TY - JOUR
T1 - Metformin Improves the Prerequisites for FGF21 Signaling in Patients with Type 2 Diabetes
AU - Nissen Pedersen, Anne Kathrine
AU - Gormsen, Lars Christian
AU - Nielsen, Søren
AU - Jessen, Niels
AU - Bjerre, Mette
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].
PY - 2024/2
Y1 - 2024/2
N2 - CONTEXT: Fibroblast growth factor (FGF) 21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21 signaling requires binding to surface receptors, FGFR1c and β-klotho. FGF21 resistance is observed in metabolic diseases and FGF21 signaling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown.OBJECTIVE: To investigate how 12 weeks of treatment with metformin affects the FGF21 signaling pathway in patients with type 2 diabetes (T2D).METHODS: Randomized, placebo-controlled study in patients with T2D (n = 24) receiving either metformin (1000 mg twice daily) or placebo. A control group of body mass index- and age-matched healthy individuals (n = 12) received a similar dose of metformin. Blood samples and muscle and fat biopsies were collected at study entry and after 12 weeks.METHODS: Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21 signaling pathway.RESULTS: Circulating FAP activity decreased after metformin treatment compared with placebo (P = .006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of β-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue.CONCLUSION: Our findings suggest that metformin suppresses the circulating FAP activity and upregulates the expression of FGFR1c and β-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity.
AB - CONTEXT: Fibroblast growth factor (FGF) 21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21 signaling requires binding to surface receptors, FGFR1c and β-klotho. FGF21 resistance is observed in metabolic diseases and FGF21 signaling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown.OBJECTIVE: To investigate how 12 weeks of treatment with metformin affects the FGF21 signaling pathway in patients with type 2 diabetes (T2D).METHODS: Randomized, placebo-controlled study in patients with T2D (n = 24) receiving either metformin (1000 mg twice daily) or placebo. A control group of body mass index- and age-matched healthy individuals (n = 12) received a similar dose of metformin. Blood samples and muscle and fat biopsies were collected at study entry and after 12 weeks.METHODS: Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21 signaling pathway.RESULTS: Circulating FAP activity decreased after metformin treatment compared with placebo (P = .006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of β-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue.CONCLUSION: Our findings suggest that metformin suppresses the circulating FAP activity and upregulates the expression of FGFR1c and β-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity.
KW - Diabetes Mellitus, Type 2/drug therapy
KW - Fibroblast Growth Factors
KW - Humans
KW - Membrane Proteins/genetics
KW - Metformin/pharmacology
KW - RNA, Messenger
KW - Signal Transduction
KW - metformin
KW - fibroblast activation protein (FAP)
KW - type 2 diabetes (T2D)
KW - fibroblast growth factor 21 (FGF21)
UR - http://www.scopus.com/inward/record.url?scp=85184212027&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgad583
DO - 10.1210/clinem/dgad583
M3 - Journal article
C2 - 37776319
SN - 0021-972X
VL - 109
SP - e552-e561
JO - The Journal of clinical endocrinology and metabolism
JF - The Journal of clinical endocrinology and metabolism
IS - 2
ER -