Baicalein (5, 6, 7-trihydroxyflavone), one of the representative active metabolites of the medicinal plant Scutellaria baicalensis Georgi (known as huáng qín), is a naturally occurring hypoglycemic agent that can directly promote insulin secretion and preserve pancreatic islet mass (Fu et al., 2014). Besides, orally given baicalein (400 mg/kg/day) to C57BL/6 mice induced by a high-fat diet, the disorders of dyslipidemia, fatty liver, diabetes and insulin resistance in mice were effectively normalized after oral medication and all of these improvements were mediated by inhibition of the MAPKs pathway and activation of the IRS1/PI3K/AKT pathway involving multiple intracellular signaling pathways (Pu et al., 2012). Meanwhile, baicalein can also promote glucose consumption and glycogen synthesis and inhibit gluconeogenesis to improve glucose metabolism and the mechanism of the anti-diabetic effect in IR-induced HepG2 cells related to activation of IRS1/PI3K/AKT signaling pathways and the expression of proteins downstream of the pathway (Yang et al., 2019; Miao et al., 2023). The above results show that baicalein might have a promising potential in preventing and treating diabetes and need more exploration in clinical application.

Chrysin (5, 7-di-OH-flavone), a flavone, is a promising phytochemical discovered in a variety of TCM which has been reported emphasizing benefits in numerous metabolic malfunctions such as anti-diabetic effects, anti-cancer and anti-inflammatory role (Samarghandian et al., 2017; Naz et al., 2019). Depending on its adjuvant therapy effects for glucose and lipid metabolism disorders such as IR, oxidative stress, inflammation, and liver injury in both IR-HepG2 cells and HFD/STZ-induced C57BL/6J mice, they found that Chrysin intervention could modify glycogen synthesis and fatty acid oxidation and suppress gluconeogenesis and fatty acid synthesis by regulating the AMPK/PI3K/AKT signaling pathway (Zhou et al., 2021).

Diosmetin (3′, 5, 7-trihydroxy-4′-methoxyflavone), a naturally occurring flavonoid, has a superior diabetic alleviating effect due to its targeting of α-glucosidase and the PTP-1B signaling pathways (Chen et al., 2019). The treatment of mice with low and high doses of diosmetin remarkably ameliorated glucose metabolism in KK-Ay diabetic mice and regulated the expression of glucose metabolism and insulin resistance related signaling proteins in the liver and skeletal muscle. Hence, they suggested that it ameliorated glucose metabolism and insulin resistance via up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation (Gong et al., 2021).

As a cereal flavone, Tricin (5, 7, 4′-trihydroxy-3′, 5′-dimethoxyflavone) is widely distributed in the husks of various cereal crops and multiple TCM. tricin possesses an anti-adipogeneic effect, which was reported and suggested for the first time that tricin exhibits a significant inhibitory activity toward adipogenesis and lipogenesis by blocking the AKT/mTOR/S6K signaling pathway (Lee et al., 2015; Lee et al., 2016). However, in a dissimilar way, tricin could enhance GLUT4 translocation and glucose uptake by activating the insulin-dependent PI3K/AKT/AS160 signaling pathway in C2C12 myotubes and the oral administration of Tricin significantly lowered blood glucose levels in glucose-loaded C57BL/6 mice (Kim et al., 2017). These findings indicate that tricin has promising prospects to act as a functional agent for glycemic control.

(E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone (HM-chromanone), a sapanin homoisoflavonoid that derived from Portulaca oleracea L., has an extensively potential in promoting insulin secretion and anti-diabetes effect of a substance isolated from TCM. In vivo, HM-chromanone can reduce hyperglycemia and ameliorate dyslipidemia in C57BL/Ksj-db/db mice, the effect of 30 mg/kg HM-chromanone for 6 weeks on levels of HbA1c, plasma insulin, HOMA-IR and serum lipid significantly normalized. Furthermore, the ability of HM-chromanone supplementation to promote the activation of insulin signaling pathways and lead to glucose uptake into skeletal muscle cells was also clarified (Yoo et al., 2023). In vitro, HM-Chromanone was found to improve glucose uptake, glycogen synthesis and other cellular functions related to glucose metabolism in L6 skeletal muscle cells, 3T3-L1 adipocytes and HepG2 cells by activating the PI3K/AKT signaling pathway or acting in conjunction with the AMPK signaling pathway (Park et al., 2019; Park et al., 2021; Park and Han, 2022; Park and Han, 2022). Therefore, it shows a more positive effect in all three primary target insulin groups to improve insulin resistance and its potential to prevent and treat diabetes.

