (G), and FXR (H). Statistical analysis was performed by using the Student’s T-test (*: P-value < 0.05). NS: not statistically significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321834&req=5

pone.0116928.g002: Comparison of hepatic gene expression between non-diabetic (No-T2D) and diabetic (T2D) patients.Gene expression levels (mRNA determined by real time qPCR) for genes modulating the bile acids-FGF19-FGF21 pathway in the liver were compared between non diabetic and diabetic patients. mRNA levels of FGF21 (A), CYP7A1 (C), and β-Klotho (E) were significantly higher in diabetic patients. There were no significant differences between diabetic and non-diabetic patients for HNF4α (B), SHP (D), GS (F), FGFR4 (G), and FXR (H). Statistical analysis was performed by using the Student’s T-test (*: P-value < 0.05). NS: not statistically significant.
Mentions: To test further the hypothesis that hepatic gene expression in the FGF19-FGF21 axis is dysregulated in diabetes, we compared gene expression levels (mRNA determined by real time qPCR) between T2D and No-T2D patients (Table A in S1 File). We found that mRNA levels of FGF21 (Fig. 2A), CYP7A1 (Fig. 2C), and β-Klotho (Fig. 2E) were significantly higher in diabetic patients. There were no significant differences between diabetic and non-diabetic patients for HNF4α (Fig. 2B), SHP (Fig. 2D), glycogen synthase (GS) (Fig. 2F), FGFR4 (Fig. 2G), and FXR (Fig. 2H).

Bottom Line: We found that T2D patients had lower FGF19 and higher FGF21 serum levels.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.These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Obesity, Geisinger Health System, Danville, PA, United States of America.

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.

Show MeSH
Related in: MedlinePlus