Anti-Diabetic Effects and Mechanisms of Dietary Polysaccharides

Diabetes mellitus is a multifactorial, heterogeneous metabolic disorder, causing various health complications and economic issues, which apparently impacts the human’s life. Currently, commercial diabetic drugs are clinically managed for diabetic treatment that has definite side effects. Dietary polysaccharides mainly derive from natural sources, including medicinal plants, grains, fruits, vegetables, edible mushroom, and medicinal foods, and possess anti-diabetic potential. Hence, this review summarizes the effects of dietary polysaccharides on diabetes and underlying molecular mechanisms related to inflammatory factors, oxidative stress, and diabetes in various animal models. The analysis of literature and appropriate data on anti-diabetic polysaccharide from electronic databases was conducted. In vivo and in vitro trials have revealed that treatment of these polysaccharides has hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects, which enhance pancreatic β-cell mass and alleviates β-cell dysfunction. It enhances insulin signaling pathways through insulin receptors and activates the PI3K/Akt pathway, and eventually modulates ERK/JNK/MAPK pathway. In conclusion, dietary polysaccharides can effectively ameliorate hyperglycemia, hyperlipidemia, low-grade inflammation, and oxidative stress in type 2 diabetes mellitus (T2DM), and, thus, consumption of polysaccharides can be a valuable choice for diabetic control.


Introduction
Diabetes mellitus is a multifactorial metabolic disorder described by chronic hyperglycemia due to insulin resistance or insulin insufficiency [1]. It is a heterogeneous disorder that can potentially cause insulin resistance in the peripheral tissues, including adipose, liver, and muscle, as well as progressive β-cell dysfunction in the islets of the pancreas, resulting in hyperglycemia [2]. In a patient with type 2 diabetes mellitus (T2DM), it is estimated that almost 90% of all the patients with diabetes show hyperglycemia, impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and persistent insulin deficiency [3]. Moreover, the long-lasting complications of T2DM cause extraordinary healthcare costs with high morbidity and mortality [2,4]. Administration of oral hypoglycemic agents, such as biguanides, thiazolidinediones, and sulfonylureas, can meritoriously regulate hyperglycemia. Nevertheless, they have noticeable side-effects, including hypoglycemia and gastrointestinal troubles [5]. Thus, there is an urgent requirement for effective substitutions to reduce the complications of diabetes with lower side-effects. In recent years, the search for alternate medications has drawn great attention to combat diabetes. Therefore, dietary active principles progressively come into the field of investigator's vision [4]. Dietary active principles, such as polysaccharides, alkaloids, olysaccharides generally extracted from medicinal plants, grains, fruits, vegetables, oom, and medicinal foods have shown more consideration from investigators due to th y and numerous pharmacological activities [10][11][12]. They are composed o accharide unit and linked by glycosidic bonds. The assessment of the effe ccharides with anti-diabetic properties has emerged as an important research fiel s investigations have presented that polysaccharides purified from pumpkin, sea cuc rry, mushroom, bean, tea, and oat exert favorable effects on glucose homeostasis (Fig the complications of diabetes through the defensive mechanism against oxidative , and eventually improve insulin sensitivity [13][14][15]. In addition, dietary non-dig ccharides obtained from plants and foodstuff are recognized potent modulators iota that can nourish certain useful microbes in the human gut. This has also led to inc on to the isolation of novel bioactive polysaccharides and their practices as fun nents, which modulate the gut microbiota to improve the host's metabolism and hea , polysaccharides are considered prebiotic substances, which are being speculated to e effects in managing metabolic diseases like diabetes. In this comprehensive r   Blood glucose, TC, LDL-C, insulin, PK, glycogen, SOD, MDA, GSH-Px IL-2, IL-6, IL-10, and TNF-α Anti-diabetic and antinephritic Activities [29] Mushroom

Mechanism of Dietary Polysaccharides on Anti-Diabetic Activities
Polysaccharides are generally extracted from dietary materials by various physical, chemical, or enzymatic digestion treatments that can be found to have anti-diabetic potentials. The previous study showed that polysaccharides consumption could alleviate diabetes through mechanisms of action on gastrointestinal viscosity, gastrointestinal satiety, colon fermentation, and anti-gastrointestinal inflammation [68]. Similarly, the present study aimed to identify the various in vivo and in vitro trials in which dietary polysaccharides have hypoglycemic, antioxidant, and anti-inflammatory effects. Dietary polysaccharides enhance pancreatic β-cell mass, trigger insulin signaling pathways through insulin receptors, and activate the PI3K/Akt pathway. They modulate ERK/JNK/MAPK pathways and, thus, alleviate β-cell dysfunction.

Hypoglycemic and Hypolipidemic Effects
Impaired glucose tolerance generally leads to permanent loss of β-cell function, which has been recognized by the occurrence of glucose toxicity and lipotoxicity. Hyperglycemia often produces an elevated reactive oxygen species in β-cells, providing succeeding impairment to cellular mechanisms [69,70]. The pancreatic lipid contents generally not relate with β-cell dysfunction in young-onset T2DM [71] and, however, pancreatic islet lipotoxicity is known as a major factor for the onset and progression of T2DM. The disorder of lipid metabolism or increasing fatty acid levels in the blood cause β-cell dysfunction, which are primary threat factors for T2DM [39]. An investigation of animal study connected with streptozotocin-induced diabetes succeeding β-cell dysfunction suggested that the polysaccharide obtained from gum exudates (Acacia tortilis), comprising of the polymer compounds (D-glucose, D-galactose, L-rhamnose, and D-glucuronic acid), showed a potential anti-diabetic effect. These extracts remarkably decreased fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), very LDL (VLDL), and an elevated concentration of high-density lipoprotein (HDL). Furthermore, reduced hepatic markers, such as aspartate transaminase (AST) and alanine transaminase (ALT), were noticed in gum extract treated groups, indicating improved lipid metabolism in the liver [72]. Various animal studies reported that well characterized, low to high molecular weight polysaccharides obtained from various edible sources showed greater anti-diabetic effects [13,18,73]. A polysaccharide purified and characterized by Lachnum calyculiforme demonstrated a significant hypoglycemic effect (p < 0.01) at dose-dependent manners in alloxan-induced diabetic mice [18]. Similarly, corn silk, pumpkin, Mactra veneriformis, Trametes gibbosa, Inula britannica, Saccharina japonica, Phellinus linteus, Talinum triangulare, and Schisandra chinensis (Turcz.) Baill containing different ranges of molecular weight polysaccharides (60, 180, 220, 350, 449.6, 3000, 3172.9 kDa) exhibited a significant anti-diabetic effect (p < 0.05) as proved by a remarkable decrease of blood glucose and improvement of OGTT, serum insulin, and lipid metabolism outcomes in STZ as well as alloxan-induced diabetic mice [13,22,[73][74][75].
The fruit polysaccharide of Morus alba L. has significant anti-hyperglycemic and anti-hyperlipidemic effects that can undoubtedly relieve symptoms of diabetes in the STZ-induced T2DM rat model. After seven weeks' treatment, the fruit polysaccharides significantly diminished FBG, OGTT, glycated serum protein, and lipid profiles and improved insulin levels in the blood. Furthermore, the polysaccharides-treated groups enhanced the insulin-signaling pathway, and their high protein expression levels of InsR (insulin receptor), IRS-2 (insulin receptor substrate 2,), Akt (serine/threonine-specific protein kinase), and GLUT4 (glucose transporter 4) were identified when compared to that of the T2DM groups [76]. High-fat diet treated with STZ-induced hyperglycemia was significantly reduced by the administration of mushroom polysaccharides [77,78]. The oral administration of mushroom extracellular polysaccharides obtained from Pleurotus tuber-regium (20 mg/kg b.w. (body weight)) and Grifola frondosa (100 or 300 mg/kg b.w.) could decline the levels of FBG, TC, TG, lipid profiles, fatty acid composition, and expression of liver peroxisome proliferator-activated receptor alpha (PPAR-α) in obese-diabetic rats. The parallel restoration and elevated HDL-C levels occurred with supplementation of mushroom polysaccharides [77,78]. These hypolipidemic properties might be connected with up-regulated expression of liver PPAR-α mRNA and protein levels [78]. All these outcomes strongly suggest that polysaccharides exert potential hypoglycemic and hypolipidemic effects in STZ-induced diabetic animal models. Therefore, polysaccharides could be considered as a nutritional supplement to treat diabetic complications.

Increasing β-Cell Mass and Reducing β-Cell Dysfunction
A recent study described that lean and obese human, with T2DM, had a 45% and 70% decreased relative β-cell mass; 10-and 3-fold elevated β-cell apoptosis, respectively, compared with the respective nondiabetic control group [79][80][81]. This research outcome suggested that the decreased β-cell mass along with elevated β-cell apoptosis rate is relatively common in T2DM. Though the underlying mechanism of β-cell apoptosis in T2DM is complex and debated [82,83], the prevention of β-cell apoptosis and connected elements are the vital approach for treating T2DM.
Several animal studies reported that purified, characterized low to high molecular weight polysaccharides obtained from dietary sources showed elevating β-cell mass and reducing β-cell dysfunction [84,85]. The oral administration of mulberry leaf containing polysaccharides (MW: 8.1 kDa) significantly prevented β-cell apoptosis and elevated insulin secretion in STZ-induced diabetic rats. These polysaccharides significantly up-regulated Bcl-2 (B-cell lymphoma 2) and PDX-1 (insulin promoter factor 1) and down-regulated mRNA expression of Bax (BCL2 associated X protein). In addition, they markedly prevented caspase-3 activation in the islets of the pancreas of STZ-diabetic rats [84]. These results suggested that polysaccharides could play a critical function in pancreatic islet cell protection from apoptosis by increasing the ratio of Bcl-2/Bax and improving insulin secretion through the restoration of PDX-1 in diabetic animals [84]. Similarly, a polysaccharide from Ganoderma atrum (MW: 1013 kDa) administration in diabetic animals significantly reduced FBG, plasma insulin, and expression of Bax and improved expression of Bcl2 as well as lipid profiles in the high-fat diet STZ-induced diabetic rats [85]. Histopathological studies also confirmed that polysaccharides from G. atrum showed elevated β-cell mass, pancreatic islets expansion, and restoration, representing that polysaccharides protected the islets of the pancreas from HFD-and STZ-induced damage [86]. Another study from fruit bodies of Ganoderma lucidum containing protein-bound polysaccharide (MW: 8.849 kDa) exhibited potential anti-hyperglycemic and anti-hyperlipidemic effects on STZ-induced diabetic rats [87]. The underlying mechanism of this study observed that G. lucidum significantly up-regulated Bcl-2 and down-regulated Bax and caspase in the pancreatic cells compared to that of STZ diabetic animals. The results strongly suggested that polysaccharide from G. lucidum exerted an anti-diabetic potential by inhibiting the β-cell apoptosis in diabetic rats [88].
Zhu et al. [89] demonstrated a low molecular weight and well-characterized polysaccharide from pumpkin fruit (MW: 115 kDa) that prevented β-cell apoptosis by regulating the mRNA expression of Bcl-2 and Bax in STZ-induced damage of pancreatic islet cells. They found that polysaccharides from pumpkin possessed strong antioxidant capacities and eventually decreased the NO level and restore the β-cells. Zhang et al. [34] also presented that water-soluble polysaccharide purified from pumpkin restored the damaged pancreatic islets via triggering β-cell multiplication. This investigation further observed that intragastric treatment of polysaccharide from pumpkin significantly decreased blood glucose, TC, TG, and HbA1c in alloxan-induced diabetic animals and restored the normalization within 21 days' treatment of polysaccharides. A low molecular weight polysaccharide purified from Sea cucumber (Cucumaria frondosa, MW: 14.76 kDa) and Lycium barbarum L (goji berry, MW: 212.14 kDa) prevented β-cell apoptosis and increased β-cell mass in pancreatic islets of mice by down-regulating the mitochondrial signaling pathway, eventually showing significant insulin-sensitizing and anti-hyperglycemic effects [86,90]. All these findings recommend that polysaccharides aid in increasing β-cell mass and reducing β-cell dysfunction. Hence, polysaccharides could be considered as a dietary supplement involved in the pathogenesis of diabetes, leading to reduce the degree of β-cell damage in pancreatic islets.

Antioxidant Effects
Diabetes is generally caused by the impairment or insufficient β-cells in the pancreas that diminishes insulin biosynthesis and gradually deteriorates whole body functions. In contrast to physiological glucose concentration, these glucose levels negatively affect a greater number of organs and tissues. Due to chronic hyperglycemia, decreasing insulin secretion, as well as up-surging insulin resistance, provides glucose toxicity [81,91,92]. It has been recognized that glucose toxicity mainly participates in the deterioration of diabetes by distressing the synthesis of β-cells. The underlying mechanism of glucotoxicity is chiefly mediated by oxidative stress, which has been associated as a primary risk factor in the onset and advancement of T2DM. Oxidative stress is usually formed by an excess free radical formation and decreases the antioxidant defense system in the body [81]. Generally, the living system generates two major forms of reactive species, viz. reactive oxygen species and reactive nitrogen species. Pancreatic β-cells are susceptible to those reactive species due to their low concentration of free-radical scavenging enzymes. They can readily injure to cellular macromolecules, such as lipids, DNA, and proteins [93]. However, the antioxidant agents derived from dietary sources are promising elements to scavenge cell generating free radicals and protects β-cells. These antioxidant agents generally augment cellular antioxidant enzymes and inhibit β-cell apoptosis, which has been demonstrated to improve β-cell dysfunction and protect β-cells against glucotoxicity in diabetic animal models [5,94,95].
In vivo, animal studies demonstrated that bioactive polysaccharide could inhibit the development of T2DM by decreasing oxidative stress. For instance, the polysaccharide obtained from Grifola frondosa (MW: 400-450 kDa) and Salvia miltiorrhiza Bunge (MW: 119.5 kDa) showed substantial defensive and antioxidative ability against the oxidative damage and increased the activities of antioxidant enzymes, such as SOD (superoxide dismutase), CAT (catalase), and GSH-Px (glutathione peroxidase) and decreased level of malondialdehyde (MDA), NO synthase, and inducible NOS (Nitric oxide synthase) in blood and liver [96,97]. MDA is measured as a fundamental chain reaction of lipid peroxidation, which produces injury to the cell membrane, necrosis, and inflammation [92]. Additionally, G. frondosa and S. miltiorrhiza improved the insulin sensitivity index and attenuated STZ-induced structural changes to the pancreas and liver [96,97]. Similarly, the low molecular weight polysaccharides from Catathelasma ventricosum (MW: 160 kDa) and Ophiopogon japonica demonstrated anti-diabetic, anti-obesity, and antioxidant activities in STZ-induced diabetic mice. Oral administration of both plants decreased the MDA levels and increased vitamin E contents, SOD, CAT, and GSH-Px activities in the hepatic and renal cells of STZ-induced diabetic mice [14,98]. Simultaneously, oral administration of these polysaccharides significantly decreased blood glucose and markedly elevated serum insulin levels. Microscopic observation in the pancreas, kidneys, and liver assay confirmed that polysaccharides protected the organs from lipid peroxidation injury and conserved tissue integrity [99]. The enhancement of antioxidant enzyme activity in the treated group designated that polysaccharides inhibited the cell injury by scavenging free radicals produced by chain reactions of lipid peroxidation [70].
Mulberry fruit polysaccharide, produced by Fructus Mori, is a biopolymer that exhibited hypoglycemic and antioxidant activities in vitro as well as in STZ-induced diabetic mice. In vitro, hypoglycemic experiments exhibited that a noteworthy insulin-sensitizing and increased insulin synthesis was observed when the treatment with polysaccharides stimulated pancreatic β cell proliferation and serum insulin levels. Oral administration of fruit polysaccharide could markedly decrease blood glucose and MDA levels and increase SOD, CAT, and GSH-Px in the hepatocytes of STZ-induced diabetic mice. Histopathological observation exhibited that fruit polysaccharide could significantly improve the tissue damage to the pancreas, liver, and kidney [100]. Likewise, ginseng polysaccharides from Panax ginseng C.A. Meyer showed significant hypoglycemic and antioxidant activities in STZ-induced diabetic mice. Oral administration of ginseng polysaccharides significantly decreased blood glucose and lipid peroxidation levels and enhanced SOD levels [101].