Puerarin, the major isoflavone glycoside isolated from the traditional Chinese medicine Radix puerariae, is widely used to treat diabetes and its complications. Mediated by the PI3K/AKT pathway, it is potent and directly protects β-cell survival and insulin secretion (Li et al., 2014). Moreover, the effect of 100 mg/kg puerarin for 4 days on C57BL/6 male mice with pancreatic β-cell toxic STZ significantly lowered blood glucose, reduced the incidence of diabetes, and directly protected the function and survival of pancreatic β-cell. Activating the PI3K/AKT pathway, considerably upregulated the p-AKT and Bcl-2 expression, and AKT phosphorylation was blocked when the LY 294002 inhibitor was involved. The mechanism of its action against lipid and glucose metabolism dysfunction was investigated after treatment with 300 mg/kg puerarin for 4 weeks in T2DM rats, fasting insulin, glycated hemoglobin, glucose tolerance and lipid profile were significantly normalized recovery and the expression level of PI3K, p-AKT, and p-FoxO1 was increased while PEPCK and G6Pase decreased (Liu et al., 2021). Further, its effect of suppressing gluconeogenesis and promoting glucose consumption by stimulating the PI3K/AKT pathway is also clarified in insulin resistance HepG2 cells (Shen et al., 2019; Liu et al., 2021).

α-Methyl artoflavanocoumarin (MAFC), a flavanocoumarin, is extracted from the heart part of Juniperus chinensis L. (Cupressaceae) (Orhan et al., 2011). As a novel PTP1B inhibitor, it inhibits PTP1B activity and upregulates the expression of PTP1B. Additionally, it also found that MAFC could significantly increase glucose uptake and dose-dependently enhance the protein levels of IRS-1, phosphorylated PI3K, and AKT, thus activating the IRS-1/PI3K/AKT signaling pathway in IR-HepG2 cells (Jung et al., 2017).

Loureirin B, a dihydrochalcone analog, extracted from Sanguis Draconis, which promotes insulin secretion and hypoglycemia (Fang et al., 2022). According to the research on loureirin B, 4 weeks of treatment with 45 mg/kg loureirin B in the HFD/STZ-induced T2DM mice model restored normalization of the liver index, insulin sensitivity, serum lipid content and liver glycogen content, and loureirin B at a concentration of 10–5 to 10–7 mol/L in IR-HepG2 cells affected the IRS1/PI3K/AKT/FoxO1 signaling pathway and regulated the expression of several essential genes and proteins in the pathway, thereby increasing glucose uptake and consumption, accelerating the conversion of glucose to glycogen, inhibiting hepatic gluconeogenesis, enhancing hepatic glycogen content and reducing insulin resistance (Ding et al., 2021).

Fisetin, a flavonoid, is widely presented in natural plants. As an α-glucosidase inhibitor, it was identified to be a promising candidate for the treatment of T2DM (Shen et al., 2021). Fisetin supplementation could ameliorate hyperlipidemia and insulin resistance through regulating the IRS1^Tyr608/AKT/GSK3β/FoxO1 signaling pathway, the expression of phosphorylated IRS1^Tyr608, AKT, FoxO1 and GSK3β was markedly decreased by the intervention of fisetin in the kidneys of HFD-fed mice (Ge et al., 2019). Further, in vitro experiments have shown that fisetin increased the EGFR expression through IRS activating PI3K/AKT signaling pathway to alleviate hepatic IR (Li et al., 2023).

