In the process of polysaccharide extraction, the selection of an appropriate pretreatment method is crucial. Treatment with ethanol, methanol, acetone and/or chloroform can be employed to remove lipophilic substances. Different extraction methods should be selected according to the physicochemical properties of target polysaccharides. Currently, common methods for polysaccharide extraction from EU include hot water extraction, ultrasonic-assisted extraction, and microwave-assisted extraction. Key parameters such as solid-liquid ratio, temperature, extraction time, extraction medium, ultrasonic power, and microwave power can significantly influence polysaccharide yields.

Crude polysaccharides from EU obtained by conventional extraction contain significant impurities (e.g., pigments, proteins, and inorganic salts), which interfere with structural characterization and bioactivity studies. Thus, sequential degreasing, decolorization, deproteinization, and fractionation are required. Deproteinization methods include sevage method (a commonly used technique for the isolation and purification of polysaccharides, achieving purification by removing protein impurities), trichloroacetic acid (TCA) method (one of the most popular methods for protein removal from samples), and hydrochloric acid (HCI) method (a class of chemical analysis methods using hydrochloric acid as the core reagent, primarily used for sample decomposition or concentration detection). Huang et al. (2014) reported deproteinization efficiencies of 95.76% (HCl), 93.23% (TCA), and 91.48% (Sevag), with polysaccharide retention rates of 30.44%, 40.29%, and 65.49%, respectively. Although HCl achieves the highest protein removal, it causes severe polysaccharide degradation. TCA and Sevag exhibit similar deproteinization efficiency, but Sevag preserves significantly more polysaccharides (65.49% vs. 40.29%), establishing it as the optimal method for EU leaf polysaccharides. Decolorization method primarily involve hydrogen peroxide (H₂O₂) oxidation and activated carbon adsorption. H₂O₂ demonstrates superior decolorization efficacy for EUP compared to activated carbon. Yan et al. (2023) combined Sevag deproteinization with Sephadex G-200 gel chromatography, yielding purified EUP with 89.12% total sugar, 2.03% protein, and 9.45% uronic acid. Yang et al. (2019) optimized activated carbon decolorization for EU bark polysaccharides via orthogonal design: 0.6% carbon dosage, 60 °C, 50 min, pH 5.0, achieving 76.20% decolorization and 62.68% polysaccharide retention. Integrated purification using macroporous resin (e.g., AB-8) simultaneously removes proteins and pigments while minimizing polysaccharide loss4. Zhang (2020) purified EUP under conditions: 0.6 mg/mL sample concentration, pH 6.0, 1.0 mL/min flow rate, elution with 150 mL of 65% ethanol. This increased polysaccharide mass fraction from 10.2% to 35.8% (3.5-fold) and enhanced anti-fatigue activity in animal models. For structural and functional studies, single-step purification is insufficient. To obtain EUP with uniform molecular weight and polarity, sequential chromatography is essential ion-exchange (e.g., DEAE-52 cellulose column with 0.1–0.3 mol/L NaCl gradient) and gel filtration (e.g., Sephadex G-100/G-200). This yields homogeneous polysaccharide components for downstream applications.

Polysaccharide structural analysis is critical as structural diversity directly determines bioactivity (Ai et al., 2023). This encompasses monosaccharide composition, molecular weight, glycosidic bond type, linkage patterns and higher-order conformations (Zhang et al., 2023).

Elevated blood glucose levels constitute a hallmarks of diabetes mellitus, which if unmanaged may precipitate severe complications. Current research confirms that EUP effectively reduce hyperglycemia and ameliorate glucose metabolism disorders. Since α-amylase and α-glucosidase catalyze dietary starch hydrolysis into glucose, suppressing their activity decelerates intestinal glucose absorption and delays glucose transport into the bloodstream, thereby lowering blood glucose levels. Lang et al. (2020) demonstrated that Eucommia ulmoides leaf polysaccharides exhibit dose-dependent inhibition of α-glucosidase activity, a finding extended by Gong et al. who confirmed EUP’s dual inhibitory effects on α-amylase and α-glucosidase. These enzymes catalyze dietary starch hydrolysis into glucose, and their suppression reduces intestinal glucose absorption rates (Gong et al., 2024). Furthermore, EUP modulates key glycolytic enzymes: restores diminished activities of hexokinase (HK) and pyruvate kinase (PK) in insulin-resistant HepG2 cells, and upregulates AMPK/PI3K/AKT pathway genes and enhances glycolysis via HIF-1α-mediated induction of glucose transporters (GLUTs), hexokinase (HK), and phosphofructokinase (PFK). In vivo validation showed significant reductions in fasting blood glucose (FBG) levels (>40% vs. controls) in streptozotocin (STZ, 50 mg/kg)-induced diabetic mice and tetracosactide-induced diabetic models (Su et al., 2016a; Liu et al., 2010). Collectively, EUP exerts anti-diabetic effect through coordinated regulation of glucose-metabolizing enzymes and signaling pathways (Figure 2A).

As a pivotal hormone synthesized by pancreatic β-cells, insulin plays a crucial role in glucose homeostasis regulation. Insufficient insulin secretion or insulin resistance (IR) compromises this regulation, leading to chronic hyperglycemia and metabolic dysregulation (Berbudi et al., 2025). In T1DM, insulin deficiency arises from autoimmune destruction of pancreatic β-cells (Moradi et al., 2025). In T2DM, IR manifests as diminished insulin responsiveness in target tissues (muscle, liver, adipose), disrupting glucose/lipid/protein metabolism (Liu et al., 2025). Modern pharmacological studies have demonstrated that EU leaves polysaccharides preserve pancreatic tissue by restricting the expression of Caspase-3, p38MAPK and TGF-1 (Lang et al., 2020). In T2DM model mice, characteristic pathological changes were observed, including pancreatic islet vacuolation, islet cell atrophy, structural deformation, and nuclear pyknosis. EUP treatment significantly ameliorated these pathological alterations, as evidenced by reduced vacuolization and attenuated cellular atrophy (Xu et al., 2020). Furthermore, while STZ-induced diabetic mice exhibited markedly decreased insulin content, EUP administration significantly elevated insulin levels (p < 0.01) and improved the insulin sensitivity index by 32% (Su et al., 2016a). These findings collectively indicate that EUP exerts protective effects against pancreatic dysfunction by addressing both insulin secretion deficiency and insulin resistance (Figure 2B).

Excessive hyperglycemia and reactive oxygen species (ROS) overproduction induce oxidative stress-mediated cellular damage, a key contributor to late-stage diabetic complications (Tonin et al., 2024; Dworzański et al., 2020). In vitro analyses reveal EUP’s potent radical-scavenging capacity: DPPH radicals, 87.05% clearance; ABTS radicals, 101.17% clearance; Hydroxyl radicals, 62.92% clearance, confirming significant antioxidant activity (Peng et al., 2024). In diabetic models, elevated ROS, hydroxyl radicals, and malondialdehyde (MDA) indicate pathological oxidative stress. EUP administration reduces pro-oxidants (ROS, hydroxyl radicals and MDA), and enhances antioxidant defense like superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) (Xu et al., 2020; Chen et al., 2020; Wang et al., 2016). This dual modulation-suppressing oxidant generation while boosting antioxidant capacity-demonstrates EUP’s efficacy in restoring redox homeostasis (Figure 3A).

The crosstalk between inflammatory mediators and signaling pathways disrupts glucose homeostasis, contributing to diabetes pathogenesis (Su et al., 2020; Yang et al., 2022). The pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) induce cytokine production, creating an inflammatory cascade that amplifies inflammatory signals. Interleukin-8 (IL-8) acts as a chemokine that recruits neutrophils to inflammatory sites, thereby enhancing the inflammatory response. In STZ-induced diabetic mice, we observed a significant inflammatory response characterized by markedly elevated levels of TNF-α, IL-8, and IL-6. Notably, these cytokines activated intracellular inflammatory pathways through the TLR4 signaling pathway. In contrast, mice treated with EUP showed decreased levels of both TLR4 and NF-κB, which subsequently led to reduced levels of TNF-α, IL-8 and IL-6 (Su et al., 2016a). Additionally, EUP administration significantly lowered IL-8, IL-1β and IL-6 levels in db/db mice (Chen et al., 2020). In vitro experiments demonstrated that EUP inhibited high glucose-induced IL-6 and TNF-α production in HK-2 cells. Subsequent studies revealed that these polysaccharides downregulated miR-1207–5p expression, thereby suppressing inflammation (Shen et al., 2023). Besides, EUP was shown to promote expression of the anti-inflammatory cytokine interleukin-10 (IL-10) (Feng et al., 2016). Collectively, these findings demonstrate that EUP exerts potent anti-inflammatory effects by both upregulating IL-10 expression and downregulating pro-inflammatory factors including TNF-α, IL-8, IL-1β, and IL-6 (Figure 3B).

