Statins can antagonize the conversion of hydroxymethylglutaryl-coenzyme (HMG-CoA) to mevalonate via inhibiting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway. In the liver, statins reduce cholesterol synthesis, resulting in increased cell-surface LDL receptor expression and increased microsomal HMG-CoA reductase production. This helps to improve the clearance of LDL from the blood, thereby reducing the amount of LDL in the body and alleviating MetS.

Statins can relieve insulin resistance through lipid-lowering and non-lipid-lowering effects. The non-lipid-lowering effects of statins refer to the inhibition of isoprene production, a vital lipid adjunct involved in the post-translational modification of various proteins, such as small GTP-binding proteins, and interference with cell signaling. Statins can inhibit the activation of protein kinase C (PKC) by downregulating the expression of Rho protein, thus weakening the phosphorylation of insulin signaling proteins such as insulin receptor (InsR) and insulin receptor substrate (IRS). It increased the phosphorylation of tyrosine residues of InsR and IRS and alleviated IR. Statins also activate phosphoesterinositol-3-kinase (PI-3K) and promote the activation of phosphoinositol-dependent protein kinase (PDK1), which phosphorylates protein kinase B (PKB), improves the insulin sensitivity of the receptor and reduces IR. Statins can reduce the level of Caveolin-1, promote the activity of endothelial nitric oxide synthase (eNOS), increase the production of nitric oxide (NO) (Kinlay, 2005), dilate blood vessels, increase circulating blood volume, facilitate tissue transport and utilization of blood sugar and insulin, and indirectly reduce IR. Finally, statins can reduce the production of free fatty acids and ameliorate IR through a lipid-lowering effect. In MetS, islet β cells are prone to inflammatory reactions and oxidative stress damage. The increase in the concentration of inflammatory factors and oxidative stress products can induce Nuclear Factor kappa-light chain-enhancer of activated B cells (NF-κB) activation, TNF-α gene expression increase, and so on to trigger cell apoptosis. At the same time, ROS acts on the leukocyte chemokines and arachidonic acid in the blood to produce leukotrienes and prostaglandins, respectively. The chemokines infiltrate the leukocytes, promote the release of inflammatory factors, and aggravate the inflammatory response, which in turn improves the sensitivity of β cells to oxygen free radicals, further stimulating the inflammatory cells and beta cells to produce free radicals, forming a vicious cycle, causing progressive damage to β cells. By inhibiting the activation of NF-κB and inhibiting the expression of pro-inflammatory cytokines such as IL-1β, TNF-α and inducible nitric oxide synthase (iNOS), statins can play anti-inflammatory and antioxidant effects and reduce the damage of pancreatic β cells (Wagner et al., 2002).

There are difficulties in identifying and diagnosing statin toxicity, but currently, known statin-associated muscle symptoms (SAMS) are the most common adverse effects of statins. The prevalence of SAMS varies with different statins. Patients taking lipophilic statins, such as simvastatin and atorvastatin, are at the highest risk for SAMS because of their nonselective spread to extrahepatic tissues, such as skeletal muscle. In contrast, hydrophilic statins, such as pravastatin and fluvastatin, are less risky due to their lower muscle penetration. It has been reported that more than half of SAMS may be caused by the combination of statins and drugs metabolized by the same hepatic cytochrome P450 isoforms (Muntean et al., 2017). Other side effects of statin may be more severe, including new-onset type 2 diabetes mellitus, neurocognitive effects, neurological and renal toxicity, and hepatotoxicity.

Metformin is the most commonly used insulin-sensitizing agent in IR diseases such as diabetes, MetS, and obesity. The main effect of metformin in improving insulin resistance is by inhibiting the production of hepatic glucose. Metformin-mediated ETC complex I inhibition inhibits ATP production, resulting in elevated intracellular ADP and AMP levels and a consequent increase in the AMP/ATP ratio (Garcia and Shaw, 2017). The elevated AMP/ATP ratio activates AMP-activated protein kinase (AMPK), a primary bioenergy metabolism regulator in eukaryotic cells, which promotes catabolic reactions, produces more ATP, and inhibits anabolic pathways of energy consumption such as gluconeogenesis (Figure 2). Gluconeogenesis is the process by which simple non-sugar precursors (lactate, glycerol, glycogenic amino acids, etc.) are converted to glucose and other carbohydrates. It is regulated by the critical regulator of hepatic glucose output called the cAMP response element-binding (CREB) co-activator complex. CREB co-activator complex can regulate gluconeogenesis by regulating the activation of transcription of gluconeogenic genes, particularly glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Activation of AMPK phosphorylates Ser436 of CREB-binding protein (CBP), evoking the disassembly of the CREB co-activator complex and then suppressing the expression of gluconeogenic genes (Shaw et al., 2005). Therefore, metformin affects the ability of liver cells to process glucose. Metformin can inhibit glucose production in the liver and increase glucose utilization rate in adipose tissue and skeletal muscle. This is because metformin is an insulin sensitizer that improves insulin sensitivity by affecting tyrosine kinase activity and insulin receptor expression. Significantly, unlike other hypoglycemic drugs, metformin does not usually stimulate endogenous insulin production and, therefore, does not put patients at risk for hypoglycemia (Panchapakesan and Pollock, 2018). Moreover, metformin has been shown to improve intestinal secretion of glucagon-like peptide 1 (GLP-1), a glucose-lowering gut incretin hormone that regulates glucose homeostasis and insulin secretion by inhibiting glucagon release from the pancreas (Bahne et al., 2016). Therefore, metformin can lower blood glucose, relieve IR, and reduce blood lipid, thus alleviating MetS.