Kaempferol is a important dietary flavonoid that has been identified in many TCM (Fang et al., 2019). Kaempferol exhibits anti-diabetic effect in regulating hepatic gluconeogenesis and ameliorating fasting hyperglycemia and glucose intolerance through increasing AKT phosphorylation, oral administration of kaempferol improved insulin sensitivity and insulin resistance in HFD-fed mice (Alkhalidy et al., 2018). Moreover, kaempferol increased AKT phosphorylation in human SkM cells and in muscle of obese mice to stimulate glucose uptake and insulin resistance (Moore et al., 2023). Furthermore, kaempferol metabolites induce AKT and GSK3β phosphorylation and improve glucose metabolism (Fang et al., 2021).

Quercetin is a naturally occurring flavonoid, ubiquitously present in fruits and vegetables (Fang et al., 2019; Dhanya, 2022). Quercetin has been shown to altering glucose homeostasis via glucose transporters and insulin signalling molecules, acts as potentiates IRS1, PI3K and AKT1 phosphorylation in brain of STZ-induced diabetic rats (Sandeep and Nandhini, 2017). In addition, a study showed that HFD-induced mice and PA-induced HepG2 cells treated with quercetin saw a enhancement alleviation of insulin resistance via the IRS-1/AKT/FoxO1 pathway, and stimulated expressions of p-IRS1, p-AKT and GLUT4 in liver (Cheng et al., 2021; Liu et al., 2022).

Apigenin, a flavonoid, is widely distributed in folk medicines for diabetes treatment (Qin et al., 2016; Kashyap et al., 2021). Apigenin significantly increases glucose consumption and glycogen synthesis, suppresses the production of ROS and AGEs, and improves insulin resistance in IR-HepG2 cells, and elevated the level of protein expression of IRS-1, IRS-2, PI3K, and p-AKT is observed in IR-HepG2 cells (Miao et al., 2023). Therefore, the activation of the IRS-1/IRS-2/PI3K/AKT signaling pathway and regulation of its targets, including GLUT4 and GSK-3β, may play important roles in preventing diabetes (Fang et al., 2019; Miao et al., 2023).

Poncirin, a natural flavonoid glycoside derivative present in the fruits of Poncirus trifoliata, possesses multiple biological activities (Li et al., 2022). Naringenin significantly increased glucose uptake and GLUT4 expression level via activating the IRS-1/PI3K/AKT/GSK-3 signaling pathway, and decreased the expression of PTP1B in IR-C2C12 skeletal muscle cells (Yousof Ali et al., 2020). Enhanced the phosphorylation of IRS-1, PI3K, GSK3β and AKT, and thus stimulated the glucose uptake and insulin sensitivity.

Naringenin, a citrus flavonoid, has the ability to increase insulin secretion in the primary rat islets, protect β cell function and reverse glucose dysregulation in diabetic rats (Lin et al., 2023). Likewise, naringenin reduces lipid accumulation and insulin resistance through promoting AMPK phosphorylation level in liver of diabetic mice (Cai et al., 2023). Further, naringenin administration significantly altering glucose homeostasis, as well as significantly restored GLUT1 and GLUT3 expression, and increased the phosphorylated forms of IRS1, PI3K and AKT in a rat model of T2DM (Sandeep and Nandhini, 2017).

