Natural products:Regulating glucose metabolism and improving insulin resistance

Fatma S.A.Saaeleen,Yun Niu,Honglin Wang,Li Zhou,Lijun Meng,Sitan Chen,Dongxiao Sun-Waterhouse,Geoffrey Ivan Neil Waterhouse,Zhenhua Liu,c,*,Wenyi Kang,c,*

a National R&D Center for Edible Fungus Processing Technology,Henan University,Kaifeng 475004,China

b Joint International Research Laboratory of Food&Medicine Resource Function,Henan Province,Henan University,Kaifeng 475004,China

c Kaifeng Key Laboratory of Functional Components in Health Food,Kaifeng 475004,Henan,China

d School of Chemical Sciences,University of Auckland,Auckland 1142,New Zealand

ABSTRACT Compounds with regulating glucose metabolism and improving insulin resistance(IR)activity are abundant in nature and can be obtained from several sources.They have high potential to be used to treat diabetes mellitus.These compounds isolated from natural plants can be classified seven categories:terpenoids, alkaloids, quinones, flavonoids, phenols, phenyl propanoids, steroids, and other types of compounds.They exert biological effects by different ways and mechanisms.This review illustrated the potential natural products as a rich resource in regulation of glucose metabolism and IR, as well as their mechanisms.

Keywords:Natural products Glucose metabolism Insulin resistance(IR)

1.Introduction

Over 90%of the diabetic patients are suffering from the Type 2 Diabetes Mellitus (T2DM), whose main pathophysiological symptom is reflected by the insulin resistance (IR).IR mainly ascribed to the dysfunction of glucose transporter 4 (GLUT4) transporting from cytoplasm to membrane,which was related to the abnormal of insulin signaling pathway in adipose cells and skeletal muscle cells[1].Many researches proved that adipose tissue to sustain glucose homeostasis by stimulating glucose uptake in adipose skeletal muscle followed by suppressing glucose production from the liver[2].After the insulin combined with its receptor,the downstream signal transduction is mainly controlled by insulin receptor substrate-Ras-mitogen-activated protein kinase (IRS-RaS-MAPK) and IRS-1-phosphoinositide-3-kinase-protein kinase B (PKB, known as Akt)IRS-1-PI3K-Akt [3-5].The former plays a significant role in various biological processes-glycogen synthesis, metabolism, glucose transport and utilization,which are indispensable in the occurrence and development of IR, while the latter regulates the growth and apoptosis of cells[6-8].

On the other hand,obesity can affect type 2 diabetes.In term of the course of obesity, excess free fatty acids and triglycerides can be deposited in the liver and muscles.In the liver,excessive oxidation of free fatty acids eventually results in the secretion of a great quantity of reactive oxygen species(ROS),which can activate c-Jun N-terminal kinase (JNK).After activation, JNK phosphorylates the threonine and serine of IRS-1 and inhibits tyrosine phosphorylation of insulin-stimulated IRS-1, thereby preventing the coupling of IRS-1 to the regulatory subunit p85 of PI3K [9,10].At the same time, a large number of inflammatory cytokines, such as resistin and leptin secreted by adipose tissue, can activate the expression of cytokine signaling inhibitors (suppressor of cytokine signaling,SOCSs) in hepatocytes and muscle cells in the process of obesity.Excessive SOCSs can bind to insulin receptors-IRS-1/2, thus block the insulin-induced tyrosine phosphorylation of IRS-1/2,and ultimately inhibit the activation of the PI3K-Akt and lead to insulin resistance[11,12].s

Table 1 Chemical Constituentsname,sources and references.

Table 1(Continued)

There are many major categories of plant secondary metabolites used as potential drugs to treat multifarious diseases,including terpenoids, alkaloids, flavonoids, phenyl propanoids and etc [13].Many researchers are currently focusing on studying the biological principles,medicinal and therapeutic properties of plant secondary metabolites.In view of the numerous literature reports on the bioactivity of natural products, particularly for the treatment of diabetes, this paper focused on the mechanisms of natural products that could regulate glucose metabolism and improve the IR.All compounds and their references are listed in Table 1.