In addition, the current study found that metformin’s treatment of IR is related to its effect on the expression of GLUT4 (Herman et al., 2022). GLUT4 is an insulin-regulated glucose transporter, and its level directly affects glucose utilization of target tissues because it mediates glucose transmembrane transport, a rate-limiting step in peripheral glucose disposal (Zisman et al., 2000a; Armoni et al., 2005). Impaired GLUT4-mediated glucose uptake is a significant mechanism that induces IR, which has been demonstrated in many studies. In a study of adipocytes in diabetic mice, glucose transport decreased by 45% after 5 days of diabetes compared to controls, and at 10 days, glucose transport was severely reduced, and insulin-stimulated reduced glucose transport was observed (Napoli et al., 1995). Data obtained from a study using transgenic specific knocking out GLUT4 in mouse muscle suggest that GLUT4 is involved in insulin-stimulated glucose transport in muscle and that specific knocking out GLUT4 led to IR in liver and adipose tissue (Zisman et al., 2000b). In addition, in studies of GLUT4 fat-specific knockouts in mice, it was found that GLUT4 protein expression was downregulated, leading to reduced insulin-stimulated glucose transport, causing insulin resistance and thus increasing the risk of diabetes (Abel et al., 2001). Studies have shown that no matter which tissues have a genetic defect in GLUT4, other insulin-target tissues are eventually affected (Graham and Kahn, 2007). Because metformin phosphorylates and activates AMPK, this may be related to its effect on GLUT4-mediated glucose transport. A study of adipocytes obtained from surgical biopsies and differentiated in vitro showed that after metformin treatment for 24 h, glucose uptake in human adipocytes increased by about 2.3-fold, and GLUT4 mRNA expression levels also increased (Grisouard et al., 2010). Some studies have found that metformin is vital in GLUT4 translocation by activating AMPK. Rab-GAP protein TBC1D1 is phosphorylated after AMPK activation, which controls the translocation of GLUT4 and plasma membrane levels (Hardie, 2013). The studies of 3T3-L1 preadipocyte cells and C2C12 skeletal muscle cell lines found that AMPK plays a crucial role in GLUT4 translocation (Lee et al., 2012; Hardie, 2013).

Patients with MetS are often accompanied by abnormal blood glucose and dyslipidemia, which commonly lead to obesity. Probiotics can regulate blood glucose and lipids by promoting glucose metabolism and cholesterol conversion and inhibiting the absorption of glucose and lipids. It has been found that probiotic fermentation metabolites short chain fatty acids (SCFAs) (e.g., acetate, propionate, and butyrate) can act as signaling molecules to activate glucose-regulated protein 41 (GPR4l) and glucose-regulated protein 43 (GPR43) through free fatty acid receptors (FFARs) in the intestinal cells and then stimulate the secretion of peptide YY (PYY) and GLP-l, controlling energy intake and promoting intestinal gluconeogenesis to reduce appetite and enhance insulin sensitivity (Vernia et al., 2000; Krokowicz et al., 2014a). Moreover, the use of probiotics can improve gut microbes. In vivo studies have found that the SCFA metabolites can stimulate the proliferation and differentiation of colonic epithelium cells, increase mucus secretion, and prevent the destruction of tight linking proteins by reducing the uptake of lipopolysaccharides (LPS) on the cell wall of Gram-negative strains by intestinal cells, maintaining normal mucosal barrier permeability and protecting epithelial cells from exposure to harmful microbiota and pathogens that lead to intestinal microbiome disturbance (Topping and Clifton, 2001; Harte et al., 2011). The dysregulated microbiome contributes to pro-inflammatory reactions that are a hallmark of the obesity phenotype, which include increased uptake of LPS and regulation of intestinal barrier permeability, resulting in increased bacterial endotoxin in the circulation (Jaffar et al., 2016). Studies of human subjects found that systemic endotoxin levels were 20% higher in glucose-intolerant or obese people than in non-obese control (Harte et al., 2011). LPS and endotoxins can translocate to the circulation to promote cytokine production and initiate inflammation (Osborn and Olefsky, 2012). When LPS binds to toll-like receptors 4 and 2 (TLR 2, 4) in peripheral tissues and mucous membranes, macrophages and dendritic cells are activated, producing more inflammatory biomarkers (e.g., TNF-α and MCP-1) and initiating a cascade of pro-inflammatory signals. Studies in animals and humans have shown that probiotics play a vital role in modulating inflammation. After binding to specific receptors of intestinal epithelial cells, probiotics can inhibit regulatory T cells (Treg cells), NF-κB pathway, and pro-inflammatory cytokines produced by macrophages and neutrophils, thereby playing an anti-inflammatory role (Park et al., 2007; Vinolo et al., 2011).

Probiotics have also been shown to inhibit the activity of α-glucosidase in the intestine. Because the primary function of α-glucosidase is to directly participate in the hydrolysis of the glucosidic bond of starch and glycogen, releasing glucose as a product and increasing the content of glucose in the body, inhibiting α-glucosidase can delay the digestion and absorption of saccharides in the intestine. The main metabolic pathway of cholesterol in the body is to convert cholesterol into bile acid through the liver, and probiotics can not only improve the activity of bile salt hydrolase (BSH) but also contain a large amount of BSH. BSH can decompose bound bile saline into free bile salts and glycine/taurine, which promotes the de novo synthesis of bound bile salts from cholesterol to compensate for the loss, thereby reducing the serum cholesterol level in the body, thereby improving hypercholesterolemia. The mechanisms of probiotics are described in Figure 3. Table 2 summarizes the other effects of different probiotics on improving MetS.