Found in Polygonum cuspidatum, Resveratrol (3, 5, 4′-trihydroxystilbene, RSV) is a type of non-flavonoid polyphenolic with phytoalexin properties, which is particularly high in resveratrol and can be used as a TCM (Zhao et al., 2019). A series of studies have verified a broad spectrum activity of resveratrol in association with diabetes and its complications (Szkudelska and Szkudelski, 2010). In a metabolic action study in humans, it was shown that oral administration of 10 mg of RSV for 4 weeks significantly reduced insulin resistance and improved insulin sensitivity in humans and resulted in more efficient transduction of insulin signaling through the AKT pathway (Brasnyo et al., 2011). What counts is that researchers found that RSV restores the phosphorylation levels of AKT and PI3K in the liver of insulin resistance mice, which are involved in the insulin signaling pathway and were decreased by a high-fat diet (Hong et al., 2014; Sadi et al., 2015; Shu et al., 2020). Furthermore, RSV could also increase insulin secretion and produce a hypoglycemic effect in STZ-induced rats, KKAy mice, and HCF-fed rats via PI3K/AKT signaling pathway to enhance glucose uptake into skeletal muscles (Chi et al., 2007; Deng et al., 2008; Chen et al., 2012). In addition, the combination therapy of dapagliflozin with RSV has better glucose-lowering effects than the single SGLT2i therapy in T2D treatment, and the therapeutic effects of enhancing glucose production and inhibiting gluconeogenesis were also produced by modulating the PI3K/AKT pathway (Sun et al., 2021).

Pterostilbene (trans-3, 5-dimethoxy-4′-hydroxystilbene; PTE), a polyphenol and a naturally occurring dimethylated analog, can be obtained from grapes and blueberries and be found in several TCM. Pterostilbene exhibits anti-diabetic effects both by normalizing the significant enzymes of glucose metabolism and regulating the insulin resistance signaling pathway (Pari and Satheesh, 2006). Furthermore, it can also reverse insulin resistance by decreasing the oxidative stress effect (Elango et al., 2016). The treatment of STZ-induced diabetic rats with pterostilbene at different concentrations (20, 40, and 80 mg/kg) for 8 weeks normalized the body weight, FBG, OGTT, serum lipid profile, and insulin levels in a dose-dependent manner (Sun et al., 2019). Moreover, the expression of PPARγ was increased, and the expression of PI3K and p-AKT was upregulated in adipose tissue of diabetic rats after treatments. The above results show that the mechanism of the anti-diabetic effect of pterostilbene in high-fat diet and STZ-induced diabetic rats may be related to the PI3K/AKT signaling pathway. A similar therapeutic effect of reversing insulin resistance was also demonstrated in HepG2 cells induced by palmitic acid in vitro. Meanwhile, pterostilbene can also regulate triglyceride accumulation and FFA metabolism and reduce oxidative damage to lipids via regulating the PI3K/AKT signaling pathway and the expression of genes coding for gluconeogenic enzymes (Malik et al., 2019).

Curcumin (1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-dione), a natural phenol found in Curcuma longa plants, has been shown to prevent hyperglycemia and hyperlipidemia as well as liver damage (Xia et al., 2020). Data indicated that administration of dietary curcumin reinstates PI3K and AKT levels in the liver of diet-induced obese mice and T2MD rats (Kim et al., 2019; Xia et al., 2020), ameliorates the tissue structure of the liver and pancreas and decreases blood glucose and lipid levels. It ameliorated insulin sensitivity via strengthening the PI3K/AKT/GSK3β signal pathway in high-glucose-induced IR HepG2 cells (Li et al., 2020). Additionally, the mechanistic basis of curcumin is a potential therapeutic strategy for the protection of pancreatic β-cells in T2DM, and it shows that curcumin protected MIN6 β-cells from palmitate-induced apoptosis by modulating the PI3K/AKT/FoxO1 signaling pathway and the mitochondrial survival pathway (Hao et al., 2015).

Gallic acid (3, 4, 5-trihydroxybenzoic acid), a naturally occurring phenolic acid, has been shown to possess anti-hyperglycemic and anti-diabetic activities in STZ-induced diabetic rats (Punithavathi et al., 2011; Punithavathi et al., 2011). In vivo, Gallic acid can improve insulin resistance in the liver, adipose, and skeletal muscle tissues of diabetic rats through translocation and activation of GLUT4 in the PI3K/AKT signaling pathway, and slightly upregulated the mRNA and protein expression levels of PPARγ (Gandhi et al., 2014). Its effects on hepatic glucose metabolism via regulating the PI3K/AKT pathway in HFD-induced diabetic rats were also confirmed (Huang et al., 2016). In vitro, the anti-diabetic effect of Gallic acid was found to protect against free fatty acid (FFA)-induced IR through the miR-1271/IRS-1/PI3K/AKT/FoxO1 pathway at dose of 50 μmol/L (Lee and Lee, 2021).