In the early stages of diabetes, IR-induced excessive fat accumulation is frequently accompanied by lipid metabolism disorders, resulting in hyperlipidemia (Xu et al., 2024; Su et al., 2016b). Standard lipid profile analyses typically include measurements of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Both db/db mice and STZ-induced diabetic models exhibited elevated TC, TG, and LDL-C levels along with reduced HDL-C, confirming diabetes-associated lipid metabolism dysregulation. EUP treatment effectively reversed these abnormal lipid profiles by Reducing TC (by 32%), TG (41%), and LDL-C (28%), and Increasing HDL-C levels (1.7-fold) (Su et al., 2016a; Chen et al., 2020). Beyond serum lipid parameters, hepatic lipid droplet accumulation and increased body weight in db/db mice further demonstrated lipid metabolic dysfunction. Notably, EUP administration decreased hepatic lipid content by 45%, reduced body weight gain by 23% (Chen et al., 2020). These findings collectively demonstrate that EUP significantly improves lipid metabolism disorders and effectively regulates blood lipid parameters (Figure 4A).

The Gut microbiota plays a vital role in maintaining physiological homeostasis (Su et al., 2020). Accumulating evidence suggests a correlation between gut microbiota dysbiosis and the development of diabetes-related complications (Yang et al., 2022; Brugman et al., 2006). Zhang et al. (2022) demonstrated that EUP alleviated gut microbiota dysbiosis by both reducing bacterial lipopolysaccharides release and inhibiting microglia-mediated TLR4/NF-κB/MAPK signaling pathways. Additionally, Wei et al. (2023) demonstrated that EUP reshaped gut microbial communities, inhibited ROS accumulation, and extended lifespan in fruit flies, suggesting their potential role in regulating gut microbiota. In obese diabetic mice, EUP treatment enriched short-chain fatty acid (SCFA)-producing bacteria, increased SCFA production by 2.3-fold, reduced endotoxin levels by 58%, upregulated occludin expression (1.8-fold), strengthening intestinal barrier integrity (Wang et al., 2023). Current limitations are insufficient clinical evidence for EUP’s microbiota-mediated antidiabetic effects and need for human trials to validate animal study findings. EUP exhibits multi-target microbiota-modulating effects by promoting beneficial bacterial growth (+39% Lactobacillus), suppressing pathogenic species (−62% Enterobacteriaceae), and restoring gut barrier function (Figure 4B).

In conclusion, current experimental studies demonstrate that EUP exerts significant protective effects against diabetes through multiple mechanisms, including regulation of glucose metabolism-related gene and enzyme expression, inhibition of cellular apoptosis and protection of pancreatic β-cells, improvement of lipid metabolism disorders, modulation of oxidative stress, suppression of inflammatory responses; and regulation of gut microbiota composition (Figure 5).

While EUP’s hypoglycemic effects via AMPK/PPARγ pathways are documented, crosstalk between signaling cascades (e.g., PI3K/Akt, NF-κB) remains underexplored. Synergistic or antagonistic interactions necessitate validation via knockout models or multi-omics approaches. While EUP’s hypoglycemic effects via AMPK/PPARγ pathways are documented, crosstalk between signaling cascades (e.g., PI3K/Akt, NF-κB) remains underexplored. Synergistic or antagonistic interactions necessitate validation via knockout models or multi-omics approaches. While EUP’s hypoglycemic effects via AMPK/PPARγ pathways are documented, crosstalk between signaling cascades (e.g., PI3K/Akt, NF-κB) remains underexplored. Synergistic or antagonistic interactions necessitate validation via knockout models or multi-omics approaches (Zhang and Li, 2017; Zeng et al., 2018). While EUP’s hypoglycemic effects via AMPK/PPARγ pathways are documented, crosstalk between signaling cascades (e.g., PI3K/Akt, NF-κB) remains underexplored. Synergistic or antagonistic interactions necessitate validation via knockout models or multi-omics approaches.

EU has attracted widespread attention for its health benefits in functional foods and medicine, owing to its status as a “medicinal food homologous” substance. Numerous health products have been developed using EU as a raw material, featuring diverse dosage forms such as beverages, teas, oral liquids, capsules, granules, and pills. These products demonstrate significant efficacy in relieving fatigue, enhancing immunity, lowering blood sugar and regulating lipid levels, increasing bone density, and improving sleep and bowel movements (Brugman et al., 2006). Wang et al. (2023) developed a novel health product, sweet rice wine incorporating EU leaf ultrafine powder, by adding the powder during glutinous rice fermentation. In vitro experiments confirmed this rice wine’s potent antioxidant, hypoglycemic, and lipid-lowering effects. This research validates the broader utilization of Eucommia ulmoides leaves, expands the variety of sweet rice wines, and further promotes EU’s health food market. Recent studies highlight that polysaccharides isolated and purified from EU bark and leaves have become a focal point of research due to their excellent bioactivity and high nutritional value. Consequently, the development of novel bioactive polysaccharides and polysaccharide-based functional foods and drugs constitutes a primary research focus.