Data from several studies suggest that patients may improve current medical therapy by using probiotics in combination with other medications to treat MetS, but this will not affect related inflammatory biomarkers or clinical characteristics of the MetS (Aoki et al., 2017; Yoon et al., 2023).

Butyrate, as a SCFA produced by gut microbes, can improve MetS. Multiple studies have found it can improve insulin sensitivity by stimulating adipogenesis (Nie et al., 2015). This is achieved through various mechanisms, mainly by increasing the expression of genes for adipocyte differentiation (He et al., 2009). For instance, the expression of SREBP-1c’s mRNA, which is a primary regulator for fatty acid de novo synthesis and adipogenesis, is activated by butyrate. In addition, butyrate promoted the upregulation of adipocyte differentiation markers C/EBPα, C/EBPβ, and PPARγ, promoting adipocyte differentiation and maturation. Increased adipocytes result in more lipids being broken down, and therefore, more lipogenesis diminishes fatty acids in the circulation, thereby protecting different organs from lipotoxicity and insulin resistance. Butyric acid can also reduce serum cholesterol levels.

Butyrate also acts on pancreatic islets to improve glucose homeostasis in patients with MetS. The study found a threefold increase in the number of islet cells but no longer produce any detectable islet hormones in T2DM patients compared to non-diabetic individuals. This dedifferentiation of islet cells is hypothesized to be caused by the pro-inflammatory cytokine IL-1β (Chen et al., 2019). IL-1β expresses upregulation in MetS and can induce pancreatic β-cell dysfunction and apoptosis (Francesca et al., 2016). The pancreatic β-cell is a type of cell whose function is reduced in patients with impaired glucose tolerance and T2DM. Butyrate can downregulate the expression of IL-1β-induced inflammatory genes to prevent IL-1β induced β-cell dysfunction and apoptosis. This is achieved by butyrate protecting β cells from IL-1β-induced impairment of insulin content and glucose-stimulated insulin secretion (GSIS) that characterize β cell dysfunction. Moreover, butyrate did not affect the expression of β cells-specific genes Ins, MafA, and Ucn3, which were reduced by IL-1β (Prause et al., 2021).

Dietary supplementation with butyrate prevents or reduces obesity and insulin resistance (Chen et al., 2018a). This is because butyrate can bind to and activate the G protein-coupled FFARs, FFAR2, and FFAR3 in the intestinal enteroendocrine cells, leading to the release of PYY and GLP-1, which reduces appetite and body weight (Fahed et al., 2022). PYY slows gastric emptying and decreases appetite, whereas GLP-1 inhibits glucagon secretion and increases insulin secretion (Gao et al., 2009b), so butyrate can improve insulin sensitivity and alleviate MetS (Figure 4). The disorder of HDAC expression promotes the development of metabolic diseases such as diabetes and CVD (Yiew et al., 2015). Studies have shown that butyrate has an antidiabetic effect in T1D and T2DM animal models, related to the inhibition of histone deacetylases (HDACs) activation. HDAC inhibition and histone acetylation are related to β cell proliferation and differentiation and insulin gene regulation (Goicoa et al., 2006; Lenoir et al., 2011). In T1D mice models, after butyrate treatment, the body weight and the function of islet beta cells of diabetic mice were significantly improved, the blood glucose level was reduced considerably, and the plasma insulin level was increased, but insulin resistance was not restored (Khan and Jena, 2014). In high-fat diet (HFD) and streptozotocin (STZ) mediated T2DM mice models, butyrate treatment significantly reduced the increase of diabetes-related plasma triglyceride and cholesterol levels, reduced diabetes-related endocrine pancreatic (islet) damage and significantly inhibited the growth of diabetes-induced HDACs activity, preventing glucagon and forkhead box protein O1 (FOXO1)-mediated liver gluconeogenesis in type 2 diabetic rats (Khan and Jena, 2016). HDACs are a class of epigenetic modification enzymes that remove acetyl groups located in the tail of histones, preventing histone acetylation. Inhibition of HDACs will promote histone acetylation, which is conducive to the dissociation of DNA from histone octamer and relaxation of nucleosome structure so that various transcription factors and co-transcription factors can bind specifically to DNA binding sites and activate gene transcription (Bose et al., 2014). It also has been found that butyrate reduces the expression of the primary genes involved in intestinal cholesterol absorption, decreasing cholesterol absorption in the gut (Chen et al., 2018b). In addition, it decreases the activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) and then reduces cholesterol synthesis of Caco-2 enterocytes. The roles of butyrate in MetS are summarized in Figure 5.

In animal and human models, studies have found that butyrate treatment can reduce HFD-mediated weight gain and improve insulin sensitivity, hyperlipidemia, hyperinsulinemia, and hyperglycemia. Table 3 summarizes these studies. Currently, a lot of clinical trials also have focused on the effects of transrectal or oral administration of butyrate on intestinal disease, with several trials showing improvement in diverticulitis, travelers’ diarrhea, and ulcerative colitis (Krokowicz et al., 2014a; Steinert et al., 2017). No serious adverse effects occurred, and they were well tolerated. Oral butyrate, which causes foul-smelling belching, is a unique drawback (Krokowicz et al., 2014b). In the study on the effect of oral butyrate on MetS, it was observed that there was no increase in butyrate levels in plasma and feces after 4 weeks of oral butyrate treatment, and it did not improve glucose metabolism in MetS subjects. However, there are benefits for glucose metabolism in lean but non-MetS subjects (Kec et al., 2018). However, there are not enough human clinical trials investigating the benefits of butyrate on MetS.

