Metformin Improves the Prerequisites for FGF21 Signaling in Patients With Type 2 Diabetes

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 beta-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 beta-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 beta-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity.