Recent Updates on Phytoconstituent Alpha-Glucosidase Inhibitors: An Approach towards the Treatment of Type Two Diabetes

Diabetes is a common metabolic disorder marked by unusually high plasma glucose levels, which can lead to serious consequences such as retinopathy, diabetic neuropathy and cardiovascular disease. One of the most efficient ways to reduce postprandial hyperglycemia (PPHG) in diabetes mellitus, especially insulin-independent diabetes mellitus, is to lower the amount of glucose that is absorbed by inhibiting carbohydrate hydrolyzing enzymes in the digestive system, such as α-glucosidase and α-amylase. α-Glucosidase is a crucial enzyme that catalyzes the final stage of carbohydrate digestion. As a result, α-glucosidase inhibitors can slow D-glucose release from complex carbohydrates and delay glucose absorption, resulting in lower postprandial plasma glucose levels and control of PPHG. Many attempts have been made in recent years to uncover efficient α-glucosidase inhibitors from natural sources to build a physiologic functional diet or lead compound for diabetes treatment. Many phytoconstituent α-glucosidase inhibitors have been identified from plants, including alkaloids, flavonoids, anthocyanins, terpenoids, phenolic compounds, glycosides and others. The current review focuses on the most recent updates on different traditional/medicinal plant extracts and isolated compounds’ biological activity that can help in the development of potent therapeutic medications with greater efficacy and safety for the treatment of type 2 diabetes or to avoid PPHG. For this purpose, we provide a summary of the latest scientific literature findings on plant extracts as well as plant-derived bioactive compounds as potential α-glucosidase inhibitors with hypoglycemic effects. Moreover, the review elucidates structural insights of the key drug target, α-glucosidase enzymes, and its interaction with different inhibitors.


Introduction
Diabetes mellitus is a metabolic condition defined by chronically high blood sugar levels [1]. The International Diabetes Federation Diabetes Atlas estimates that it affected 537 million people globally in 2021, and that number is expected to rise to 643 million by 2030 [2]. Diabetes mellitus was the ninth major cause of mortality in a worldwide study conducted by the World Health Organization (WHO) (2019), and it is projected to be the seventh leading cause of death by 2030. According to the International Diabetes Federation (IDF), 6.05 million individuals in Korea suffer from diabetes mellitus as of 2020 [3]. The insulin hormone is generated by pancreatic β-cells and plays a key role in regulating blood glucose levels. It is required for several cellular activities such as glucose absorption and transport, glycogen synthesis, protein synthesis and fatty acid synthesis. Inadequate insulin production or insulin resistance hinders proper glucose homeostasis, resulting in hyperglycemia [4]. Chronic hyperglycemia can have major long-term consequences such as cardiovascular disease nerve damage and renal failure [5]. Depending on the mechanism of its manifestation, diabetes mellitus can be categorized into three types; type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and gestational diabetes. T1DM affects roughly 5-10% of all diabetes patients and is characterized by the death Since the 1990s, anti-diabetic medicines with α-glucosidase inhibitory capabilities, such as acarbose, miglitol and voglibose, have been commercially accessible for treating postprandial hyperglycemia. Since their molecular structure is comparable to that of disaccharides or oligosaccharides, those antidiabetic drugs can bind to the carbohydratebinding site of α-glucosidase. The complexes that result from such binding have a higher affinity than carbohydrate-glucosidase complexes, which consequently leads to a delay in carbohydrate digestion and absorption and thus reduces the PPHG. Nonetheless, the repeated ingestion of them causes flatulence, severe stomach discomfort, allergic responses, etc. [15][16][17]. Despite the commercial availability of efficient AGIs, researchers are continuously working developing novel bioactive AGIs with strong inhibitory potential and fewer adverse effects. Several bioactive compounds have been reported to alleviate various pathophysiological conditions [18][19][20][21][22][23][24][25][26]. Additionally, numerous attempts have been made to synthesize non-cytotoxic compounds with α-glucosidase inhibition activity [27][28][29]. In recent decades, there has been a surge of growing interest in using natural products as medicinal agents, particularly in the prevention and management of T2DM. Medicinal blue; catalytic domain, green; subdomain b1, pale green; subdomain b2, lemon; C-terminal domain 1, red; and C-terminal domain 2, orange. (b) Human Nt MGAM/acarbose complex active site; sticks represent residues situated within a 4-A • radius of a valienamine unit. The acarbose is colored cyan and is shown as sticks and wire for a and b, respectively. (a,b) were adopted from the structure, with PDB entry code: 2QMJ [39], and were generated using PyMol [40].