Long-term use of statins and metformin in the treatment of MetS may cause side effects such as headache and dizziness. Therefore, it is urgent to discover new therapeutic targets for MetS and then reduce the side effects. Due to Chinese herbs’ characteristic low side effects, ginsenosides have been used in recent years to study the treatment of MetS. Ginsenosides are active ingredients in ginseng, which have rich pharmacological activities and different phenotypes in MetS. It regulates immune response, diabetes, and cardiovascular disease treatment (Shi et al., 2019). There are more than 100 different types of ginsenosides, of which Rb1, Rb2, Rc, Rd, Re, Rg1, and Rg3 are the most abundant, accounting for more than 90% of the total saponins in ginseng (Mohanan et al., 2018). Among them, ginsenoside Rb1 has been found to aid in the treatment of diabetes, obesity, and CVD and delay the development and progression of complications of these diseases by exerting insulin sensitization, anti-diabetic, anti-hyperglycemic, and anti-obesity properties, as shown in Figure 6. Ginsenoside Rb1 may exert these properties mainly by improving glucose tolerance, increasing insulin sensitivity, regulating adipocyte development and function, reducing liver fat accumulation, and inhibiting adipocyte lipolysis.

Current in vivo results (Table 4) show that intraperitoneal injection of Rb1 (10 mg/kg body mass, daily) in HFD-induced obese rats significantly reduced weight gain, body fat content, fasting blood glucose, and fasting plasma insulin, and improved glucose tolerance in HFD-induced obese rats compared with controls (Xiong et al., 2010). In HFD-induced T2DM mouse models, ginsenoside Rb1 (10 mg/kg body mass daily) after 21 days of treatment improved HFD-induced weight gain, fat mass accumulation, and glucose tolerance compared with the vehicle treatment group (Wu et al., 2014). Significantly, Rb1 treatment also reduced levels of pro-inflammatory cytokines (TNF-a and IL-6) in adipose tissue and the liver, which further inhibits the NF-kB pathway molecules (p-IKK and p-IkBα) and the leptin p-STAT3 signaling pathway, and reduces transcription of negative regulators of the low leptin signaling pathway (SOCS3 and PTP1B) (Wu et al., 2014). These studies suggest that Rb1 has the potential to be used in the treatment of obesity and diabetes, improving body weight and reducing obesity-induced inflammation, thereby improving insulin sensitivity. In addition, ginsenoside Rb1 treatment of HFD-induced T2DM mice improved fasting blood glucose, glucose tolerance, and insulin sensitivity, and GRb1 appeared to reduce levels of 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) and its mRNA in adipose tissue and liver, to play its anti-diabetic role (Song et al., 2017). Moreover, after 14 days of intraperitoneal injection of ginsenoside Rb1 (20 mg/kg, daily) in db/db obese diabetic mice, homeostasis model assessment insulin resistance (HOMA-IR), fasting glucose, and fasting insulin were significantly reduced. Glucose consumption was increased in 3T3-L1 adipocytes of mice, GLUT1 and GLUT4 expression was upregulated, and AKT phosphorylation was restored in mouse adipose tissue (Shang et al., 2014). Therefore, ginsenoside Rb1 can activate the insulin signaling pathway (PI-3K-Akt), upregulate the expression of GLUTs in adipose tissue, and increase glucose uptake by adipose cells, thereby regulating glucose metabolism and insulin-sensitizing activity. In vitro, studies have also shown that ginsenoside Rb1 regulates adipose tissue metabolism, regulates glucose metabolism, and has insulin-sensitizing activity, among which mouse adipose cell 3T3-L1 cells have been widely used in studies (Hanél Sadie-Van, 2019).

In vitro studies on 3T3-L1 adipocytes and C2C12 myotubes demonstrated that ginsenoside Rb1 promotes translocation of GLUT1 and GLUT4 to the cell surface by activating phosphorylation of insulin receptor substrate-1 and PKB, thereby stimulating glucose transport in insulin-sensitive cells, and stimulated PI3K activity in the absence of the insulin receptor activation, which exerts hypoglycemic and anti-diabetic properties (Shang et al., 2008). Moreover, ginsenoside Rb1 promoted adipogenesis in 3T3-L1 preadipocytes dose-dependently, and lipid accumulation increased by about 56% after 10 μM Rb1 treatment. It is thought that ginsenoside Rb1 is partially involved in enhancing the expression of Peroxisome proliferator-activated receptor γ 2 (PPARγ2) and CCAAT/enhancer binding protein (C/EBP), thereby playing roles in anti-diabetic and insulin-sensitizing activities (Ambele et al., 2020). PPARγ2 and C/EBP are molecules that are recognized to regulate the differentiation process of preadipocytes into mature adipocytes and promote downstream adipose-specific gene expression, thereby exerting an influence on adipocyte abundance and promote reverse cholesterol transport and glucose and lipid metabolism (Rosen, 2005). It was also found that Rb1 significantly increased 3T3-L1 cellular glucose uptake and GLUT4 expression and promoted adipogenesis by increasing the expression of PPARγ2 and C/EBP, as well as ap2, one of their target genes, thereby exerting anti-diabetic, anti-obesity, and insulin-sensitizing activities (Shang et al., 2007).

