Research progress on mechanism of Chinese material medica in preventing and treating insulin resistance and type 2 diabetes mellitus

Jianglan Long, Dan Yan,＊

1 Beijing Institute of Clinical Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

Abstract Insulin resistance (IR) is a significant feature and one of the basic links in the pathogenesis of type 2 diabetes mellitus (T2DM).Chinese material medica (CMM) has promoted the development of traditional Chinese medicine due to its definite clinical efficacy in the treatment of IR and T2DM.However, owing to the fact that the mechanism of CMM is characterized by “multiple components and multiple targets”, which has not been effectively interpreted, result in the scientificity of clinical efficacy with CMM is controversial.Therefore, this article summarized the mechanisms of CMM and its main active components in improving IR and preventing and treating T2DM, whose aim is to provide valuable reference for the research mechanism on the treatment of IR and T2DM.

Keywords:Chinese material medica, Active components, Insulin resistance, Type 2 diabetes mellitus, Mechanism of action

Background

Insulin resistance (IR) that refers to the pathological changes and clinical manifestations caused by the reduction or loss of insulin sensitivity of target tissues is a significant feature and one of the links in the pathogenesis of type 2 diabetes mellitus (T2DM) [1].The number of T2DM patients worldwide increases year by year.With a large population and a serious aging problem, China has become a country with high incidence of T2DM [2].Therefore, the prevention and treatment of IR and T2DM are extremely important.

It has been well established at IR and impaired insulin secretion remain the core defects in T2DM, but other multiple pathophysiological abnormalities contribute to the dysregulation of glucose metabolism.Inflammation, oxidative stress and dysregulation of lipid metabolism can promote the occurrence and development of IR and T2DM.The immune system is the first line of defense for human health.It has been argued that a disorder of the innate immune system underlies the pathophysiology of IR and T2DM [3,4].Autoimmunity and chronic inflammatory are closely related to T2DM.Lymphocytes, inflammatory factors, and autoantibodies are all involved in the process of islet cell damage in T2DM patients [5].With increasing evidence, it is considered that the 90% of true T2DM subjects without evidence of autoimmunity nevertheless have innate immune system dysfunction [6].

Over the long history of thousands of years, the clinical efficacy of Chinese material medica (CMM) has been continuously verified, and the traditional Chinese medicine system has been continuously improved and developed, gradually forming a classical medication system that is indeed effective for the diseases.Ranging from compound CMM, single CMM, active component compositions to single active component for the prevention and treatment of IR and T2DM, various studies have advantages [7-9].CMM prescription in clinical application can better reflect the holism of traditional Chinese medicine treatment, and a single active component has a clearer mechanism of action in the application, reflecting the scientific nature of clinical application of CMM.

The vast majority of CMM administration routes are oral, which highlights the pharmacological effects of single CMM/compound CMM active components with low oral bioavailability.Natural products are the main active components of single CMM/compound CMM, and the oral bioavailability of most natural products is low, such as berberine and mangiferin [10,11].Although the oral bioavailability is low, berberine and mangiferin both exhibit good pharmacological effects.In treating T2DM, berberine and mangiferin have significant effects on improving IR and anti-diabetes [12-14].

The organism is complex and diverse, so the pathological mechanism is not immutable after the occurrence of the disease.The use of single CMM/compound CMM in the treatment reflects the holism of traditional Chinese medicine treatment, balancing, and overall regulation of the body state.However, due to the combination of multiple drugs after the compatibility of compound CMM, the mechanism has the feature of “multiple components and multiple targets” and has not been effectively explained, thus the scientificity of clinical efficacy of CMM is controversial.Therefore, in order to prevent and treat IR and T2DM and understand the mechanism of CMM, we reviewed the mechanisms of single CMM/compound CMM and their main active components in preventing and treating of IR and T2DM.