The catalytic domains of MGAM and SI are duplicated, with an N-terminal membraneadjacent domain (ntMGAM and ntSI) and a C-terminal luminal domain (ctMGAM and ctSI) (Figures 1a, 2a and 3a). An O-glycosylated stalk produced from the N-terminal domain attaches the domains to the brush border membrane of the small intestine [41]. The Nand C-terminal domains of MGAM and SI have more sequence similarity (~60%) when compared to the N-and C-terminus domains of the same enzyme in other species (~40 percent sequence identity). This is due to the MGAM and genes evolving from a previously duplicated ancestor gene through duplication and divergence. The N-and C-terminals of MGAM and SI are members of the glycoside hydrolases (GH) 31 family. The nonreducing ends of α (1-4)-glycosidic bonds are hydrolyzed by the four domains, although they have different inclinations for malto-oligosaccharides of variant lengths [35][36][37][38]. MGAM favors α-1,4-oligosaccharides and can effectively hydrolyze lengths up to glucohexaose. α-1, 6-glycosidic linkages are hydrolyzed by MGAM at just a 2% rate compared to α-1,4-glycosidic bondage, and there is a little sum of α-1,2and α-1,3-hydrolyzing activity. On the other hand, SI represents almost 80% of the total intestinal maltase activity (α-1,4 glycosidic linkages) and nearly all sucrase activity (α-1,2-glycosidic linkages) in the small intestine. SI may also hydrolyze isomaltose's α-1,6-glycosidic bonds, and there is modest α-1,3-hydrolyzing activity [41,42]. The hydrolyzed glucose is then transported by glucose transporter (GLUT)-2 and sodium/glucose cotransporter-1 (SGLT1) from intestinal mucosa into the blood circulation, causing postprandial hyperglycemia (PPHG) [38]. Nt SI important active site residues (catalysis/substrate binding). The kotalanol is colored cyan and is shown as sticks. (a,b) were adopted from the structure, with PDB entry code: 3LPP [43], and were generated using PyMol [40].
Since the inhibition of α-glucosidase enzymes results in a glucose production delay, which contributes to its therapeutic role in T2DM, the relationship between α-glucosidases' catalytic characteristics, particularly substrate selectivity, and their structures have been the subject of much research in the past two decades. Except for CtSI, the three-dimensional structures of these subunits are now available [39,43,44]. The α-glucosidases' structures are protein complexes containing inhibitors such as acarbose and kotalanol. (Figures 1-3). Each α-glucosidase structure consists of four main domains; an N-terminal domain, a catalytic domain of the (the (β/α) 8 -barrel and two C-terminal domains. Inserts 1 and 2 of the catalytic domain are located right after β-strands 3 and 4, respectively (Figure 1a). The general architectures of these subunits' structures are almost similar, except for insert 1. Ct-MGAM insertion 1 differs from the others because it includes an additional helical segment of 21 amino acid residues [44] (Figure 3a). In the catalytic domain, the active site pocket (Subsite-1) is formed by β-barrel loops, and the residues involved with subsite-1 formation are highly conserved among α-glucosidases' subunits. At subsite-1, twelve residues reside within 4-A • of an acarbose valienamine unit and may contribute to enzyme/inhibitor  interactions (Y299, D327, I328, I364, W406, W441, D443, M444, R526, W539, D542 and H600) (Figure 1b). D443 and D542 each supply a catalytic nucleophile and a generic acid/base. The hydroxy groups of the valienamine establish a hydrogen bond with the side chains of D327, R526 and H600 (Figure 1b). In NtMGAM, the aromatic