Fibroblast growth factor 19(FGF19) functions as a hormone by affecting glucose metabolism. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. A functional cellular FGF19 receptor consists of FGF receptor(FGFR) and glycosaminoglycan complexed with either α Klotho or β Klotho. Interestingly, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar levels to a healthy range. FGF1 binds heparin with high affinity whereas FGF19 does not, indicating that polysaccharides other than heparin might enhance FGF19/FGFR signaling. Using a FGFs/FGFR1 c signaling-dependent Ba F3 cell proliferation assay, we discovered that polyguluronate sulfate(PGS) and its oligosaccharides, PGS12 and PGS25, but not polyguluronate(PG), a natural marine polysaccharide, enhanced FGF19/FGFR1 c signaling better than that of heparin based on ~3H-thymidine incorporation. Interestingly, PGS6, PGS8, PGS10, PGS12, PGS25, and PGS, but not PG, had comparable FGF1/FGFR1 c signal-stimulating activity compared to that of heparin. These results indicated that PGS and its oligosaccharides were excellent FGF1/FGFR1 c and FGF19/FGFR1 c signaling enhancers at cellular level. Since the inexpensive PGS and PGS oligosaccharides can be absorbed through oral route, these seaweed-derived compounds merit further investigation as novel agents for the treatment of type 2 diabetes through enhancing FGF1/FGFR1 c and FGF19/FGFR1 c signaling in future. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. A functional cellular FGF19 receptor consists of FGF receptor (FGFR) and glycosaminoglycan complexed with either α Klotho or β Klotho. Interestingly, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar levels to a healthy range. FGF1 binds heparin with high affinity while FGF19 does not, indicating that polysaccharides other than heparin might enhance Using a FGFs / FGFR1 c signaling-dependent Ba F3 cell proliferation assay, we discovered that polyguluronate sulfate (PGS) and its oligosaccharides, PGS12 and PGS25, but not polyguluronate (PG), a natural marine polysaccharide, enhanced FGF19 Interestingly, PGS6, PGS8, PGS10, PGS12, PGS25, and PGS, b ut not PG, had comparable FGF1 / FGFR1 c signal-stimulating activity compared to that of heparin. These results indicate that PGS and its oligosaccharides were excellent for FGF1 / FGFR1 c and FGF19 / FGFR1 c signaling enhancers at cellular levels. Since the inexpensive PG and PGS oligosaccharides can be absorbed through oral route, these seaweed-derived compounds merit further investigation as novel agents for the treatment of type 2 diabetes through enhancing FGF1 / FGFR1 c and FGF19 / FGFR1 c signaling in future.