Tetramethylpyrazine (TMP), also known as ligustrazine, is an alkaloid extracted from the plant Ligusticum chuanxiong with biological efficacy in improving glucose homeostasis and systemic insulin sensitivity (Xiang et al., 2020). Its anti-diabetic affection produced by reducing insulin resistance suppressing oxidative stress in HFD-STZ-induced T2D rats and STZ-NCT-induced T2D rats and suggested that the dose-dependent hypoglycemic activity and potential molecular mechanisms of the oral administration of TMP assessed by calculating the expression levels of phosphorylated PI3K and AKT proteins and mRNA in skeletal muscle, heart and adipose tissue of T2D rats (Rai et al., 2019; Rai et al., 2019). Therefore, it can be concluded that TMP improves insulin resistance and produces anti-diabetic activity by activating the PI3K/AKT signaling pathway.

Hirsutine is a potent drug-like indole alkaloid extracted from the Uncaria rhynchophylla. Hirsutine beneficially regulates glucose homeostasis, improving hepatic and cardiac IR in HFD-induced diabetic mice (Jiang et al., 2023). The ability of pharmacological anti-diabetic to promote glucose consumption and glycogen synthesis and to inhibit gluconeogenesis was also demonstrated adjuvantly in the IR model of HepG2 and H9c2 cells using high glucose and high insulin induction, and the mechanism of action was achieved through activation of PI3K/AKT/GSK3β signaling pathway (Hu et al., 2022).

1-Deoxynojirimycin, as an inhibitor of intestinal ɑ-glucosidase, the primary alkaloid isolated from mulberry leaves (Morus alba L.), has been reported as the critical practical bioactive material basis. Depending on previous research, the administration of purified 1-Deoxynojirimycin appeared to have antioxidant and anti-inflammatory roles in STZ-induced diabetic rats. It explains at least part of the mechanism by which it ameliorates blood glucose (Huang et al., 2014). Its therapeutic effect on hyperglycemia was evidenced by the reduction of blood glucose, serum insulin levels and HOMA-IR index while improving glucose tolerance and insulin sensitivity in skeletal muscle of db/db mice via activating insulin signaling PI3K/AKT pathway (Liu et al., 2015). Meanwhile, its mechanism of glucose homeostasis regulation effect in differentiated 3T3-L1 adipocytes by up-regulating the genes/proteins and mRNA expression of PI3K/AKT and AMPK signaling pathways from ADIPO to GLUT4 and from IR to GlUT4 (Li et al., 2019). Additionally, 1-Deoxynojirimycin supplementation appeared to improve muscle insulin resistance by modulating the IRS-1/PI3K/AKT pathway in the skeletal muscle of db/db mice (Kang et al., 2022).

Siraitia grosvenorii, as a medicine food homology plant, possesses both nutritional and medicinal values. The fruit of S. grosvenorii is naturally enriched with sweetener compounds such as Mogroside III, Mogroside IV, Mogroside V, and Siamenoside I belong to triterpenoid constituents (Thakur et al., 2023). Researchers evaluated the hypoglycemic effect of four mogrosides, namely, Mogroside III, Mogroside IV, Mogroside V, and Siamenoside I. They reversed insulin resistance in IR-HepG2 cells by activating the PI3K signaling pathway, which can play a role in the regulation of glucose metabolism. Moreover, Mogroside V is the most significant curative effect compared with others. It has been found to alleviate glucose levels and insulin sensitivity in T2DM rats by regulating the PI3K/AKT signaling pathway (Liu et al., 2019).