In addition, ginsenoside Rb1 plays a vital role in the treatment of CVD due to its control of NO production, endothelial oxide synthetase (eNOS) expression, and Ca²⁺ channels. In vitro, it was found that Rb1 rapidly phosphorylates endothelial oxide synthetase (eNOS) (Ser1177) through I3 kinase/Akt and MEK/ERK pathways and androgen receptors, upregulates eNOS, thereby stimulating the production of NO in aortic endothelial cells (Yu et al., 2007). Another study showed that Rb1 could improve the effect of oxidized low-density lipoprotein (oxLDL) on NO production in oxLDL-injuring human umbilical vein endothelial cells (HUVECs) and reverse oxLDL’s effects on NO, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in endothelial cells (He et al., 2007). Compared with the control group, high-dose Rb1 (10 mg/mL) treatment blocked the effect of oxLDL on lactate dehydrogenase (LDH) activity and the levels of NO and t-PA, which are vascular endothelial active substances with various anti-atherosclerotic effects, were significantly increased, and the levels of PAI-1 were decreased (He et al., 2007). Rb1 also plays a role in ion channel regulation. Studies have found that Rb1 promotes NO release in cardiomyocytes, reduces intracellular free Ca²⁺, and reduces the expression of monocrotaline (MCT) -mediated transcription factors GATA binding factor-4 (GATA4) and nuclear factor of activated T cells 3 (NFAT3) by attenuating the calcineurin signal transduction pathway, thus playing an antihypertrophic effect (Jiang et al., 2007). Furthermore, ginsenoside Rb1 inhibits eating desire by regulating serum PYY during HFD-induced obesity (Lin et al., 2014).

Other ginsenosides also have anti-diabetic, anti-hyperglycemic, and anti-obesity effects. Previous studies have shown that ginsenoside Rb2 can effectively improve insulin sensitivity (Hong et al., 2019). In addition, it inhibited the increase of plasma triglyceride levels in diet-induced obese mice and prevented triglyceride deposition (Gu et al., 2013). Ginsenoside Rg1 reduces intestinal glucose uptake mediated by sodium-dependent glucose transporter 1, thereby lowering blood glucose and alleviating insulin resistance (Wang C. W. et al., 2015). Furthermore, the glycosyl moiety of ginsenoside Rg3 stimulates GLP-1 secretion in the intestine through a sweet taste receptor-mediated signal transduction pathway, thereby having an anti-hyperglycemic effect. Meanwhile, ginsenosides Rg1 and Rb3 could protect renal endothelial function and reduce hypertension by stimulating endothelial-dependent vessel dilatation and alleviating oxidative stress in renal arteries, respectively (Pan et al., 2012; Wang et al., 2014). The study revealed that ginsenoside Rc significantly reduced the body weight of obese mice induced by a high-fat diet. This effect was attributed to the upregulation of PPARα and liver glycogenic genes PPARγ coactivator l alpha (PGC-1α) in skeletal muscle by Rc, as well as the activation of the sirtuin 6/AMP-activated protein kinase (SIRT6/AMPK) pathway, thereby promoting the oxidative decomposition of fatty acids. Another study found that ginsenosides Rc significantly reduced insulin levels and fasting blood glucose in mice fed a high-fat diet, which may be related to RC-mediated downregulation of PEPCK, PGC-1a, and G6Pase expression (Yang et al., 2023). In addition to the above therapeutic effects, ginsenoside also has anti-ischemic heart disease, anti-atherosclerosis, and other effects (Fan et al., 2020). Therefore, ginsenosides have great potential in preventing and treating diabetes, obesity, and MetS by inhibiting adipogenesis, regulating insulin resistance, and lowering blood pressure.

Originating in Africa, hibiscus is a species of the Malvaceae family that includes more than 250 species of herbs, shrubs, and trees. The leaves, flowers, calyx, and bark of hibiscus are used as medicine due to their antioxidant properties, which destroy free radicals to reduce the risk of inflammatory maladies such as MetS and CVD (Jeffery and Richardson, 2021). The antioxidant properties of hibiscus are the fact that it contains saponins, alkaloids, terpenes, and a large quantity of polyphenols. A study in patients with MetS and spontaneously hypertensive rats found that polyphenols rich in Hibiscus sabdariffa (H. sabdariffa) calices reduced hypertension and TNF-α expression and increased eNOS and NO in endothelial cells (p < 0.05). Therefore, hibiscus plays an anti-inflammatory and antihypertensive role and should be a candidate for managing metabolic cardiovascular risks (Joven et al., 2014).

