Combined with the upregulation of IR and GLUT4 mRNA expression, the increased production of phosphorylated AMPK by oligomannuronate and its chromium complexes enhanced the GLUT4 expression to improve the glucose uptake. Further studies need to be carried out to decipher the intracellular targets of oligomannuronate and its chromium complex both in vitro and in vivo. A published report showed that polysaccharides could enter into liver cells by receptor-mediated endocytosis. We found FITC-labeled OM and OM2 could enter into the C2C12 cells within 15 min. The molecular mechanism of OM and OM2 internalization and its association with insulin related signaling pathway will be an interesting future research subject. Moreover, these two oligosaccharides distributed to mitochondria after internalization into C2C12 cells. These results FTY720 cost suggested that the insulin sensitizing effects of marine oligosaccharides might be associated with the functions of mitochondria in skeletal muscle cells. Insulin resistance was reported to be associated with impaired skeletal muscle oxidation capacity and reduced mitochondrial number and function. AMPK increases GLUT4 expression by a PGC-1a-dependent pathway. Here we showed that the oligosaccharides significantly increased the production of PGC-1a, and enhanced the phosphorylation of ACC protein, which suggested that these oligosaccharides could enhance the fatty acid oxidation in skeletal muscle cells. Combined with the result that the oligosaccharides distributed to the mitochondria, we suppose that these oligosaccharides could improve the functions of mitochondria to attenuate the insulin resistance by regulating energy metabolism. Chromium is a cofactor for insulin function that increases insulin binding, the number of insulin receptors, and insulin receptor phosphorylation, resulting in enhanced glucose transport into liver, muscle, and adipose tissue. Furthermore, it was suggested that Chromium, like insulin, affects protein phosphorylation-dephosphorylation reactions. The IR tyrosine kinase, responsible for the phosphorylation, can be activated by Chromium, to increase insulin sensitivity. Moreover, chromium picolinate was reported to activate AMPK signaling pathway in cardiac and skeletal muscle. Here we showed that the oligomannuronate-Chromium complex OM2 had a better effect on increasing insulin sensitivity than the original oligosaccharide OM, which suggested the introduction of Chromium to the oligosaccharide might be able to increase the phosphorylation of AMPK and PI3K in the signaling pathway. However, the insulin sensitizing effect of OM4 was lower than that of OM2 although it had higher content of chromium than OM2, which indicates that the content of chromium is not the major reason for the observed insulin sensitizing effect and the oligomannuronate-Chromium complex OM2 itself has best insulin sensitizing effect.In conclusion, we found that oligomannuronate and its chromium complexes, which were less cytotoxic than metformin, enhanced glucose uptake in C2C12 cells.