residue of Y299 of the catalytic domain is oddly different. Both MGAM subunits feature Tyrosine residue (Y299 in NtMGAM and Y1251 in CtMGAM) (Figures 1b and 3b), and NtSI has W327 (Figure 2b). This Tryptophan residue is thought to be key in giving the α-(1→6)-specificity of NtSI [43] ( Figure 2b). Mutational studies have shown that substituting Tryptophan residues for the Y299 of NtMGAM and Y1251 of CtMGAM enhances the enzyme catalytic activity for isomaltose hydrolysis [44]. The binding of α-glucosidase with isomaltose (α-(1→6) specific) was clarified using the crystal structure of α-glucosidase from Ruminococcus obeum [45]. The W169 bulky side chain appeared to impede its mobility by being opposed to the flexible α-(1→6)-glucosidic linkage with three bonds. A site-directed mutagenesis investigation demonstrated the relevance of W169 to α-(1→6)-specificity, in which the replacement of W169 with Y significantly lowered the hydrolysis activity toward isomaltose and turned the α-(1→6) specific α-glucosidase into an α-(1→4)-specific enzyme [45]. These structural insights can help us to understand α-glucosidase interactions with different AGI to produce AGI with fewer side effects. Human ctMGAM important active site residues (catalysis/substrate binding). The acarbose is colored cyan and is shown as sticks. (a,b) were adopted from the structure, with PDB entry code: 3TOP [44], and were generated using PyMol [40].

Plant Extracts as α-Glucosidase Inhibitor Sources
Many herbal medications have been advocated for diabetes treatment in addition to the already available therapeutic alternatives. Traditional plant remedies are utilized all over the world to treat a variety of diabetes symptoms. The fact that plant preparations have fewer adverse reactions than current conventional medications [46][47][48][49], along with their lower cost, is encouraging both the general population and national health care organizations to examine natural medical items as alternatives to synthetic drugs [50]. As a result, research into such compounds derived from traditional medicinal herbs has become increasingly significant [51].
Artemisia absinthium belongs to the Asteraceae family, which is considered to be the most common traditional Moroccan medicine used for diabetes [55]. The hypoglycemic effect of A. absinthium L. aqueous and ethyl acetate extracts have been studied in diabetic rats [56]. A. absinthium ethyl acetate extracts show higher α-glucosidase inhibition activity in vitro than the aqueous extract (IC 50 for ethyl acetate extract 0.155 ± 0.0009 mg/mL, aqueous extract 0.170 ± 0.0002 mg/mL as compared to acarbose 0.148 ± 0.002 mg/mL). However, in vivo, only the aqueous extract of A. absinthium leaves show significant hypoglycemic activity, whereas the ethyl acetate extract shows no α-glucosidase activity. Such activity could be due to the high content of polyphenols in the A. absinthium extract.
Several extracts (20) from edible spices such as mace, nutmeg, coriander, star anise and fenugreek were investigated for their anti-diabetic potential as α-glucosidase inhibitors [57]. Among them, the ethyl acetate extract of star anise has the most potent anti-α-glucosidase activity in vitro (IC 50 4.76 ± 0.71 to 201.34 ± 20.07 µg/mL of control acarbose). The mechanism of inhibition was further investigated, and the kinetic analysis revealed the competitive and reversible binding of star anise ethyl acetate extract to α-glucosidase. The study showed that star anise ethyl acetate extract injection in hyperglycemic rabbits decreases blood glucose levels significantly and in a time-dependent manner.