Prevention and treatment of IR and T2DM with CMM

Single CMM

The pharmacological studies have proved that many single CMM have the effects of improving IR and antidiabetes, such as Huanglian(Coplis chinensisFranch), Huangqi(Astragalus membranaceus(Fisch.) Bge), Dihuang (Rehmannia glutinosaLibosch.), Maidong(Ophiopogon japonicus(Thunb.) Ker-Gawl), Renshen(Panax ginsengC.A.Mey.), Rougui (CiNNamomum cassiaPresl), Shanyao(Dioscorea oppositaThunb.), Zhimu(Anemarrhena asphodeloidesBge.), Fuling (Poria cocos(Schw.) Wolf), Gegen (Pueraria lobata(Willd.) hwi), Tusizi (Cuscuta chinensisLam.), Kugua(Momordica charantiaL.), Xuanshen (Scrophularia ningpoensisHemsl.), Danshen(Salvia miltiorrhizaBge.), Guijianyu(Euonymus alatus(Thunb.) Sieb.), Xianhecao (Agrimonia pilosaLedeb.), etc [15-22].This review focuses on the relationship between commonly used drugs with their active components and IR as well as T2DM.

Berberine (Figure 1), the main active anti-diabetic component inRhizoma Coptidis, can reduce body weight, significantly improve impaired glucose tolerance (IGT) and IR [9].Berberine mediates protein kinase C to increase the expression of insulin receptor and exert the anti-IR effect through insulin signaling pathway to increase insulin sensitivity [23].Plasma levels of lipopolysaccharide, Toll-like receptor 4, nuclear factor kappa B (NF-κB) and tumor necrosis factor-α (TNF-α) in rats with IGT are increased, and the above indicators can be reversed after administrat- ion of berberine.Furthermore, berberine can improve the structure of gut microbiota and restore species diversity [24].

Figure 1.The structure of some representative components in Chinese material medica.

After administration of the aqueous extract ofRadix Astragali, there are lose weight, improving insulin sensitivity and reducing fatty liver in rats with T2DM [25].In addition, polysaccharide ofRadix Astragaliincreases the activities of phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB) and Glucose transporter (GLUT) GLUT4, which promotes glucose uptake in IR adipocytes.At the same time, polysaccharide increases insulin sensitivity to improve IR in 3T3-L1 adipocytes [26].The combination of berberine and astragalus polysaccharide has a synergistic effect, in that it can inhibit the key gluconeogenesis enzyme, phosphoenolpyruvate carboxykinase (PEPCK), regulating the gluconeogenesis pathway to improve IR.Moreover, the combination of berberine and astragalus polysaccharide can promote the expression of GLUT2 to increase glucose uptake [27].

Catalpol (Figure 1), a natural product extracted fromRadix Rehmanniae, has been reported to improve IR and inflammation in adipose tissue induced by high fat diet (HFD) by inhibiting c-Jun N-terminal kinase (JNK) and NF-κB pathways [28].Studies have shown that in the IR model of HepG2 cells induced by glucosamine and the T2DM animal model induced by HFD and streptozocin (STZ), catalpol treatment can improve the NADPH oxidase 4-mediated oxidative stress in the liver, activate AMP-activated protein kinase (AMPK) and PI3K/AKT pathways and improve IR [29,30].

Radix Ophiopogonisis a common CMM for the treatment of diabetes and its complications.The research from Wang et al.[31] shows that the polysaccharide extract ofRadix Ophiopogoniscan reduce the body weight of mice induced by HFD, reduce the lipid accumulation, and increase the lipid metabolism in the liver.The study has shown that after administration ofOphiopogonjaponicuspolysaccharide extract, the fasting blood glucose (FBG) of db/db mice is significantly decreased, and the insulin secretion is increased [17].Although the oral bioavailability ofOphiopogonjaponicuspolysaccharide is low, it can improve the structure of gut microbiota in obese mice induced by HFD and reduce the ratio ofFirmicutes/Bacteroidetes(F/B), resulting in improving metabolism of obese mice [32].