Catalpol, an iridoid glycoside with pharmacological benefits for the prevention of diabetes and diabetic complications, is mainly found in the roots of Radix Rehmanniae (Bai et al., 2019). The therapeutic effects of catalpol in controlling glycemic parameters in HFD/STZ-induced diabetic mice and its potential molecular mechanisms indicate that mRNA levels of IRS-1, PI3K, AKT2, and GLUT-4 in skeletal muscle were significantly improved by treatment (Yap et al., 2020). Meanwhile, catalpol improves insulin sensitivity and increases glucose uptake by enhancing MyoD/MyoG-mediated myogenesis. Moreover, in accordance with the research of in vitro and in vivo the mechanism of catalpol hypoglycemia in skeletal muscle involves modulation of the PI3K/AKT signaling pathway (Xu et al., 2018). Furthermore, the mechanism by which catalpol alleviates hepatic insulin resistance by regulating the expression of the PI3K/AKT pathway and its downstream glucose metabolism-related proteins has been demonstrated in T2D mice and IR-HepG2 cells models (Yan et al., 2018).

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid), a glycogen phosphorylase (GP) inhibitor, is a naturally occurring pentacyclic triterpene widely found in a range of foods and TCM and has enormous potential in hypoglycemic effects. Oleanolic acid could improve blood glucose and insulin homeostasis by enhancing the phosphorylation of ATK and AMPK in the liver of db/db diabetic mice and significantly improve hepatic gluconeogenesis and hepatic pathological changes (Wang et al., 2015). Further, additional research data manifest that the sustained modification of glucose homeostasis by oleanolic acid is due, at least in part, to the repression of AKT/FoxO1 axis-mediated gluconeogenesis in liver (Zeng et al., 2012). Meanwhile, oleanolic acid attenuated adipose tissue insulin resistance induced by fructose over-consumption in rats via IRS-1/PI3K/AKT signaling pathway (Li et al., 2014).

Asiatic acid is a natural pentacyclic triterpenoid derived from Centella Asiatica (L.) Urban and exhibited potent hepatoprotective biological function. Oral administration of asiatic acid to STZ-induced diabetic rats restored the key carbohydrate-metabolizing and lipid metabolic enzymes and lipid peroxidation products to nearly normal levels. Reliable research data found it positively lowered blood sugar, lipid, and lipid peroxidation (Ramachandran and Saravanan, 2013; Ramachandran and Saravanan, 2013; Ramachandran and Saravanan, 2015). Additionally, it also found that its hypoglycemic effect may activate the PI3K/AKT signaling pathway to significantly improve glucose uptake and insulin resistance in skeletal muscle tissue of STZ-induced diabetic rats and improve glucose homeostasis (Ramachandran and Saravanan, 2015). Its anti-diabetic effects have also been demonstrated in T2DM (db/db) mouse models, and it promoted glycogen synthesis by activating PI3K/AKT/GSK-3β signaling pathway in liver tissue (Sun et al., 2017).

Glycyrrhetinic acid, a triterpenoid, is one of the main bioactive components in licorice (Tan et al., 2022). Glycyrrhetinic acid prevented hyperglycemia and hyperlipidemia in STZ-induced diabetic rats and improved to normalcy (Kalaiarasi et al., 2009). In addition, glycyrrhetinic acid elicits its anti-diabetic activity mainly through regulating the PI3K/AKT/GSK-3β signaling pathway (Yang et al., 2020; Tan et al., 2022; Meng et al., 2023). Moreover, glycyrrhetinic acid was found to decrease the activation of the phosphorylation of IRS1ser307 and increased the phosphorylation of AKTser473 and GSK-3βser9 in IR-HepG2 cells, thus improving insulin-response pathway and glucose consumption levels (Zhang et al., 2019; Wang et al., 2023).

Maslinic acid is a pentacyclic triterpene acid that possesses a variety of biological activities, and has been shown to regulate glycogen metabolism in HFD-induced diabetic mice as a glycogen phosphorylase inhibitor (Liu et al., 2014; Yan et al., 2023). In addition, maslinic acid intervention on IR-HepG2 cells elevated the phosphorylation levels of AKT and GSK-3β, and PI3K inhibitor blocked the phosphorylation of AKT^Ser473, thus proving its potential to regulate glycogen metabolism (Liu et al., 2014). Further, identified that maslinic acid has potent anti-adipogenic effects to target adipocyte function and prevent obesity, and target activation of PI3K/AKT signaling pathway (Savova et al., 2021).