Another study in white oyster culinary-medicinal mushroom polysaccharide, which was obtained from Pleurotus florida (MW: 155 kDa), showed decreased blood glucose, HbA1c, lipid profiles, and urinary glucose in STZ-induced diabetic rats. P. florida decreased the levels of MDA and nitric oxide and restored the levels of GSH, SOD, and CAT in diabetic rats. These findings recommended that administration of P. florida could attenuate diabetic complications along with hyperglycemia and hypercholesteremic effects [102]. Based on the investigations, all these results strongly suggest that polysaccharides possess antioxidant properties that can be applied as an adjunct therapy and control the effect of T2DM.

Anti-Cholesterolemic and Anti-Triglyceridemic Effects
Various in vitro and in vivo studies demonstrated that dietary polysaccharides potentially have lipid-lowering effects and eventually reduce the effects of diabetic complications. Polysaccharides activate serine/threonine protein kinase (AMPK) pathway to regulate lipid metabolism by decreasing the levels of triglycerides and cholesterol. Studies have revealed that AMPK switches off anabolic processes, including the biosynthesis of fatty acids, triglyceride, and cholesterol, through repressing the expression of genes, such as Acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein -1c (SREBP-1c), and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase [103][104][105].
Normally, the reduction of triglycerides occurs in the human body through activation of an enzyme, adipose triglyceride lipase, or up-regulation of peroxisome proliferator-activated receptor-α (PPAR-α) and PPAR gamma coactivator-1 alpha pathways [106,107]. These signaling pathways are highly connected with energy expenditure as well as reduce the uptake of energy substrates. Furthermore, triglyceride levels can be decreased by triggering another enzyme, ACC, and up-regulation of SREBP-1c or down-regulation of FAS (fatty acid synthase)-carnitine palmitoyltransferase-1 (CPT1) signaling pathways. Studies have shown that over-expression of CPT1 can elevate fatty acid oxidation, lessen cellular triglyceride accumulation, and reduce high-fat-diet-induced insulin resistance [107,108]. The activity of CPT1 is generally regulated by ACC, through the manufacturing of malonyl-CoA, which acts as an inhibitor of CPT1 [108].
The consumption of dietary polysaccharides can be another effective treatment or can prevent hypercholesterolemia. The dietary polysaccharides exert cholesterol lowering effects via activation of sterol regulatory element binding protein -2 (SREBP-2) or inhibition of rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). The expression of HMG-CoA reductase gene is controlled by the SREBP, which play vital roles in managing the biosynthesis of cholesterol and fatty acids. Dietary polysaccharides have inhibitory effects on HMG-CoA reductase through the activation of SREBP-2 [107,[109][110][111]. Increasing plasma LDL-cholesterol (LDL-C) level is a major cardiovascular risk for diabetic patients [112,113]. Uptake of these LDL-C through LDL receptor-mediated endocytosis is an essential step for the regulation of cholesterol homeostasis [114]. Hence, the activation of the LDL receptor reduces the plasma LDL-C levels. Proprotein convertase subtilisin/kexin type 9 is a class of proteinase, that can usually degrade LDL receptor resulting in the elevation of LDL-C in the blood [115]. Dietary polysaccharides are known to activate LDL receptors via inhibiting this enzyme and prevent the elevated LDL-C levels in diabetic patients [111]. Anti-cholesterolemic and anti-triglyceridemic effects of dietary polysaccharides are listed in Table 2. Based on the studies, all these outcomes strongly suggest that polysaccharides possess anti-cholesterolemic and anti-triglyceridemic effects that can be applied as an adjunct therapy for CVD (Cardiovascular diseases) and control the effect of T2DM.  Cholesterol-lowering effects [120] Abbreviations: ATGL-adipose triglyceride lipase; PPAR-α-peroxisome proliferator-activated receptor alpha; FAS-fatty acid synthase; HMG-CoA reductase-3-hydroxy-3-methylglutaryl-CoA reductase; p-AMPK-phosphorylated serine/threonine protein kinase; CAPT1-carnitine palmitoyltransferase-1; p-ACC-phosphorylated acetyl-CoA carboxylase; SREBP-2-sterol regulatory element binding protein-2; SREBP-1c-sterol regulatory element binding protein-1c, ↑ increase; ↓ decrease.