Ginseng is one of the most widely used CMM.Ginsenoside Rb1 (Figure 1), the main component of ginseng, has anti-diabetes effect [33,34], probably because ginsenoside Rb1 can improve IGT, reduce liver fat accumulation and increase insulin sensitivity [35].After administration of ginsenoside Rb1, HFDinduced obese mice and rats can significantly reduce food intake and reduce body weight gain, which helps to improve IGT and insulin sensitivity [36,37].Administration of ginsenoside Rb1 to HFD-induced T2DM mice can reduce FBG, improve IGT, and enhance insulin sensitivity by inhibiting 11βhydroxysteroid dehydrogenase type I [38].Ginsenoside Rb1 treatment can also reduce the expressions of interleukin-1β (IL-1β), IL-6 and TNF-α in adipose tissues and liver, and regulate glycolipid metabolism through the NF-κB pathway, thereby improving insulin sensitivity [37].In vitro experiments, it shows that ginsenoside Rb1 can promote the transport of GLUT1 and GLUT4 by increasing the phosphorylation of insulin receptor substrates-1 and PKB, to stimulate insulin-mediated glucose uptake in 3T3-L1 adipocytes [39,40].Furthermore, ginsenoside Rb1 is able to activate AMPK and activate insulin signaling pathway to promote glucose uptake and improve insulin sensitivity, thus exerting the effect of insulin sensitization [41].In summary, ginsenoside Rb1 has the effects of regulating glucolipid metabolism and improving insulin sensitivity, making it become one of the candidate drugs for the prevention and treatment of IR and T2DM [42].

Cortex Cinnamomi, as an anti-diabetic spice, has a long history and clinical applications.The research results of Kirkham et al.[18] have shown thatCortex Cinnamomihas a significant effect of lowering FBG and improving IGT in clinical trials.In diabetic mouse model induced by STZ and cell models induced by IL-1β and interferon, the extract ofCortex Cinnamomican prevent STZ- and IL-1β- induced β-cell injury by inhibiting NF-κB [43].The polyphenol components inCortex Cinnamomican increase insulin sensitivity and improve FBG, glucose tolerance and insulin sensitivity of women with polycystic ovary syndrome with IR [44].Cinnamaldehyde in cinnamon can activate PI3K and mitogen-activated protein kinase pathways, suggesting that cinnamic aldehyde may improve IR [45].In addition, in the L6 myotube, although cinnamic acid inCortex Cinnamomihas no significant effect on PI3K activity, it can activate GLUT4 and regulate glucose transport [46].

Compound CMM

Compound CMM exerts synergistic therapeutic effect due to the compatibility of multiple drugs, with clear clinical efficacy.However, its mechanism, characterized by “multiple components and multiple targets”, has not been effectively explained, so the scientificity of the clinical efficacy of the compound prescription is controversial.The compound prescriptions for the treatment of IR, T2DM and its complications include Jinqi Jiangtang tablets (JQJT), Huanglian Jiedu decoction (HLJD), Gegen Qinlian decoction (GGQL), Danggui Liuhuang decoction (DGLH), Liuwei Dihuang decoction/pill (LWDH), Xiexin decoction (XXT), Xiaoke pill, Yuquan pill, Shenqi Jiangtang granules, etc [44-52].

JQJT is an effective prescription for the treatment of T2DM, which consists ofRhizoma Coptidis,Radix Astragaliand Jinyinhua (Lonicera japonicaThunb.) [53].After treatment with JQJT for diabetic mice, the FBG and hemoglobin A1c levels are decreased.JQJT can reduce the levels of IL-6, TNF-α and intestinal mucosal permeability, while increase the abundance ofAkkermansiamuciniphila[16], which is related to the improvement of IR.In the HFD-induced IR mouse model, FBG and insulin tolerance are both improved after treatment with JQJT, which might be due to the fact that JQJT enhances insulin sensitivity by activating AMPK signaling pathway, thus improving the function of β cells in IR caused by HFD [54].

HLJD that is composed of four CMMs withRhizoma Coptidis, Huangqin (Scutellaria baicalensisGeorgi), Huangbo (Phellodendron chinenseSchneid.) and Zhizi (Gardenia jasminoidesEllis), is first recorded in Wai Tai Mi Yao in the Tang Dynasty, and has been applied to the clinical treatment of T2DM in China [55].In the model induced by HFD combined with STZ, the treatment with HLJD significantly improves the hyperglycemia and inflammation in T2DM rats [56].In addition, the results reported by Chen et al.[56] show that treatment with HLJD can improve the gut microbiota structure of T2DM rats, manifested as increased abundance of bacteria producing short chain fatty acids (SCFAs) and anti-inflammatory bacteria, such asParabacteroides,AkkermansiamuciniphilaandBlautia; and reduce the abundance of conditional pathogenic bacteria, such asCorynebacterium,StaphylococcusandAerococcus[57].SCFAs can regulate the function of skeletal muscle, liver and adipose tissues to improve glucose homeostasis and insulin sensitivity [58].