In addition to its anti-inflammatory capacity, hibiscus has also been identified to have pharmacological anti-diabetic and hyperglycemic properties for regulating insulin resistance and lowering blood glucose (Table 5) (Zahid et al., 2014; Amaya-Cruz et al., 2019). After intra-gastric administration of Hibiscus rosa sinensis (H. Rosa-sinensis), streptozotocin (STZ)-induced diabetic rats’ blood glucose and glycated hemoglobin (HbA1c), which can reflect chronic blood glucose, are significantly reduced. This suggests that Hibiscus rosa-sinensis controls long-term hyperglycemia (Pillai and Mini, 2016b). Moreover, compared with the control group, the mRNA expressions of NF-κB and P38MAPK were significantly downregulated after H. rosa-sinensis treatment, and the activities of antioxidant enzymes such as CAT, SOD, GPx, and GRd were increased considerably (Pillai and Mini, 2016b). Thus, H. rosa-sinensis may play an antidiabetic role by alleviating excessive ROS-mediated islet beta cell dysfunction. The study found that the overall effect of 25 mg/kg body weight H. rosa-sinensis treatment was comparable to metformin. Other studies also have compared hibiscus with anti-hyperglycemic medicines already on the market. Taking lovastatin, metformin, and glibenclamide as an example, a dose of 200 mg/kg H. sabdariffa had the same therapeutic effect as lovastatin in lowering blood glucose (Farombi and Ige, 2007). The therapeutic effect of 25 mg/kg flower extract from H. rosa-sinensis on insulin resistance was comparable to a 4-fold dose of metformin (Pillai and Mini, 2016a). The root extract from H. rosa-sinensis was as effective as glibenclamide in lowering fasting blood glucose (Aba et al., 2014). A human study found that patients with MetS who took hibiscus alone or combined with a preventive treatment diet for a month had lower blood glucose levels than pre-treatment (Gurrola-Díaz et al., 2010).

In addition to the anti-hyperglycemic effect, hibiscus has anti-lipidemic and anti-atherosclerotic activities. Multiple studies have shown that when animals have a high-fat diet, hibiscus generally inhibits increases in LDL cholesterol and TG and sometimes increases HDL cholesterol, and the therapeutic effect is dose-dependent (Lee et al., 2018) (Table 6). A study on the effects of ethyl acetate, an extract of the flower H. rosa sinensis flowers (HRF), on 3T3-L1 cells found that HRF reduced triglyceride content and intracellular lipid accumulation by activating AMPK (Lingesh et al., 2019). After activation of AMPK, phosphorylated AMPK inhibited the expression of cholesterol synthesis rate-limiting enzyme HMGCR and sterol-regulatory element binding protein 1c (SREGBP-1C), indirectly decreased the downstream expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and decreased TG levels (Lingesh et al., 2019). Or directly inhibit ACC activity, decrease ACC expression, reduce the inhibition of carnitine palmitoyl transferase 1 (CPT-1), a key enzyme for fatty acid β-oxidation, promote fatty acid oxidation, and reduce TG synthesis (Lingesh et al., 2019). Another study found that H. sabdariffa calices also significantly reduced TG, total cholesterol, and LDL levels in obese adolescents. Therefore, H. sabdariffa is expected to prevent and treat dyslipidemia and atherosclerotic diseases in adolescents (Sabzghabaee et al., 2013). After consuming 5%, 10%, and 15% of H. sabdariffa extract in high-calorie diet-mediated rats for 28 days, the TG and LDL levels of the three groups of mice were reduced (Farombi and Ige, 2007). The total cholesterol level of rats treated with the 5% H. sabdariffa extract group was significantly decreased compared with the 10% and 15% H. sabdariffa extract groups (Farombi and Ige, 2007). Therefore, 5% extract has the best effect on reducing blood lipids in rats, and the effect of H. sabdariffa extract on treating dyslipidemia is dose-dependent. Moreover, in vitro studies of high-glucose treated vascular smooth muscle cells (VSMC) found that polyphenolic isolate of H. sabdariffa (HPI) timing (24 h–96 h) and dose (HPI, 0.01 mg–1.0 mg) dependently reduces the proliferation and migration of high-glucose stimulated cells by inhibiting the activity of matrix metalloproteinase (MMP), an extracellular matrix (ECM) degrading enzyme during cell migration (Huang et al., 2009). HPI may, therefore, be a promising herb for treating atherosclerosis caused by the proliferation and migration of VSMCs.