Anti-Inflammatory Effects
In general, oxidative stress is connected with chronic inflammation in T2DM. During inflammation, several pro-inflammatory cytokines, namely, interleukin (IL)-1, IL-6, IL-8, IL-12, IL-18, interferon gamma (IF-γ), and tumor necrosis factor alpha (TNF-α), serve key functions in the dysfunction of islet cells and insulin receptors in the pancreas and eventually β-cell death [3,4,95,121]. Studies have shown that treatment using anti-inflammatory agents, including IL-1 and receptor antagonists, normalize glucose in the blood, improve insulin secretion, and decrease inflammation causing islet fibrosis. These findings suggested the improvement of β-cell dysfunction and cell survival [122].
Various preclinical studies validated that bioactive polysaccharide can inhibit the progression of T2DM by decreasing pro-inflammatory factors. A high molecular weight polysaccharide (MW: 72.9 kDa), which was obtained from the roots of Angelica sinensis (Oliv.) Diels, exhibited hypoglycemic and hypolipidemic effects in STZ-induced diabetic mice. These root polysaccharides markedly exhibited anti-inflammatory effects by decreasing the insulin receptor-associated inflammatory factors, including IL-6 and TNF-α, in STZ-induced diabetic mice [123]. Generally, IL-6 is synthesized by macrophages and T cells for triggering immune responses to the host. IL-6 can also certainly avert insulin synthesis, and excess IL-6 leads to severe pancreatic islet cytotoxicity and cause insulin resistance [4]. TNF-α is a well-recognized cell signaling protein, which is certainly correlated with the insulin receptor and β-cell dysfunction and vastly articulated in adipose cells [124,125]. Animal studies connected with T2DM exhibited that the polysaccharide from Rehmannia glutinosa (Gaertn.) DC (MW: 63.5 kDa) meritoriously improved hyperglycemia, vascular inflammation, hyperlipidemia, and oxidative stress [124].
A low molecular weight polysaccharide (MW: 50-210 kDa) acquired from Pseudostellaria heterophylla demonstrated a hypoglycemic potential in STZ-induced type 2 diabetic rats. These polysaccharides improved insulin sensitivity and markedly decreased lipid profiles and TNF-α expression and elevated IL-10 concentration. IL-10 has generally pleiotropic properties on inflammation, in which the polysaccharides avert the inflammatory mechanism by condensing the secretion and activities of proinflammatory cytokines. These findings clearly exhibited that polysaccharides attenuated low-grade inflammation connected with T2DM [126]. Similarly, the fruit body of mushroom polysaccharide from Pleurotus sajor-caju and Ramulus mori and the polysaccharide extracted from Morus alba L. reduced blood glucose and attenuated hyperglycemia and hyperinsulinemia in diabetic mice. In addition, the polysaccharides decreased the expression of various proinflammatory cytokines, including IL-6, IL-8, COX-2 (cyclooxygenase-2), TNF-α, by down-regulating the signaling of nuclear factor kappa B (NF-kB) [127,128]. Preventing these inflammatory factors are normally positive strategies for averting or alleviating pancreatic islet damage and reducing T2DM development. Hence, polysaccharides greatly normalize the pancreatic function from STZ-induced damage, and this normalization could be connected with a reduction of inflammatory factors and oxidative stress in pancreatic islets [129].
Various low molecular weight polysaccharides extracted and purified from Misgurnus anguillicaudatus (MW: 130 kDa), Anoectochilus roxburghii, Vigna radiata L., and Hedysarum polybotrys demonstrated anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-hyperlipidemic effects in diabetic animals, which was reflected by decreased blood glucose, MDA, MCP-1 (Monocyte chemoattractant protein 1), TNF-α, IL-6, lipid profiles, and boosted the synthesis of insulin and elevated activities of SOD and GSH-Px in STZ induced diabetic animals [124,125,130,131]. Taken together, polysaccharides obtained from various dietary sources can effectively ameliorate hyperglycemia, hyperlipidemia, low-grade inflammation, and oxidative stress in T2DM, and, therefore, intake of polysaccharides can be a potential beneficial choice for diabetes.