GGQL is composed of seven CMMs includingRhizoma Coptidis,RadixScutellariae,Radix Puerariae,Rhizoma Anemarrhenae, Xiyangshen (Panax quinquefoliumL.), Chishao (Paeonia lactifloraPall.) and Ganjiang (Zingiber o.officinaleRose.) [9].Clinical studies have shown that GGQL can increase the abundance ofFaecalibacterium,BifidobacteriumandGemmiger.These bacteria and their metabolites are helpful to increase insulin sensitivity and improve IR, which can be used for the prevention and treatment of T2DM [59,60].In T2DM model rats, after treatment with GGQL, the FBG and insulin levels are significantly decreased, and IR is reduced [9].Moreover, after treatment with GGQL, the abundance of some beneficial bacteria includingRoseburia,Clostridium,FaecalibacteriumandRuminococcusis increased, and these bacteria can produce SCFAs and play a beneficial role as probiotics for the host [61,62].In addition, GGQL and its main active component berberine can effectively prevent the occurrence of HFD-induced obesity [63].

DGLH is a compound CMM composed of six CMMs including Danggui (Angelica sinensis(Oliv.) Diels),Radix Rehmanniae,Radix Rehmanniae Preparata,Radix Scutellariae,Rhizoma CoptidisandChinensis Phellodendri Cortex.The clinical report shows that DGLH has a protective effect on inflammatory conditions, including T2DM and its complications [64].The results from Cao et al.[65] show that DGLH can reduce fat accumulation and fat generation, and promote glucose uptakein vitro.In vivo, DGLH can inhibit the proliferation of T lymphocytes, promote the transfer of pro-inflammatory cytokines to anti-inflammatory cytokines, and exert anti-IR by improving abnormal immune and metabolic homeostasis [65].

LWDH is a traditional prescription that consists of six herbs includingRadix Rehmanniae Preparata, Shanzhuyu (Cornus officinalisSieb.et Zucc.), Mudanpi (Paeonia suffruticosaAndr.),Rhizoma Dioscoreae,Poriaand Zexie (Alisma orientalis(Sam.) Juzep.), which is used to treat many diseases in clinic [66].Treatment with LWDH in obese rats can significantly reduce the body weight of the rats and improve IR [67].In the T2DM model induced by HFD and STZ, LWDH significantly reduces the FBG and insulin levels of T2DM rats.Furthermore, LWDH promotes the expression of PI3K, Akt and insulin receptor substrate 2 in PI3K/Akt signaling pathway, thereby improving IR [47, 50].

XXT, a classical prescription composed of Dahuang (Rheum palmatumL.),Radix ScutellariaeandRhizoma Coptidis, has the effects of anti-inflammation, antioxidation and immune regulation.It is clinically used to treat constipation, high fever, irritability and insomnia [68-70].In recent years, it has been found that XXT can inhibit the expression of TNF-α and IL-6, which shows the effect of anti-diabetic nephropathy by inhibiting NF-κB-mediated inflammation [71].In addition, XXT can significantly reduce FBG level and improve lipid metabolism disorder, which can be used for the treatment of T2DM [72].Meanwhile, the gut microbiota structure of T2DM rats treated with XXT changes significantly, especially the SCFAs-producing bacteria and anti-inflammatory related bacteria (Figure 2).