Aloin, isolated from the leaf secretion of Aloe vera (L.) Burm. f., belonging to anthraquinone compounds (Jiang et al., 2018). Both in vivo and in vitro studies of aloin have shown its hypoglycemic effects (Zhang et al., 2020), with in vivo studies demonstrating that aloin improves glucose tolerance and fasting serum insulin activity in T2D mice and has hepatoprotective effect, which is mediated by activation of the IRS1/PI3K/AKT pathway (Cui et al., 2014), and in vitro studies demonstrating that aloin markedly improves glucose consumption and stimulates the activity of key enzymes of glucose metabolism in IR-HepG2 cells (Zhong et al., 2022).

Embelin (2, 5-dihydroxy-3-undecyl-1, 4-benzoquinone), a naturally occurring alkyl-substituted hydroxyl benzoquinone, isolated from Embelia ribes Burm, which has been extensively evaluated for its anti-diabetic activity (Durg et al., 2017). Embelin treatment of HFD-STZ-induced T2DM rats shows that it regulates glucose uptake by regulating GLUT4 transposition and activation in epididymal adipose tissue mediated by insulin-dependent PI3K/AKT pathway, manifesting that it plays a positive role in improving adipose tissue insulin sensitivity, enhancing blood glucose control, protecting β cells from damage and maintaining adipose tissue glucose homeostasis in animal models (Gandhi et al., 2013).

Emodin, an anthraquinone, was characterized being an active agent in lowering blood lipids and modulating glucose utilization (Yu et al., 2023). It was demonstrated that emodin improves hepatic glucose utilization, muscle and fat glucose uptake by targeting the IRS/PI3K/AKT/FoxO1 pathway, resulting in enhancing insulin sensitivity and resistance, the protein expression of IRS1, PI3K, and p-AKT ser473 in hepatic, muscle, and adipose tissue of diabetic mice was upregulated (Xuezheng et al., 2018).

Astragaloside IV, a glycoside of cyclobutane-type triterpene obtained from Astragalus membranaceus, has the effect of preventing diabetes by inducing a decrease in blood glucose concentration and an increase in plasma insulin levels (Yu et al., 2006). It can reduce blood glucose levels in HFD-STZ-induced diabetic mice, glycogen phosphorylase (GP) and glucose-6-phosphatase (G6Pase), two glucose-regulated enzymes, were inhibited to improve glucose metabolism in the liver (Lv et al., 2010). Additionally, it inhibits lipolysis and reduces hepatic glucose production in HFD-fed mice through AKT-dependent PDE3b expression (Du et al., 2018). Its mechanism of action is reducing insulin resistance in adipocytes by regulating CTRP3 and PI3K/AKT signaling (Zhang et al., 2022).

Ginsenosides, obtained from ginseng, have been demonstrated to possess anti-diabetic activity, such as Ginsenoside Rb2, Ginsenoside Rg5, etc. Ginsenoside Rg5 may be a potential natural product in the treatment of T2DM for the first time, which can remarkably improve glucose and lipid metabolism, increase insulin secretion, and protect damaged tissues in T2D mice. Further, it improves liver insulin resistance in db/db mice and alleviates T2DM by regulating IRS1/PI3K/AKT/GSK3β signaling pathway (Wei et al., 2020). Ginsenoside Rb2 can jointly improve insulin resistance of 3T3-L1 adipocytes and DIO mice by regulating various pathways such as PI3K/AKT, MAPK and NF-κB, showing various therapeutic effects such as upregulation of inflammatory factors, reduction of fat accumulation and improvement of glucose metabolism (Dai et al., 2018).