The Mediterranean diet (MedDiet) refers to the dietary patterns and cooking methods followed by people living in the Mediterranean Basin (Barreto et al., 2014). MedDiet calls for daily intake of whole grains, low-fat dairy products, vegetables, fruits, and legumes; monthly consumption of red meat; moderate intake of fish, red wine, eggs, and poultry; olive oil as the primary source of lipids; regular physical activity (Bagetta et al., 2020). Compounds that are beneficial to human health are found in foods advocated in the MedDiet, such as fruits, nuts, vegetables, grains, red wine, and olives, including polyphenols, polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and anti-oxidants (vitamin A, C, and E) which have been linked to lower TG levels, reduced risk of CVD, a stable glycemic index (GI) and lower LDL oxidation (Bagetta et al., 2020). In the MedDiet, fruits and vegetables are the primary sources of polyphenols; polyphenols have sound antioxidant effects, can block oxidative stress, reduce the plasma concentration of LDL, increase the plasma concentration of HDL, and thus improve IR, dyslipidemia, and hypertension (Liu et al., 2019). Resveratrol is also the primary polyphenol in red wine. It can activate sirtuin 1, which is involved in lipolysis, and adenosine monophosphate protein kinase, increasing insulin sensitivity (Hou et al., 2019). Besides, it also has anti-inflammatory effects. Polyphenols contained in olive oil may reduce the risk of developing MetS by lowering blood pressure, IR, lipid peroxidation, and visceral obesity, while polyphenols also block the signaling pathways of NF-κB and reduce pro-inflammatory cytokines secretion (Priscilla et al., 2017). In a 6-week clinical trial, randomized, 8 g dried grape residue (mainly containing polyphenols such as proanthocyanidins) or placebo was given daily to 50 subjects exhibiting two or more MetS abnormal medical phenotypes. After 6 weeks, the subjects’ quantitative insulin sensitivity test index (QUICKI) elevated from 0.42, HOMA-IR reduced significantly from 2.1 to 1.4, and insulin resistance improved (Hui et al., 2018). In another 12-week clinical trial, 33 subjects with central obesity who had a body mass index (BMI) of more than 25 kg/m² or a waist circumference of more than 80 cm (female) or 94 cm (male) were randomly distributed into two groups. 500 g/day of Caralluma Fimbriata extract (gallic acid) and placebos were administered. After exercise and diet intervention, body weight, BMI, body weight, total fat, triglyceride levels, and saturated fat intake were significantly reduced in both groups, but the decline was more pronounced in the C. fimbriata extract group (Astell et al., 2013). Moreover, olive oil also contains MUFA, such as oleic acid, which inhibits angiotensin-converting enzyme, thereby regulating blood pressure, as well as increasing HDL concentration, reducing plasma LDL concentration, and improving dyslipidemia (Massaro et al., 2020). Antioxidants such as vitamins A, C, and E, which are contained in the MediDiet, may increase insulin secretion, promote weight loss, and alleviate IR (Said et al., 2021). In addition, these vitamins reduce reactive oxygen species and pro-inflammatory cytokine production, improve lipid metabolism, and protect cardiovascular health (Villa-Etchegoyen et al., 2019). Moreover, MedDiet includes fruits and vegetables with high amounts of fiber, which helps with weight control and provides a sense of satiety.

The dietary components of MedDiet, which have antioxidant and anti-inflammatory properties, reduce the incidence of CVD and T2DM and also reduce the severity and associated complications in established patients, which may be a possible explanation for the relief of MetS by MedDiet. Substantial scientific evidence suggests high adherence to this dietary pattern can prevent and delay many diseases, such as T2DM, CVD, Alzheimer’s disease, and MetS (Stadlbauer et al., 2015). Table 7 summarizes studies on the link between MedDiet and MetS.

A high-protein diet refers to foods that contain more protein in the daily diet. 20%–30% of the daily energy intake in a high-protein diet comes from protein (Stadlbauer et al., 2015). The International Nutrition Society recommends a standard-protein diet of 0.8 g grams of protein per kilogram of body weight for healthy adults. In contrast, the high-protein diet recommends that people consume 1.34–1.5 g of protein per kilogram of body weight per day. At present, studies have found that a high-protein diet may improve glucose homeostasis, lower lipids, lower blood pressure, and lower body mass (Layman et al., 2009; Pedersen et al., 2013; Daly et al., 2014; Heer and Egert, 2015), so it has been proposed to control blood glucose and treat obesity and MetS. However, controlling blood glucose and weight on high-protein diets remains uncertain and controversial. A meta-analysis of 18 randomized controlled trials involving 1,099 adults with T2DM showed that the high-protein diet group had no significant weight and blood pressure reduction compared to low-protein diets but triglyceride levels reduction (Zhao et al., 2018). However, after 6 months on a standard protein diet and a high-protein diet in a randomized group of 118 adults with MetS, overall weight loss was 5.1 ± 3.6 kg in the SPD group and 7.0 ± 3.7 kg in the high-protein diet group (Campos-Nonato et al., 2017). In another study, obese adults with MetS lost 7.4% (95% CI 5.7%–9.2%) of their body weight after adhering to a high-protein diet that limited cholesterol (Rock et al., 2014). Moreover, in another study, 100 overweight and obese older adults (55–80 years old) were randomly assigned to a standard or high-protein diet and to do or not do resistance exercise during a 10-week weight loss period. Measure the change in fat-free mass (FFM). Analysis of in-group results showed that high protein binding exercise significantly increased FFM (+0.6 ± 1). 3 kg, p = 0.011) (Verreijen et al., 2015). Therefore, adherence to a high-protein diet is effective for weight loss in obese patients with MetS, with even more weight loss combined with exercise. Some studies have also found that high protein intake increases feelings of fullness and reduces energy intake at the next meal (Halton and Hu, 2004; Eisenstein et al., 2010). The high protein intake helps to increase the thermal effect of eating and maintain rest energy expenditure during energy restriction, thus promoting weight loss.

In a randomized, controlled, cross-feeding, three-phase study, participants were 164 patients with high blood pressure and no diabetes. The patients received three dietary interventions: a high-carbohydrate diet, a high-protein diet, and an unsaturated fat diet. Changes in the QUICKI, an adequate measure of insulin sensitivity, were then assessed. Each diet lasts 6 weeks, with a 2 to 4-week washout between diets (Gadgil et al., 2013). The results showed that the insulin sensitivity was not improved significantly with a high-protein or high-cholesterol dietary pattern, whereas it was improved with an unsaturated diet, which suggests that replacing a high-protein or high-cholesterol dietary with an unsaturated fat diet (e.g., MedDiet) is one way to improve insulin sensitivity (Gadgil et al., 2013). Subsequent studies, however, have shown different results. In a 21-day randomized trial, 16 morbidly obese women with insulin resistance were divided into two groups and given an equal-calorie Mediterranean diet or a high-protein diet intervention. The results showed that the high-protein diet was more effective in reducing insulin resistance (HOMA-IR: −1.78 [95% CI: 3.03−−0.52]) and regulating blood glucose steady state (−3.13 [−4.60, −1.67] mg/dL) (Menni et al., 2021). In the future, more experiments are needed to demonstrate the effect of a high-protein diet on insulin sensitivity. Table 8 summarizes studies on the link between the high-protein diet and MetS.