Inhibition of α-Amylase and α-Glucosidase
Generally, an experimental indicator of T2DM is hyperglycemia; it is well-defined as abnormally elevated fasting and postprandial glucose levels in the blood. Hence, managing postprandial hyperglycemia is a main beneficial strategy for the management of diabetes. Dietary carbohydrates are naturally digested into monosaccharides, such as glucose and fructose; these monosaccharides can be readily uptaken by the small intestine and transfer into the blood circulation. The human body normally has several dynamic carbohydrates-digestive enzymes, of which α-amylase (saliva or pancreas) and α-glucosidase (small-intestine) are most distinct. α-amylases are present in saliva and pancreas that degrade polysaccharide into glucose. Likewise, α-glucosidases are vital for assimilating oligosaccharides to monosaccharides in the small intestine. Hence, restraining of these digestive enzymes notably inhibit the conversion of polysaccharides into blood glucose, which serves as an effective step to control the blood glucose in diabetic patients [132]. In addition, the hypoglycemic effect of polysaccharides has been achieved by changing the small intestine transit time and preventing the carbohydrate digestion by suppression of digestive enzyme. These inhibitions are generally accomplished by dietary components, such as inulin, tannin, and phytic acid [133]. All these steps can be an effective strategy in diabetes for controlling the blood glucose level.

Increasing Insulin Signaling Pathways
Elevated blood glucose normally elicits the synthesis of insulin in the pancreatic β-cells. Secretion of insulin instantly binds to its membrane receptor, which stimulates a cascade sequence of mechanism. This series of mechanism subsequently aids to increase glucose influx and metabolic effects, including glycolysis, glycogenesis, and avert glycogenolysis. Furthermore, insulin triggers regular cellular and physiological functions, comprising the cell division, apoptosis, and autophagy [3,142]. This cascade mechanism starts with the autophosphorylation of tyrosine residues in the intracellular components of the insulin receptor, which phosphorylate various substrates, including IRS1 and IRS2. Both substrates fix and activate the PI3K (PI3K: phosphoinositide 3-kinase)/Akt pathway as well as the MAPK (MAPK: mitogen-activated protein kinase) pathway. Akt is a main mediator to activate the most biochemical mechanism in glucose metabolism via activating phosphofructokinase and deactivating glycogen synthase kinase, resulting in stimulation of glucose transporter system translocation [3]. MAPK is a specific protein kinase involved in various physiological and biochemical mechanisms, including cell differentiation, proliferation, apoptosis, and cell endurance. ERK1/2 (extracellular-signal-regulated kinase 1/2) and JNK (c-Jun N-terminal kinase) are other cell signaling kinases co-task with MAPK, involved in cell growth, differentiation, inflammatory response, and apoptosis [4] (Figure 2). Overstimulation of MAPK generally provides the failure of insulin synthesis linked with apoptosis process in pancreatic islet cells [3].  [26,123,143] and improves diabetic-associated renal disease [144]. Moreover, treatment of these polysaccharides increased GLUT4 levels in pancreas and decreased glycogen synthase kinase-3β levels in most of the cells. This observation showed that polysaccharides demonstrated anti-diabetic agents by triggering the signaling pathways of PI3K/Akt/GSK-3/GLUT-4 [144].
Polysaccharide derived from Ganoderma atrum, Enteromorpha prolifera, and Liriope spicata var. prolifera (MW: 3.2 and 4.29 kDa) markedly decreased FBG and significantly improved plasma lipid profiles and glucose tolerance in diabetes-induced endothelial dysfunction in animal models. In addition, administration of polysaccharides remarkably inhibited the expression of GSK-3β (glycogen synthase kinase-3β) and elevated expressions of the insulin receptor, IRS1, PI3K, AKT, eNOS, and GLUT4 in the liver of diabetic rats [85,99,[145][146][147]]. An in vitro study also showed that the polysaccharide from Grifola frondosa significantly increased glucose metabolism and glycogen synthesis in HepG2 cells. Western blot findings demonstrated that polysaccharide triggered insulin receptor and elevated Akt expression, thereby inhibiting GSK-3β expression [148]. Another in vitro study demonstrated that the fruit of high molecular weight polysaccharide Lycium barbarum L. (MW: 33.867 kDa) elevated expressions of PI3K, p38 MAPK, and glucose uptake by GLUT4 in isolated adipocytes and reduced insulin receptors in obese and diabetic rats [74,149].