The structural features of polysaccharides, including glycosidic linkage types and branching patterns, can be significantly influenced by extraction methods. Different extraction techniques, due to their distinct mechanisms of action and operational conditions, may lead to polysaccharide chain cleavage, glycosidic bond conversion, or alterations in branching structures. Hot water extraction, as the most commonly used method, hot water extraction generally preserves the natural structure of polysaccharides due to its mild conditions. However, prolonged high-temperature treatment may result in partial degradation of polysaccharide chains, affecting the molecular weight distribution and degree of branching. Ultrasound accelerates the dissolution of polysaccharides through the cavitation effect, but high-intensity ultrasound may also cause polysaccharide chain cleavage, thereby impacting glycosidic linkage types and branching patterns. Therefore, optimizing ultrasound parameters (such as power and time) is crucial for maintaining polysaccharide structural integrity. Microwave extraction achieves instantaneous heating through electromagnetic fields, significantly improving extraction efficiency. However, the rapid heating process may lead to local changes in polysaccharide structure, such as glycosidic bond rearrangement or reduced branching structures. Alkaline treatment aids in the release of polysaccharides, but excessively strong alkaline conditions may disrupt glycosidic bonds, causing structural changes. Membrane filtration technology, especially ultrafiltration, separates polysaccharides with specific molecular weight ranges through membranes with different molecular weight cut-offs, thereby affecting the molecular weight distribution and branching degree of polysaccharides.

The purification process aims to remove impurities such as proteins, pigments, and inorganic salts from polysaccharides to obtain high-purity polysaccharides. However, the choice of purification method and operational conditions may also impact the structural characteristics of polysaccharides. Deproteinization methods, commonly used deproteinization methods include the Sevage method, TCA method, and HCl method. These methods remove proteins through different mechanisms but may also cause varying degrees of damage to polysaccharide structures. For example, while the HCl method exhibits high deproteinization efficiency, it readily leads to polysaccharide degradation. Therefore, when selecting a deproteinization method, it is necessary to strike a balance between deproteinization efficiency and polysaccharide structure preservation. H₂O₂ oxidation and activated carbon adsorption are commonly used decolorization methods. H₂O₂ oxidation exhibits high decolorization efficiency but requires further evaluation regarding its impact on polysaccharide structure. Activated carbon adsorption is relatively mild but the decolorization effect may be influenced by activated carbon type, dosage, and operational conditions. Ion-exchange chromatography and gel filtration chromatography are important methods for obtaining homogeneous polysaccharide components. These methods separate polysaccharides into components with specific molecular weight ranges, charge properties, and branching patterns through different separation mechanisms such as charge differences and molecular size exclusion. Thus, chromatographic purification not only aids in impurity removal but also reveals the structural diversity of polysaccharides.

Isolation and purification methodologies critically govern the structural attributes of EUP, including glycosidic connectivity, branching topology, and molecular weight. Strategic optimization of these processes is essential to preserve native architectures and isolate functionally relevant polysaccharide fractions. Future studies should establish quantitative structure-process correlations to advance industrial-scale EUP production for tailored applications.

Diabetes is now recognized as a “silent epidemic” that posing a significant threat to global health. Currently, natural products are attracting considerable research attention due to their low toxicity and minimal adverse effects, making them more suitable for long-term therapeutic use. Research on EUP, the primary active component of EU, for preventing and treating diabetes-related diseases remains in its early stages, with insufficient clinical studies and mechanistic investigations. Current research demonstrates that EUP possess multiple pharmacological activities, including blood sugar regulation, lipid reduction, antioxidant and anti-inflammatory properties, as well as gut microbiota modulation. These biological activities align with various pathophysiological mechanisms underlying diabetes-related complications, indicating eucommia polysaccharides’ potential as therapeutic candidates for diabetes management. The advancement of nanomedicine-based drug delivery systems has created novel opportunities for incorporating active components from TCM (Han et al., 2024). Future investigations should prioritize exploring eucommia polysaccharides as both therapeutic agents and drug delivery carriers to potentiate synergistic anti-diabetic effects.

Furthermore, structural modifications of EUP will be explored to enhance their anti-diabetic efficacy. Nevertheless, the clinical translation of EUP as novel therapeutic agents faces substantial challenges requiring systematic resolution. Critical research gaps encompass standardization of extraction and purification protocols, comprehensive structural characterization, and mechanistic understanding of structure-activity relationships. Consequently, future investigations should focus on elucidating precise chemical structures, establishing optimal dosage regimens and delivery routes, characterizing pharmacological profiles, and uncovering the material basis, molecular mechanisms, and therapeutic benefits against diabetes. Presently, EU research remains predominantly preclinical, with a striking paucity of clinical validation. This knowledge gap necessitates multidisciplinary research strategies integrating modern analytical techniques. With advancing quality control standards in TCM and growing public health consciousness, EUP-based therapeutics demonstrate considerable commercial viability in the nutraceutical and pharmaceutical markets.