Amomum villosum plant fruit from the Zingiberaceae family is a Korean traditional medicine used in the treatment of different digestive diseases. The fruit water extract used by healthy individuals shows a positive effect on postprandial glycemia and insulin secretion during clinical assessment [58]. A. villosum water extract was investigated for its αglucosidase activity at different concentrations of 1, 3 and 5 mg/mL, which proportionally increased the inhibition against rat α-glucosidase with IC50 of 31.99 ± 6.79%, 48.85 ± 4.75% and 62.58 ± 6.69%, respectively. Although A. villosum water extract has lower inhibition on α-glucosidase than the reference acarbose, it showed a considerable drop in blood glucose levels in the sucrose loading test when administered to the rats compared to the control group [59].
Merremia tridentata (L.) is a traditional medicinal plant used for the treatment of diabetes and several other disorders in Vietnam. The antidiabetic effect of stem-ethanol extract (SE) as well as flavonoid-rich fractions (FF) of the stem of M. tridentata were investigated in diabetic mice [60]. The study revealed that the daily administration of 100 mg/kg SE and 50, 75 mg/kg FF to diabetic mice for twenty days has a higher hypoglycemic effect than the reference drugs, metformin (10 mg/kg) and glibenclamide (5 mg/kg), without affecting the body weight of tested mice. Moreover, SE and FF showed decent α-glucosidase inhibition activity when compared with acarbose (IC 50 (mg/mL) 0.44 ± 0.11, 0.24 ± 0.08 and 0.29 ± 0.06, respectively) ( Table 1). Several medicinal plant extracts have been recently reported to exhibit potent αglucosidase inhibitory activity and hypoglycemic effects in animal models. For one of the most famous and commercial green teas in China (Lu'an guapian green tea (LGGT)), its methanol extract shows α-glucosidase inhibition activity, and when supplemented with the diet, it improves insulin sensitivity and glucose tolerance in mice [61]. For another edible spice/medicinal herb from China, Amomum tsao-ko, its methanol extract shows hypoglycemic activity in a dose-dependent manner while treating STZ-induced diabetic mice as well as in vitro [62]. After six weeks of treatment, the extract significantly decreases the fasting blood glucose in diabetic mice. The study identifies bioactive constituents from methanol extracts such as phenols, flavonoids, oligosaccharides, coumarins and others that could be responsible for α-glucosidase inhibition/hypoglycemic activity. Recently, edible and hydroponically grown Lactuca sativa soil have been reported to substantially reduce blood glucose levels in diabetic rats besides in vitro α-glucosidase inhibition activity [63]. The crude extract and two isolated compounds Coniferol (1) and dillapiole (2) (from chloroform phyto-fractions) of Allium consanguineum were investigated for their hypoglycemic effects [64]. The in vivo studies revealed that two compounds, coniferol and dillapiole, substantially lower blood glucose levels in albino mice. The ethanolic leaves extract of Amischotolype mollissima has shown α-glucosidase enzymatic activity in addition to the antihyperglycemic effect that was observed in the swiss albino mice oral glucose tolerance test in a dose-dependent manner [65]. The methanolic flower extract of Descurainia sophia showed in vitro α-glucosidase activity with mixed (competitive/non-competitive) inhibition [66]. Moreover, consuming the flower extract reduced blood glucose levels in the male rats when compared to the control group. The authors propose that the hypoglycemic effect of the D. sophia flower extract is due to flavonoid and phenolic phytochemical contents in the extract (Table 1).
