**5. Conclusions**

For the first time, in vitro (Caco-2 monolayer and SPR assay), semi-in vivo (everted gu<sup>t</sup> sac), and in vivo (Kunming mice and db/db mice) models were used to evaluate the effects of various fucoidans on suppressing hypoglycemia, especially postprandial hyperglycemia. Our data indicated the potential effects of AnF on the regulation of blood glucose levels by direct inhibition of glucose transport via SGLT1, therefore, remarkably reducing glucose transport and relieving postprandial hyperglycemia. In conclusion, fucoidans with type II structures (such as FvF and AnF) have the potential to be a promising candidate compound in the treatment of postprandial hyperglycemia via its direct binding to SGLT1 and inhibition of its glucose transport activity, while KcF and LjF with type I structures cannot. Our study demonstrates that the type of glycosidic linkages of fucoidans may play a more crucial role in their hypoglycemic effects via inhibiting SGLT1 activity. However, further research is still necessary to clarify the exact structure–activity relationship of fucoidans as SGLT1 inhibitors and the precise molecular binding mode between fucoidans and SGLT1 protein.

**Author Contributions:** X.S. performed the major experiments. X.W. performed the SPR experiment and wrote the manuscript. X.W., H.J., and C.C. revised the manuscript. X.W. and H.J. analyzed experimental data. G.Y. and J.H. conceived the project and designed the experiments. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the National Natural Science Foundation of China (31670811, 81991522, 81402982), National Major Science and Technology Project of China (2018ZX09735-004), NSFC-Shandong Joint Fund for Marine Science Research Centers (U1606403), Shandong Provincial Major Science and Technology Innovation Project (2018SDKJ0404), and Natural Science Foundation of Shandong Province (ZR2017BC007).

**Acknowledgments:** The authors are grateful to all members of the laboratory for their continuous technical advice and helpful discussion.

**Conflicts of Interest:** The authors declare no competing financial interest.