Polysaccharide triggers the PI3K/Akt signaling pathway through IRS1, PI3K-p85, and phosphorylated Akt develops insulin sensitivity [26,123,143] and improves diabetic-associated renal disease [144]. Moreover, treatment of these polysaccharides increased GLUT4 levels in pancreas and decreased glycogen synthase kinase-3β levels in most of the cells. This observation showed that polysaccharides demonstrated anti-diabetic agents by triggering the signaling pathways of PI3K/Akt/GSK-3/GLUT-4 [144].  Sea cucumber containing polysaccharides consisted of a chondroitin sulfate E backbone, which decreased the level of glucose in the blood by stimulating PI3K/GLUT4 and elevated the phosphorylation of insulin receptors, IRS1, and p85-PI3K in the skeletal muscles of T2DM [90,150,151]. Western blot findings demonstrated that polysaccharides enhanced the protein expressions of IRS2, PI3K, and glycogen synthase and lowered that of GSK-3β in the liver of type 2 diabetic mice. At the end of the experiment, these findings suggested that sea cucumber polysaccharides increased glucose metabolism through the PI3K/GLUT4/GSK-3β signaling pathway [90,150,151]. A low molecular weight polysaccharide (120 kDa) extracted from tea (Camellia sinensis L.) demonstrated hypoglycemic, hypolipidemic, and insulin-sensitizing effects in obese and diabetic mice. In addition, these polysaccharides improved SOD, CAT, and GSH-Px activities in liver and kidney tissue of diabetic mice. Tea polysaccharides increased the expressions of PI3K/AKT p-AKT and GLUT4 signaling pathway [27,88,152]. All these above findings proved that administration of polysaccharides remarkably inhibited the expression of GSK-3β and elevated expressions of the insulin receptor, IRS1, PI3K, and AKT in type 2 diabetic animal models.

Conclusions
Diabetes is currently a serious health issue worldwide producing significant morbidity and mortality, and there is no route to cure diabetes completely. The commercial oral hypoglycemic and anti-hyperglycemic drugs have their self-limitations, adverse effects, high cost, and secondary failure. In addition, these oral diabetic drugs cause serious complications, such as hypoglycemia, weight gain, abdominal pain, nausea, vomiting, edema, diarrhea, gas trouble, bloating, and an increase levels of LDL-C. Hence, screening active anti-diabetic agents from natural sources, including polysaccharide, is of greater attraction due to its lesser side effects. Various in vivo, in vitro, and clinical experiments in this review clearly showed that oral administration of polysaccharides reduced hyperglycemia and hyperlipidemia through underlying various molecular mechanisms. Anti-diabetic effects are mediated primarily by their antioxidant properties, as well as the succeeding methods include inhibition of α-amylase and α-glucosidase activity, improving glucose metabolism, increasing β-cell mass, and reducing β-cell dysfunction. Insulin signaling pathways are also increased through activating PI3K/Akt pathway and modulating MAPK/JNK/ERK pathway. Hypercholesterolemic and hyperlipidemic activities are also associated with diabetes in which dietary polysaccharides have a vital function in the activation of AMPK pathway and down-regulation of ACC, SREBP-1c, and HMG-CoA reductase that leads to reduce the levels of triglycerides and cholesterol. Hence, dietary polysaccharides could be considered as anti-diabetic agents and involved in alleviating the pathogenesis, leading to reduce the degree of β-cell damage in the pancreas.
Author Contributions: K.G. and B.X. conceived and designed the review; K.G. wrote the paper; B.X. critically revised and improved the manuscript.
Funding: This research was funded by one research grant from Zhuhai Higher Education Construction Project (Zhuhai Key Laboratory of Agricultural Product Quality and Food Safety).

Conflicts of Interest:
The authors declared no conflicts of interest.  T2DM  T2DM  TC  total cholesterol  TG  triglycerides  TGF-β1 transforming growth factor-β1 TNF-α tumor necrosis factor-α UA uric acid γGT gamma-glutamyltransferase