Other traditional plant extracts have been recently reported for their α-glucosidase potency, and further in vivo studies are required to verify their hypoglycemic biological effect. These studies have examined the potential role of herbal plants against α-glucosidase activity (Table 2). Among the most recent plant extract studies in the literature that are included in this review, Cerasus humilis, Gymnanthemum amygdalinum, and Paliurus spinachristi Mill have the highest α-glucosidase inhibition activities compared to the positive control acarbose. Cerasus humilis (Sok. leaf-tea) has been identified as a good source of α-glucosidase inhibitors [84]. C. humilis methanol extract with a high flavonoid/phenolic content has a substantially higher α-glucosidase inhibition activity ((IC50 = 36.57 µg/mL) in comparison to acarbose (IC50 = 189.57 µg/mL). Among the phenolic compounds isolated from C. humilis methanol extract in this study, myricetin, avicularin, pruning, quercitrin, guajavarin and isoquercitrin were accountable for their α-glucosidase activity. The Paliurus spina-christi mill fruit is used as an antidiabetic traditional medicine in Turkey, and a recent study showed that n-hexane fractions derived from the methanolic fruit extract have remarkably higher α-glucosidase inhibitory effects than acarbose with IC 50 of 445.7 ± 8.5 and 4212.6 ± 130.0 µg/mL, respectively [85]. The phytochemical analysis of the fruit extract identified three terpenic compounds (betulin, betulinic acid and lupeol) with a higher α-glucosidase inhibitory activity than acarbose. Gymnanthemum amygdalinum (Delile) is another folk medicine plant that has been traditionally used in Nigeria to treat diabetes, and the flavonoid-rich fractions of its leaf extract show a substantial antidiabetic effect [86]. A recent study showed that flower methanol extract also exhibits great α-glucosidase inhibitory activity with IC 50 greater than the positive control [87]. The flower methanolic extract fractionation with ethyl acetate solvent yield in two flavonoid compounds with luteolin showed the highest α-glucosidase activity than 2-(3,4-dihydroxy phenyl)-5,7-dihydroxy-3methoxy-4H-chromen-4-on compared to the positive control. Polysaccharides extracted from the water extract of Evodiae fructus, a Chinese medicinal herb, show promising αglucosidase inhibition activity [88]. The polar extracts of Oryza sativa L (black rice) bran possess potent α-glucosidase inhibitory activity [89]. The preliminary analysis of these traditional medicinal plant extracts revealed promising α-glucosidase inhibition activity, and further analysis is required to support their anti-diabetic effect.

Plant-Derived Bioactive Compounds as Potential α-Glucosidase Inhibitors
There have been reports of various plants having α-glucosidase inhibition activity. Potential AGI inhibitors have been shown to exist in a wide variety of bioactive substances that fall under several classes of secondary metabolites. Numerous secondary metabolites, including flavonoids, terpenes, phenolic acids, polysaccharides, tannins, anthocyanins, stilbene and many others, have been discovered to have α-glucosidase inhibition activity (Table 3).   3β,8β,14β,20-tetrahydroxy-

Flavonoids
Flavonoids are polyphenolic metabolites that are often present in plants as different glycosides. Typically, they consist of two phenyl rings and one heterocyclic ring in a 15-carbon phenolic structure. They include different subgroups as flavones, isoflavones, flavans, flavanones and flavonols [141]. Flavonoids play an important role in carbohydrate metabolism. Several flavonoid molecules are found to be more effective at inhibiting α-glucosidase.
Le et al. discovered six globunones A-F, two new flavonoids and nine other known compounds that displayed potent inhibition of α-glucosidase with IC 50 values between 0.4 and 26.6 µM. When compared to acarbose (IC 50 = 93.6 µM), the well-known flavonoid compound Calodenin A (Figure 4a) (IC 50 = 0.4 µM) had the greatest effect and exhibited a non-competitive mode of action during kinetic studies [114]. Similarly, Sgariglia et al. [113] isolated five polyphenolic derivatives from the bark of Caesalpinia paraguariensis. Among them, (-) epigallocatechin-gallate (Figure 4b) (IC 50 = 5.2 ± 0.15 µM) showed the most significant inhibitory effect against α-glucosidase, which was almost 270-fold higher than the control acarbose (IC 50 = 1400.0 ± 0.51 µM). were isolated from Morella rubra. These compounds had a 100-fold stronger inhibitory impact on α-glucosidase enzymes than acarbose (IC 50 = 369 µM). According to the molecular docking analysis, the flavonol-enzyme binding was improved due to pi-conjugations between the galloyl functional group and key residues of α-glucosidase at the active site, which may help to explain the significantly higher activity of these two compounds [110]. Even though the in vitro α-glucosidase assay produced encouraging results, further research must be conducted on the preclinical safety and toxicity assessment of these compounds before considering them as potential anti-diabetic medication candidates.