Mechanism of CMM in prevention and treatment of IR and T2DM

CMM for the treatment of IR and T2DM mainly contains chemical components such as polysaccharides, flavonoids, alkaloids, saponins, phenols and terpenes.Although the hypoglycemic effect of some CMMs and Chinese patent medicine is not very obvious, their clinical application value cannot be ignored.It is proved to achieve the purpose of treating diabetes with some CMMs in application through other effects.For example, mangiferin, a flavonoid component, has an anti-diabetic effect by inhibiting inflammatory reaction [12]; berberine, an alkaloids anti-diabetic component, can significantly improve IGT and IR [9].According to the effects of various components, the mechanisms of CMM in the prevention and treatment of IR and T2DM are mainly include the following: 1) hypoglycemic effect; 2) increasing insulin sensitivity and improving IR; 3) insulin-like effect or repairing of islet function; 4) inhibiting inflammation; 5) reducing oxidative stress; 6) regulating lipid metabolism.

Hypoglycemic effect

The hypoglycemic mechanisms of CMM in the treatment of T2DM are mainly reflected as follows: 1) the inhibition effect of CMM components on αglucosidase; 2) inhibiting the decomposition of glycogen and increasing the content of hepatic glycogen; 3) promoting the uptake and utilization of glucose by peripheral tissues.

Inhibition of α-glucosidase can delay the absorption of carbohydrates in small intestine, thereby reducing the increase of postprandial blood glucose in T2DM.The results from Seong et al.[73] show that daidzein, genistein and calycosin (Figure 1) inRadix Puerariaehave the obvious α-glucosidase inhibition effect.Orthosiphon stamineusis a kind of CMM that can induce diuresis and remove dampness.The study shows that its alcohol extract can inhibit α-glucosidase and significantly reduce the FBG concentration of STZ-induced diabetic rats [74].

Inhibition of the hepatic gluconeogenesis pathway can decrease the elevation of FBG.In the T2DM rat model induced by the combination of HFD and STZ, the FBG concentration is significantly decreased after oral administration ofOphiopogon japonicuspolysaccharide.In addition,Ophiopogon japonicuspolysaccharide also inhibits the liver PEPCK enzyme activity of T2DM rats, inhibits the hepatic gluconeogenesis pathway and increases the glycogen content in the liver and skeletal muscle [75].Eurycoma longifoliahas the effect of benefiting dampness and reducing jaundice and has effect on the treatment of T2DM.The hypoglycemic active component ofEurycoma longifoliais 9-hydroxycanthin-6-one.The research indicates that 9-hydroxycanthin-6-one can activate the phosphorylation of glycogen synthase kinase 3β to increase the synthesis of liver glycogen, thus exerting the hypoglycemic function [76].

Catalpol, the active component extracted fromRehmannia glutinosa, is used for the treatment of STZinduced diabetic rats.The results show that catalpol can inhibit the expression of PEPCK in the liver and inhibit the hepatic gluconeogenesis pathway.Moreover, catalpol can increase the expression of GLUT4 in skeletal muscle and increase glucose utilization [77].Deoxyandrographolide isolated from Chuanxinlian (Andrographis paniculate(Burm.f.) Nees) can reduce FBG and serum insulin levels in db/db mice, whose mechanism may be that deoxyandrographolide activates PI3K and AMPK-dependent signaling pathways, promotes the translocation of GLUT4 to the cell surface, and increases the glucose uptake by skeletal muscle [78].

Increasing insulin sensitivity and improving IR

The main mechanisms of increasing insulin sensitivity and improving IR in the treatment of T2DM with CMM are as follows: 1) increasing the number of insulin receptors and their binding to insulin; 2) increasing the phosphorylation of insulin receptors and substrates; 3) increasing the content of GLUT4.

The ability of tissue to absorb insulin and utilize glucose is decreased.In order to maintain glycemic homeostasis, the body compensatory secretes excessive insulin, which is manifested as IR.Momordicae Charantiaetreatment significantly improves IGT and insulin sensitivity of rats induced by HFD, which might be related to the inhibition of NF-κB and JNK pathways in the liver and muscle of rats.For the T2DM rat model induced by the combination of HFD and STZ, after treated with theMomordicae Charantiaeextract, the levels of FBG, insulin, TNF-α and IL-6 are decreased.In addition, theMomordicae Charantiaeextract inhibits JNK expression to enhance the role of insulin signal transduction pathways, thereby improving IR [79].Furthermore, the results of Yang et al.show that the levels of pro-inflammatory factors in liver, muscle and epididymal fat of rats are significantly downregulated after supplementation withMomordicae Charantiae[80].The research from Shih et al.shows that treatment withMomordicae Charantiaenot only effectively improves hyperglycemia and hyperinsulinemia caused by high fructose, but also increases the expression of GLUT4 mRNA and protein in skeletal muscle [81].Gallic acid from Yuganzi (Phyllan-thus emblicaL.) can increase insulin sensitivity and improve IR, whose mechanism is related to the activation of Akt, GLUT4 and peroxisome proliferator-activated receptor-γ [82].