Foods containing primarily protein, such as meat and processed meats, are related to higher risks for T2DM, CVD, and MetS, so dietary guidelines recommend choosing protein-rich plant-based foods such as soy, legumes, and nuts over meat and processed meats in a high-protein diet (Stadlbauer et al., 2015). Moreover, the study suggests that weight loss and CVD improvement are more significant with a high-protein diet pattern than with a standard-protein diet (Stadlbauer et al., 2015).

Current research has found that a high-protein diet is expected to improve weight regain after weight loss (Zarrinpar, 2022). After short-term dietary restriction, weight gain caused by ingestion is due to increased intestinal lipid absorption, fatty acids and triglycerides synthesis, and white adipose tissue. Studies have found that this is related to the fact that a high-protein diet can reduce intestinal lipid absorption and improve the utilization of fatty acids (Zhong et al., 2022). Microbiome analysis of the mice’s gut showed a significant increase in a Lactobacillus murinus species (named Lam-1) in the mice’s cecum after the short-term dietary restriction in all refeeding scenarios, but Lam-1 was suppressed by a high-protein diet. When specific antibiotics inhibited Lam-1, refeed-induced adipose tissue accumulation after the short-term dietary intervention was inhibited. Lam-1 treatment of gnotobiotic mice increased fatty acid and intestinal lipid uptake in white adipose tissue. Lam-1 induced increased intestinal fatty acid absorption was associated with five specific metabolites: 4-hydroxyphenyl acetic acid (HPLA), 1-alcohol-lactic acid, 2-hydroxyisopropionic acid (HICA), 1-indole-lactic acid (ILA), 2-hydroxy-3-methylbutyric acid (HMBA), and DL-3-phenyllactic acid (PLA) (Zarrinpar, 2022). This is attributed to the impact of Lam-1 and its intestinal metabolites on suppressing fatty acid oxidation while enhancing lipid absorption in white adipose tissue (WAT), collectively contributing to refeed-induced obesity following short-term dietary intervention.

Circadian regulation of the autonomic nervous system, endocrine system, and nutrient metabolism contribute to physiological and metabolic homeostasis (Panda, 2016). Erratic eating patterns, such as prolonged periods of food intake per day and irregular mealtimes, can disrupt circadian rhythms. Chronic circadian rhythm disorders lead to high blood pressure, obesity, insulin resistance, inflammation, and dyslipidemia, which increase the risk of metabolic syndrome (Pot et al., 2016; Zarrinpar et al., 2016; Ha and Song, 2019). Therefore, novel approaches to modify circadian rhythms by restoring dietary patterns are promising for patients with MetS. Improving diet patterns and lifestyle is an essential measure for the treatment and intervention of MetS. Time-restricted eating (TRE) is one of the emerging dietary interventions in which patients eat at a fixed time but do not engage in any prohibited calorie restriction or dietary composition changes to sustain consistent daily fasting and feeding cycles to maintain a robust circadian rhythm (Świątkiewicz et al., 2021; Das and Webster, 2022). Since TRE does not require restricting food intake or changing diet patterns, this method of dietary control may be an easier way to maintain a healthy weight in the long term. It alleviates circadian rhythm disruption by introducing continuous fasting periods of 12–16 h per day without altering total food intake. This method imposes an eating-fasting cycle, which effectively controls the patient’s eating patterns, regulates the circadian rhythms, and improves the metabolic regulation mechanisms, thus benefiting the treatment of MetS. In diet-induced obesity (DIO) mice models, time-restricted feeding (TRF) restores metabolic regulators in circulation, such as CREB and AMPK, as well as circadian clock oscillation. Moreover, the body weight of TRF mice was significantly reduced, and glucolipid homeostasis was improved considerably, which was also accompanied by reduced inflammation and steatosis (Panda, 2016). In the ovariectomized (OVX) female mice models, TRF effectively reversed metabolic syndrome in mice by reducing body weight, insulin resistance, and circulating triglycerides and cholesterol (Chung et al., 2016). Several studies of TRE have focused on healthy people or people who are overweight but do not have metabolic disease. In overweight men, 9-h TRE improved insulin resistance and glycemic response to test meals (Hutchison et al., 2019a). In men with prediabetes, 6-h TRE relieves insulin resistance signs but does not reduce energy intake (Sutton et al., 2018a). These studies suggest that TRE can prevent MetS. In a study of patients with MetS, a reduction in participants’ daily eating window from greater than 14 h to a time-restricted diet of 10 h resulted in weight loss, lower levels of cardiovascular disease, and lower blood pressure. TRE is likely to act as an “add-on” therapy to antihypertensive medications (such as statins) in patients with MetS. Table 9 summarizes studies on the link between the TRE and MetS. However, TRE strictly controls the eating time, changes the nutrition intake, increases physical activity, and supports a low-calorie diet to address the disorder of metabolic homeostasis, leading to poor patient compliance. Large-scale clinical trials are still needed to confirm the effects of TRE in preventing and treating MetS. Furthermore, because this stage is challenging to maintain over a long period, its efficacy in decreasing cardiometabolic risk in MetS patients is limited.