Terpenoids
Terpenoids are vitally important plant metabolites that are required for both abiotic and biotic stress resistance as well as growth and development. The structural units of terpenoids are composed of isoprene and its derivatives [142]. Based on the isoprene unit number present in the structures, they can be categorized into monoterpenoids, diterpenoids, triterpenoids and sesquiterpenoids [143]. These terpenoids possess anti-cancer, anti-inflammatory and antimicrobial properties [144]. Terpenoid-based drugs such as Taxol (anti-cancer) and Artimesinin (anti-malarial) are commercially available. Lately, researchers have been encouraged to explore terpenoid molecules for anti-diabetic properties.

Phenolic Acids and Their Derivatives
Phenolic acids are a group of bioactive molecules ubiquitous in plants. Their structure consists of functional carboxylic acid groups attached to aromatic phenols. Depending on the number and position of hydroxyl groups, phenolic acids can be classified into cinnamic and benzoic acid derivatives. These natural compounds are powerful antioxidants against free radicals and other reactive oxygen species (ROS) [145,146].
Tergallic acid dilactone isolated from Eugenia jambolana exhibit potent α-glucosidase inhibitory properties with IC 50 5.0 ± 0.34 µM, which is 50 times higher than the positive control [121]. Aleixandre et al. [147] investigated the interactions between phenolic acids and α-glucosidase or the substrate by using different conditions such as the preincubation of phenolic acids with the enzyme or substrate and starch gelation in the presence of phenolic acid. Their studies revealed that, in comparison to phenolic acids with more hydroxyl groups, such as caffeic acid (Figure 6a) (IC 50 = 0.39 ± 0.02 mM), phenolic acids with fewer hydroxyl groups such as vanillic acid (Figure 6b) (IC 50 = 8.38 ± 0.01 mM) showed better inhibition against α-glucosidase. Similarly, Sgariglia et al. [113] reported ellagic acid and its derivatives isolated from Caesalpinia paraguariensis and performed in silico structure-activity relationship studies to evaluate the molecular interactions between α-glucosidase and the inhibitors. Ellagic acid (Figure 6c .05 µM, respectively, which are much lower than acarbose (IC 50 = 1400 µM). Such promising results make them a potential candidate for lead optimization. However, further research is required to assess their toxicity.

Polysaccharides
Polysaccharides are one of the major classes of biomacromolecules, which comprises long chains of several smaller monosaccharides. They are found in a variety of plants and animals. Growing research evidence suggests that plant-derived polysaccharides exhibit a range of biological activities with low or no toxicity [148]. Additionally, the composition of monosaccharides, glycosidic linkage and molecular weight of the polysaccharides could affect their bioactivity [149,150].
Recent evidence from the literature revealed that polysaccharides from different plant species could inhibit α-glucosidase activity [88,122,151]. A polysaccharide fraction, AXA-1, isolated from wheat bran showed a potential non-competitive mode of inhibitory effects against the α-glucosidase enzyme [123]. Zheng et al. [125] investigated the α-glucosidase inhibitory activity of several polysaccharides extracted from Sargassum fusiforme at different pH conditions. According to the study, SEP-7-40, which has relatively high levels of xylose and galacturonic acid and low molecular weight, exhibits a considerable inhibitory effect (IC 50 = 0.304 mg/mL). Similarly, an acidic polysaccharide, SFP-1, isolated from Sargassum fusiforme inhibits α-glucosidase significantly (IC 50 = 0.681 mg/mL) in a mixed-type inhibition mode [124]. Such potential α-glucosidase inhibitory effects shown by polysaccharides in combination with their low toxicity could be promising in the development of drugs against diabetes mellitus. Therefore, further and more organized research work is essential to understand the therapeutic role of polysaccharides in the treatment of diabetes mellitus.