Insulin-like effect or repairing of islet function

The mechanisms of CMM having insulin-like effect or repairing islet function in the treatment of T2DM are mainly reflected as follows: 1) directly insulin-like effect or directly promoting insulin secretion; 2) secreting insulin by stimulating islet beta cell; 3) maintaining islet function through repairing β cells.

Inadequate insulin secretion is an important factor leading to the development of T2DM.One of the mechanisms of drugs for the treatment of IR and T2DM is to improve IR and reduce FBG by directly acting in an insulin-like manner or by directly promoting insulin secretion.Changchunhua (Catharanthus roseus(L.) G.Don) is a medicinal plant traditionally used to control diabetes.It is previously considered that the main active components ofCatharanthus roseusfor lowering FBG is indole alkaloids [83].The results form Espejel-Nava et al.[84] show that the phenolic components such as chlorogenic acid and gallic acid (Figure 1) inCatharanthus roseuscan promote insulin secretion and reduce FBG in diabetic mice.Lotus (Nelumbo nuciferaGaertn) plumule polysaccharide can promote the increase in the number of islet cells and increase insulin secretion, which has a protective effect on type 1 diabetic mice [85].Polysaccharides isolated fromMomordicae Charantiaecan increase the serum insulin concentration of diabetic mice, achieving the effect of lowering FBG [86].

One of the causes of hyperglycemia in the body is the lack of insulin secretion by pancreatic β cells, so increasing insulin secretion by stimulating pancreatic β cells can effectively reduce FBG.In India, the extract of Chigengteng (Gymnema sylvestre) has been used for the treatment of T2DM.In clinical trials, it is shown that the fasting and postprandial blood glucose of patients with T2DM are significantly decreased after treatment with the extract ofGymnema sylvestre, andin vitroandin vivo, studies have shown that the hypoglycemic effect with extract ofGymnema sylvestreis related to the stimulation of insulin secretion by pancreatic β cells [87].The active component ellagic acid inEmblica officinaliscan promote insulin secretion by increasing the number of β cells in diabetic rats, so as to reduce FBG of rats [88].

Impaired β cells function will lead to insufficient insulin secretion, leading to T2DM.Therefore, protecting and repairing the damaged islet β cells and promoting insulin secretion are one of the mechanisms for lowering FBG.The results have shown that administration of Sangye (Morns albaL.) can increase the proliferation of islet β cells and maintain the islet β cell function in the db/db mouse model of spontaneous diabetes [89].The extract ofRhizoma Anemarrhenaecan promote the regeneration of islet β cells and recover the function of islet β cells by overexpressing peroxiredoxin 4 [8].

Inhibiting inflammation

Inflammatory reaction coexists with IR, islet β -cell dysfunction and T2DM.The pro-inflammatory factors (such as IL-1β and IL-6) cross the intestinal barrier and enter the blood, thus affecting the insulin sensitivity and islet β-cell function [90].Therefore, inhibiting inflammatory factors and reducing inflammatory reaction can improve insulin sensitivity and IR [91-92].Lotus plumule polysaccharide can inhibit the production of pro-inflammatory TNF-α and IL-6 cytokines in the spleen of non-obese diabetic mice [93].Mangiferin (Figure 1), a flavonoid compound inRhizoma Anemarrhenae, can reduce the production of IL-1β, IL-6 and TNF-α in BV2 cells, and inhibit the NF-κB and NLRP3 signaling pathways [94].The polysaccharide extract ofOphiopogon japonicuscan inhibit the secretion of NF-κB, IL-1β and TNF-α, and the FBG level of db/db mice is significantly reduced [17].

