**1. Introduction**

Diabetes mellitus (DM) is a group of metabolic disorders that are characterized by hyperglycemia [1]. Hyperglycemia is caused by the combined action of insulin deficiency and/or insulin resistance in diabetic patients [2]. Long-term hyperglycemia is associated with microvascular complications and leads to cardiovascular disease, diabetic nephropathy, and other severe complications, which are the major causes of death in diabetic patients [3]. In the early stages of DM, the effective control and strict managemen<sup>t</sup> of postprandial blood glucose levels are crucial for alleviating DM. The current effective ways to reduce

postprandial blood glucose level are as follows: (I) inhibit the activities of digestive enzymes, such as glucosidases and α-amylase, which can produce glucose from starch and other carbohydrates [4]; (II) promote the secretion of insulin, such as by inhibiting dipeptidyl peptidase 4 (DPP-4) and elevating glucagon-like peptide 1 (GLP-1) activities [5,6]; (III) reduce glucose reabsorption in the kidney by inhibiting Na+/glucose cotransporter 2 (SGLT2) activity [7]; (IV) suppress the glucose absorption into the bloodstream via the small intestinal by inhibiting the function of Na+/glucose cotransporter 1 (SGLT1) [8].

Although there are several oral hypoglycemic agents that can reduce the blood glucose level in DM, these agents are mainly chemically synthetic, costly, and can cause severe adverse side-e ffects (e.g., serious hypoglycemia and kidney damage) [9,10]. Thus, the discovery of e ffective, safer, and a ffordable drugs for DM patients has attracted significant research attention. Research suggests that certain natural herbal products can exert hypoglycemic e ffects and are safer and easier to obtain than other synthetic chemicals [11]. Convincing evidence suggests that bioactive compounds (e.g., proteins, polyphenols, tannins, and phenolic acids) can directly a ffect intestinal glucose uptake by competitive inhibition of the glucose transporter SGLT1 [12–14]. In the small intestine, SGLT1 is expressed in the apical cell membrane constituting the brush border [15], which is of primary importance for glucose absorption from the lumen to the epithelial cells of the intestine [16,17]. Ina et al. demonstrate that rice albumin could alleviate postprandial hyperglycemia by inhibiting SGLT1 function via in vivo and in vitro assays [18]. Müller et al. confirmed that the extracts of guava leaves and fruits, which contain polysaccharides, polyphenols, and other bioactive substances, can e ffectively reduce intestinal glucose transport by inhibiting the function of SGLT1 in vivo [19].

An increasing number of studies have demonstrated that non-toxic biological macromolecules, especially polysaccharides, possess prominent e fficacies for treating DM and other metabolic diseases [20–24]. In addition, Tang et al. reported that water-soluble polysaccharides from *Lycium barbarum* have a conspicuously inhibitory e ffect on glucose uptake in vitro [25], which may have been due to the inhibitory e ffect on the intestinal glucose transporter SGLT1. Fucoidan is a family of sulfated fucan predominantly existing in the cell walls of brown algae and several marine invertebrates (e.g., sea cucumbers and sea urchins) [26]. These water-soluble heteropolysaccharides are composed of various percentages of L-fucose and sulfate ester groups. Fucoidans from natural sources are usually composed of two types of chain structures, type I, with α (1 →3)-linked fucose, and type II, made up of alternating α (1 →3)- and α (1 →4)-linked fucose molecules [27]. In recent years, fucoidans isolated from di fferent sources have been extensively studied due to their diverse biological activities, including anticoagulant, anti-inflammatory, antivirus, antitumor, lipid-lowering, antidiabetic nephropathy, antimetabolic syndrome, and prebiotic e ffects [26,28]. Due to their promising therapeutic e ffects and availability from various kinds of cheap brown algae, an increasing number of studies have been devoted to the development and utilization of fucoidans in the fields of drugs and functional foods. Although the application prospects of fucoidans are promising, it is worth noting that the bioactivities of fucoidans are probably highly dependent on their structural properties (such as type of glycosidic linkages, molecular weight (MW), and branches) [26,29] and little attention has been devoted to determining the e ffects of fucoidans with various structure on attenuating postprandial hyperglycemia and its underlying mechanism.

We reported that fucoidan from *Fucus vesiculosus* (FvF) with a type II structure can significantly inhibit α-glucosidase and the glucose transport activities in the small intestine, and regulate glucose consumption and lipid metabolism via reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK) and protein kinase B (Akt) signaling pathways, thus improving postprandial hyperglycemia in diabetic mice [30,31]. To explore the relationship between the inhibitory e ffect of glucose absorption and fucoidan, it is necessary to rule out the other factors related to antihyperglycemia. Therefore, we prepared three fucoidans as follows: fucoidan from *Ascophyllum nodosum* (AnF) with a type II structure [32] and mild inhibition of α-glucosidase [31], and fucoidans from *Laminaria japonica* (LjF) and *Kjellmaniella crassifolia* (KcF) with type I structures [33,34]. Additionally, we investigated the pharmacological e ffects of the above fucoidans on alleviating postprandial hyperglycemia using in vitro (Caco-2 monolayer model), semi-in vivo (everted gu<sup>t</sup> sac model), and in vivo (oral glucose tolerance test (OGTT) in Kunming and leptin receptor-deficient (db/db) mice) assays. Based on previous studies [25,30], we also focused on evaluating the binding affinity of various fucoidans to SGLT1 via surface plasmon resonance (SPR). Taken together, as we have previously reported, FvF with a type II structure could alleviate the postprandial hyperglycemia. Thus, this study aimed to evaluate the effects of fucoidans with different types of fucosidic linkages on alleviating postprandial hyperglycemia and preliminarily elucidated the underlying mechanism.