Tannins
Tannins are polyphenolic natural compounds, which play a major role in carbohydrate metabolism [152]. They can be categorized into hydrolyzable tannins and condensed tannins. Tannins have strong anti-oxidant properties that are beneficial in the dietary and healthcare industries. Tannins are widely used in the dietary, leather and chemical industries due to their abundancy in raw materials, chemical reactivity and safe extraction [153,154].
Sheikh et al. [126] studied the role of tannin, procyanidin A2 (Figure 7a) in the postprandial management of diabetes mellitus. The study revealed that procyanidin A2 exhibits significant α-glucosidase inhibitory activities (IC 50 = 0.27 ± 0.01 µg/mL). It also significantly reduced elevated G-6-Pase and mRNA levels in diabetic mice. Another study conducted by Zhang et al. [128] revealed that gallotannins isolated from Euphorbia fischeriana steud have antidiabetic potential. Specifically, 1,2,3-tri-O-galloyl-β-D-glucopyranose (Figure 7b) showed the most significant and highly selective α-glucosidase inhibitory effect. Additional SAR studies have indicated that the galloyl and glucopyranosyl groups are crucial in the inhibition of α-glucosidase. Despite these promising results, more thorough research on the mechanism and in vivo evaluations are still needed. Overcoming these drawbacks is essential in developing tannin-based significant α-glucosidase inhibitors.
These results and conclusions, however, are derived based on the reactions to αglucosidase in vitro and may not accurately represent the processes involved in vivo. Despite the fact that numerous bioactive substances with various structural moieties display notable α-glucosidase inhibitory activity, the pharmacodynamics behind their inhibition remain unexplored. Therefore, comprehensive and detailed research is required to assess the toxicity, potential drug interactions and long-term side effects of these reported compounds to develop them as α-glucosidase inhibitors for the treatment and management of diabetes mellitus.

Conclusions
Diabetes mellitus is a carbohydrate metabolic disorder caused by decreased insulin production or increasing insulin resistance. Herbal remedies for diabetes have been utilized in patients with insulin-dependent and insulin-independent diabetes, diabetic peripheral neuropathy, diabetic retinopathy and other diabetic-related conditions. According to the research on their potential effectiveness against diabetes, natural compounds have a significant role to play in diabetes care, which requires additional investigation for drug development and nutraceuticals from natural plant resources. However, many herbal medicines in use today have not been well researched, and some have the capacity to induce significant adverse effects and substantial drug-to-drug interactions. To understand the pharmacological activity of herbal treatments presently being used in traditional folk medicine to treat diabetes mellitus, further study is required. Although a tremendous effort has been made by scientists to analyze the antidiabetic effects of several natural products, shortcomings are still remaining. Most of the research focuses on the in vitro studies of natural products with fewer researchers conducting in vivo studies and further pharmaceutical advanced studies. Moreover, there is a need for more structural insight into the interaction between glucosidases and the promising anti-diabetic drug targets, which can have great value in new antidiabetic drug discoveries. The goal of this review paper is to summarize the most recent discoveries in research on natural products that act as α-glucosidase enzyme inhibitors. Indeed, reducing postprandial hyperglycemia is one therapeutic strategy for diabetes in its early stages. This is accomplished by slowing glucose absorption in the digestive system by inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidases. Therefore, inhibitors of these enzymes reduce the rate of glucose absorption, hence dampening the postprandial plasma glucose spike. This study reviews over forty extracts collected using various solvents and more than fifty natural products. This review's insight should contribute to the ultimate objective of discovering new therapeutic medications with greater efficacy and safety for the treatment of type 2 diabetes or to avoid hyperglycemia.