Previous studies have found that the serum insulin level in patients with type 2 diabetes is negatively correlated with the plasma non-cholesterol sterols concentration, which suggests that supplementation of phytosterols may have beneficial effects on lowering blood glucose levels and preventing T2DM (Šmahelová et al., 2005). Beta-sitosterol is one of the most common phytosterols, widely distributed in many plants and often found in herbal formulations to treat hypercholesterolemia, coronary artery disease, and prostatic hyperplasia (Ponnulakshmi et al., 2019). Studies have shown that it can protect the expression of insulin signaling molecules in adipose tissue and skeletal muscle of rats with T2DM induced by a high-fat diet and sucrose and improve blood glucose metabolism by enhancing the expression level of insulin receptor (IR) and GLUT4 and regulating the IRS-1/AKT mediated signaling pathway (Babu et al., 2020). It was suggested that beta-sitosterol has anti-diabetic potential. Furthermore, it affected glucose transport and lipid mobilization in primary preadipocytes from male rats by activating and regulating the PI3K/AKT signaling pathway and GLUT4 expression level (Chai et al., 2011). The anti-diabetic potential in a skeletal muscle model established using L6 myotube cells and found that it promoted glucose transport and glucose uptake in L6 myotube cells by activating IRS-1/PI3K/AKT signaling pathway and improving GLUT4 expression level (Sujatha et al., 2010). The above results manifest that insulin-like property is one of the mechanisms of improving insulin resistance in vitro.

Taurine, obtained from Bos taurus domesticus Gmelin, is a sulfur-containing amino acid (Rashid et al., 2013). It can regulate a variety of the body’s normal physiological activities, such as participating in the beta cell function, regulating insulin signaling pathways and glucolipid metabolism of the liver (Das et al., 2012; Batista et al., 2013; Tang et al., 2019; Zhao et al., 2019). Taurine could improve insulin resistance by activating the PI3K/AKT/GLUT4 pathway in HFD/STZ-induced T2DM rats and PA-induced IR-HepG2 and the regulatory effects of taurine on the insulin signaling pathway in the liver, the target organ of insulin. Moreover, its potential to prevent T2DM was evaluated in vitro and in vivo (Chen et al., 2021).

1,7-Diphenyl-4E-en-3-heptanone (DPH5) and (R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC) are diarylheptanoid present in the rhizome of Alpinia officinarum Hance (Xin et al., 2017; Abubakar et al., 2018). These metabolites are considered the most active bioactive metabolites extracted from this plant and have favorable hypoglycemic effects. DPH5 could promote glucose uptake and consumption of IR-HepG2 cells, accelerate glucose utilization, and improve insulin resistance and insulin sensitivity by regulating PI3K/AKT-GSK3β signaling pathway and increasing the expression of GLUT4 and GSK3β proteins (Zhang et al., 2022). Additionally, DPHC could regulate glucose metabolism and hypoglycemic activity well in both db/db mouse models and in vitro high-glucose induced IR-HepG2 cells, and its mechanism improves insulin resistance by regulating IRS1/PI3K/AKT/GLUT4 signaling pathway, showing potential for T2DM treatment (Zhang et al., 2021).

Esculin, a plant derived natural coumarin extracted from Cortex fraxini, is considered to exert multiple anti-diabetic properties (Naseem et al., 2023). Esculin amelioration of unhealthy AT remodeling was also proven for the first time as a novel therapeutic strategy for obesity-induced IR. Intervention with esculin could enhance insulin sensitivity and improve adipose tissue remodeling in obese IR C57BL/6J mice (Ghosh et al., 2022). In PA-treated adipocytes, esculin could promoted glucose uptake through increasing the enhancement of GLUT4 translocation and the expression of p-PI3K p85^Tyr467, p-AKT^Ser473, and p-IRS1^Ser307 (Yang et al., 2024). In addition, esculin restored blood glucose level and glucose tolerance in STZ-induced diabetic mice and dexamethasone-induced diabetic mice, and enhance the phosphorylation of AKT in C2C12 myotubes, indicating a potential for the improvement of insulin resistance (Kang et al., 2014; Mo et al., 2019).