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Cited by 123Fibroblast Growth Factor ResearchLiver physiology and pathologyGrowth Hormone and Insulin-like Growth Factors

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Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans

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Hansen, Jakob Schiøler, Clemmesen, Jens Otto, Secher, Niels Henry, Hoene, Miriam, Drescher, Andrea, Weigert, Cora, Pedersen, Bente Klarlund, Plomgaard, Peter·2015·Molecular Metabolism
DOI 10.1016/j.molmet.2015.06.001PMC PMC4529499
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Abstract

BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF-21) is a liver-derived metabolic regulator induced by energy deprivation. However, its regulation in humans is incompletely understood. We addressed the origin and regulation of FGF-21 secretion in humans. METHODS: By determination of arterial-to-venous differences over the liver and the leg during exercise, we evaluated the organ-specific secretion of FGF-21 in humans. By four different infusion models manipulating circulating glucagon and insulin, we addressed the interaction of these hormones on FGF-21 secretion in humans. RESULTS: We demonstrate that the splanchnic circulation secretes FGF-21 at rest and that it is rapidly enhanced during exercise. In contrast, the leg does not contribute to the systemic levels of FGF-21. To unravel the mechanisms underlying the regulation of exercise-induced hepatic release of FGF-21, we manipulated circulating glucagon and insulin. These studies demonstrated that in humans glucagon stimulates splanchnic FGF-21 secretion whereas insulin has an inhibitory effect. CONCLUSIONS: Collectively, our data reveal that 1) in humans, the splanchnic bed contributes to the systemic FGF-21 levels during rest and exercise; 2) under normo-physiological conditions FGF-21 is not released from the leg; 3) a dynamic interaction of glucagon-to-insulin ratio regulates FGF-21 secretion in humans.

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Crossref · 10.1016/j.molmet.2015.06.001