Reducing oxidative stress

T2DM is a disease with increased oxidative stress [95].The increase of reactive oxygen species under oxidative stress activates many cells stress-sensitive pathways that indirectly induce pancreatic tissue damage, thereby affecting the function of pancreatic β cells and leading to IR [96].Therefore, inhibiting excessive oxidative stress can improve IR and T2DM.The combination ofRadix PuerariaeandRadix Salviaecan reduce the levels of serum insulin, nitric oxide and vascular cell adhesion molecule-1 in diabetic rats, and increase the levels of superoxide dismutase and catalase, thereby protecting the diabetic vascular injury [97].After treatment withOphiopogon japonicuspolysaccharide, the activities of superoxide dismutase and glutathione peroxidase in STZ-induced diabetic rats are significantly increased, indicating thatOphiopogon japonicuspolysaccharide treatment can improve the antioxidant capacity of diabetic rats [98].Clinical randomized controlled trials have shown that resveratrol significantly increases the total plasma antioxidant capacity of patients with T2DM.After intake of resveratrol, the expression of transcription factor Nrf2 and superoxide dismutase is significantly increased [99,100].

Regulating lipid metabolism

IR and T2DM are often accompanied by abnormal lipid metabolism.To improve the glucose and lipid toxicity brought by the abnormal lipid metabolism is the key to the treatment of IR and T2DM.Nuciferine is an alkaloid in theNelumbo nucifera, which can relieve dyslipidemia.Nuciferine recovers the IGT and IR in T2DM mice induced by HFD combined with STZ, and its mechanism is reflected in the fact that nuciferine can reverse the palmitic acid-induced inhibition of peroxisome proliferator-activated receptor (PPAR) PPARα transcriptional activity, which can improve the dyslipidemia induced by HFD [101].Ophiopogon japonicuspolysaccharide has been proved to improve abnormal blood lipid levels [102].The results of Wang et al.show thatOphiopogon japonicuspolysaccharide can prevent HFD-induced obesity in mice and improve abnormal blood lipids, which might be related to the fact thatOphiopogon japonicuspolysaccharide can act on PPARα and PPARγ, activating PPARα and inhibiting PPARγ at the same time [103].

In addition to the above-mentioned mechanisms, lipophagy might also be one of the mechanisms underlying the treatment of IR and T2DM with CMM [104].Lipophagy could be a bridge connecting T2DM with lipid dysregulation through lipid droplets, which plays the same role as nutrient restriction that been demonstrated to be the most efficient strategy in reducing visceral fat in both animals and humans [105,106].Besides, the studies conducted by The Diabetes Remission Clinical Trial confirmed the benefits of nutrient restriction by weight loss after several steps.These treatments ultimately lead to a major fall in liver fat export and intra-pancreatic fat that link to the remission of T2DM [107].Therefore, lipophagy might be a potential therapeutic target of IR and T2DM.

Limitations

There are some limitations.First, there are many CMMs used for treating diabetes in clinical application, we would like to elaborate those with more studies and clear effects.Therefore, single/compound CMMs and their mechanisms summarized in this review are limited.Second, owing to the fact that CMM is characterized by “multiple components and multiple targets”, the representative components of CMMs are selected for mechanism explanation rather than all components.Furthermore, the whole-body homeostasis of glucose metabolism is orchestrated by multiple organs/tissues, including pancreatic β cells, liver, adipose tissues, and skeletal muscles, in which signaling pathways are differentially regulated.With characterized by “multiple components and multiple targets”, and the targeted organs/ tissues of CMM is no single.Therefore, the mechanism diagram represents compositive mechanisms of CMM in treating diabetes rather than signaling cascades in specific various organ/tissues.

Conclusion

We summarized single CMM/compound CMM for prevention and treatment of IR and T2DM, and the mechanisms of CMM and its main active components in preventing and treating of IR and T2DM.Due to the differences in active components, CMM has multiple mechanisms for the prevention and treatment of IR and T2DM.At present, some clinically applied CMM have clear mechanisms.However, for a few drugs with low oral bioavailability, the mechanisms have not been clearly elucidated.Therefore, elucidating the drug action mechanism with low oral bioavailability is of great significance for reflecting the scientificity of clinical application of CMM.