Rather than a traditional growth factor, fibroblast growth factor (FGF)-21 is considered to be a metabolic hormone. In the current study, we investigated serum FGF-21 levels in the self-contained population of Sorbs. Serum FGF-21 concentrations were quantified by ELISA and correlated with insulin-like growth factor (IGF)-1, as well as metabolic, renal, hepatic, inflammatory, and cardiovascular parameters in 913 Sorbs from Germany. Moreover, human IGF-1 protein secretion was investigated in FGF-21-stimulated HepG2 cells. Median FGF-21 serum concentrations were 2.1-fold higher in subjects with type 2 diabetes mellitus (141.8 ng/l) as compared to controls (66.7 ng/l). Furthermore, non-diabetic subjects with FGF-21 levels below the detection limit of the ELISA showed a more beneficial metabolic profile as compared to subjects with measurable FGF-21. Moreover, FGF-21 was significantly lower in female as compared to male subjects after adjustment for age and BMI. In multiple regression analyses, circulating FGF-21 concentrations remained independently and positively associated with gender, systolic blood pressure, triglycerides, and ? glutamyl transferase whereas a negative association was observed with IFG-1 in non-diabetic subjects. Notably, FGF-21 significantly inhibited IGF-1 secretion into HepG2 cell culture supernatants in preliminary in vitro experiments. FGF-21 serum concentrations are associated with facets of the metabolic syndrome, hepatocellular function, as well as growth hormone status.