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Figure 1 Splanchnic plasma FGF-21 kinetics in young men (n = 10) during exercise. At baseline, there is a significant arterial-venous difference (A) and net production of FGF-21 (B). During exercise, plasma FGF-21 increases (C) and the arterial-venous difference across the splanchnic circulation (D) and net hepatic production is significantly increased (E). * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. † significant by Student's t-test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM. In (A) and (B) individual data are presented.
Figure 1 Splanchnic plasma FGF-21 kinetics in young men (n = 10) during exercise. At baseline, there is a significant arterial-venous difference (A) and net production of FGF-21 (B). During exercise, plasma FGF-21 increases (C) and the arterial-venous difference across the splanchnic circulation (D) and net hepatic production is significantly increased (E). * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. † significant by Student's t-test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM. In (A) and (B) individual data are presented.CC BY-NC-ND · PubMed Central
Figure 2 Leg plasma FGF-21 kinetics in young men (n = 9) during one-legged exercise. At baseline, there is no arterial-venous difference (A) or net production/uptake of FGF-21 (B) over neither leg. During exercise, plasma FGF-21 increases (C) and the arterial-venous differences across the exercising leg (D) increases. Net muscle uptake is not significantly increased in the exercising leg (E). * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. † significant by Student's t-test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM. In (A) and (B) individual data are presented.
Figure 2 Leg plasma FGF-21 kinetics in young men (n = 9) during one-legged exercise. At baseline, there is no arterial-venous difference (A) or net production/uptake of FGF-21 (B) over neither leg. During exercise, plasma FGF-21 increases (C) and the arterial-venous differences across the exercising leg (D) increases. Net muscle uptake is not significantly increased in the exercising leg (E). * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. † significant by Student's t-test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM. In (A) and (B) individual data are presented.CC BY-NC-ND · PubMed Central
Figure 3 Glucagon and insulin regulation during exercise in young men (n = 10). Glucagon and glucagon/insulin ratio increases in the hepatic vein (A, C, blue line) and artery (A, C, red line) with exercise. Insulin decreases in the hepatic vein (B, blue line) and artery (B, red line) with exercise. Peak glucagon (D) and peak glucagon/insulin ratio (F) correlate with peak FGF-21. No significant correlation between nadir insulin and peak FGF-21 (E). * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM.
Figure 3 Glucagon and insulin regulation during exercise in young men (n = 10). Glucagon and glucagon/insulin ratio increases in the hepatic vein (A, C, blue line) and artery (A, C, red line) with exercise. Insulin decreases in the hepatic vein (B, blue line) and artery (B, red line) with exercise. Peak glucagon (D) and peak glucagon/insulin ratio (F) correlate with peak FGF-21. No significant correlation between nadir insulin and peak FGF-21 (E). * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM.CC BY-NC-ND · PubMed Central
Figure 4 Hormone and glucose changes during glucagon or/and somatostatin infusion in young men (n = 10). Glucagon infusion increases glucagon, insulin and blood glucose (5A). Somatostatin-glucagon infusion increases glucagon, blood glucose and decreases insulin (5B). Somatostatin infusion decreases glucagon and insulin and induces moderate excursions in blood glucose (5C). Saline infusion induces small changes in glucagon, insulin and blood glucose (5D). Gray bar indicates glucagon infusion. Dashed gray bar indicates somatostatin infusion. White bar indicates saline infusion. * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM.
Figure 4 Hormone and glucose changes during glucagon or/and somatostatin infusion in young men (n = 10). Glucagon infusion increases glucagon, insulin and blood glucose (5A). Somatostatin-glucagon infusion increases glucagon, blood glucose and decreases insulin (5B). Somatostatin infusion decreases glucagon and insulin and induces moderate excursions in blood glucose (5C). Saline infusion induces small changes in glucagon, insulin and blood glucose (5D). Gray bar indicates glucagon infusion. Dashed gray bar indicates somatostatin infusion. White bar indicates saline infusion. * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM.CC BY-NC-ND · PubMed Central
Figure 5 Plasma FGF-21 is regulated by changes in glucagon and insulin in young men (n = 10). Glucagon infusion decreases FGF-21 (A), whereas somatostatin-glucagon infusion (B) and somatostatin (C) increases plasma FGF-21. Saline infusion does not change plasma FGF-21 (D). Gray bar indicates glucagon infusion. Dashed gray bar indicates somatostatin infusion. White bar indicates saline infusion. * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM.
Figure 5 Plasma FGF-21 is regulated by changes in glucagon and insulin in young men (n = 10). Glucagon infusion decreases FGF-21 (A), whereas somatostatin-glucagon infusion (B) and somatostatin (C) increases plasma FGF-21. Saline infusion does not change plasma FGF-21 (D). Gray bar indicates glucagon infusion. Dashed gray bar indicates somatostatin infusion. White bar indicates saline infusion. * significant by one-way ANOVA. # significant by one-way ANOVA and Dunnett's post hoc test. p < 0.05 was considered statistically significant. Data are presented as mean ± SEM.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Hansen, J. S., Clemmesen, J. O., Secher, N. H., Hoene, M., Drescher, A., Weigert, C., Pedersen, B. K., & Plomgaard, P.
Affiliations
  • University of Copenhagen (DK)
  • Rigshospitalet (DK)
  • University of Tübingen (DE)
  • Helmholtz Munich (DE)
Corresponding author
Plomgaard, Peter
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2015-08
Volume
4
Issue
8
Pages
551-560
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2015.06.001
PMC
PMC4529499
OpenAlex
W1906775291
Cited by
123
References
58
Citations by year
2026: 8 · 2025: 6 · 2024: 7 · 2023: 15 · 2022: 8 · 2021: 13 · 2020: 14 · 2019: 15 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 4
FWCI
5.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Site cant be reached (submittedVersion, cc-by-nc-nd)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
Funders
  • Danmarks Grundforskningsfond (DNRF55)
  • Bundesministerium für Bildung und Forschung
  • Region Hovedstaden
  • Strategiske Forskningsråd (09-067009, 09-075724)
  • Center for Muskelforskning
  • Deutsche Forschungsgemeinschaft (GRK 1302/2)
  • Leibniz-Gemeinschaft (SAW-FBN-2013-3)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
FGF21, splanchnic circulation, physical activity, insulin, glucagon, legs, energy deprivation, metabolic regulation

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