2.Active compounds and their mechanisms

2.1.Terpenoids

Twenty-four terpenoids (1-24) (Fig.1) isolated from plants,showed the effect of regulating glucose metabolism and improving IR, were isolated from 17 genera (14 families) plants.Compound 1, 20 and 21 were obtained from Araliaceae plants (Panax ginseng, Panax quinquefolius, Eleutherococcus senticosus).Compounds 11 and 12 were isolated from Pinaceae plants(Abies grandis,Pinus contorta).Compounds 2-7, 10, 14-21 were isolated from plants of different families.(Poria cocos, Trichosanthes dioica, Viburnum odoratissimum, Abroma augusta, Centella asiatica, Psidium guajava,Cyclocarya paliurus,Andrographis paniculata,Aucuba japonica,Plantago asiatica,Paeonia lactiflora,Stevia rebaudiana).Other compounds(such as ursolic acid)are widespread in various plants.The type of these terpenoids belongs to three tetracyclic triterpenoids(1-3),seven pentacyclic triterpenes(4-10),seven terpenoid glycosides(13-21)and five diterpenes(11-12,22-24).

Protopanaxatriol (1) is a novel antagonist of peroxisome proliferators-activated receptor-γ (PPARγ), which regulates metabolic and inflammatory gene expression such as interleukin-1β (IL-1β), interleukin-10 (IL-10), interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS) and CD68 improving insulin sensitivity,dyslipidemia and steatosis[14].

In addition to increase glucose transporter type-4 (GLUT4)translocation and expression, pachymic acid (2) promoted the phosphorylation of IRS-1, Akt and adenosine monophosphateactivated protein kinase (AMPK), induced the emergence of triglyceride and inhibited lipolysis in adipocytes to improve insulin resistance[15].

Cucurbitacin B (3) is a kind of tetracyclic triterpenoid isolated from Trichosanthes dioica.Cucurbitacin B improved insulin tolerance and glucose utilization through translocation of GLUT4,which was related to the activation of PI3K/Akt signaling pathway[16].

6α-Hydroxylup-20(29)-en-3-on-28-oic acid (4) inhibited 3T3-L1 adipocyte differentiation via mediating gene transcription of PPARγ and CCAAT-enhancer-binding protein (C/EBP) expression,and repaired dexamethasone (DXM)-induced IR via restoring insulin pathway and stimulating down-stream signaling transduction through phosphorylation of AS160,Akt2 and PI3K/p85[17].

Taraxerol (5) derived from the Abroma augusta leaf.Taraxerol(20 mg/kg) could stimulate glucose consumption in skeletal cells,regulate blood glycemic condition and lipid content in the sera,reduce the emergence of pro-inflammatory factors, and restore the renal damage in T2D rats.Molecular docking research confirmed the potential interactions between taraxerol and receptors like PKCb(protein kinase C),PKCd,NF-κB,PARP,PI3K,IRS,Akt and AMPK.[18].

Asiatic acid is the metabolite of asiaticoside,which suppressed hyperglycemic effect by increasing antioxidant defense and glucose utilization in skeletal cells via PI3K-Akt signaling pathway[19].

Guavenoic acid(0.3-30 nmol/L)(7)could significantly improve the insulin resistance of INS-1 cells, which was related to the down-regulation of protein tyrosine phosphatase 1B(PTP1B)gene expression and up-regulation of PPARγ gene expression[20].

Ursolic acid (UA) (8) stimulated glucose utilization in 3T3-L1 adipocytes through regulation of the PI3K signaling pathway and the translocation of GLUT4 protein to the cell cytomembrane.Moreover,2.5,5 and 10 mmol/L of UA improved glucose metabolism in a concentration-dependent manner(17%,29%and 35%,respectively)[21].

Oleanolic acid(9)is a triterpenoid existing in over 1620 plants.Oleanolic acid (25 mg/kg) can improve fructose induced IR in rats through the IRS-1/PI3K/Akt pathway[22].

Cyclocaric acid B (10) and cyclocarioside H (19), were isolated in Cyclocarya paliurus(Batal)Iljinsk(Juglandaceae),regulated organism glucose homeostasis with insulin deficiency likewise mediated IRS-1/PI3K/Akt pathway by suppressing inflammation.Above effects had a close relationship with the regulation of AMPK insulin signaling pathway[23].

Dehydroabietic acid (DAA) (11) is a powerful PPARα/γ dual activator.DAA (50 μmol/L) obviously inhibited the secretion of pro-inflammatory mediators including NO, TNF-α, and monocyte chemotactic protein-1 (MCP-1) in the co-culture of RAW 264.7 mouse macrophages and 3T3-L1 adipocytes.It could improve inflammatory responses associated with obesity-related diabetes[24].

Deoxyandrographolide (DeoAn) (12) mainly derived from the Andrographis paniculata, which concentration-dependently induced glucose uptake by increasing the translocation of GLUT4 to cell surface and activated PI3K and AMPK dependent signaling pathways[25].

Fig.1.The structures of active terpenoids.

Fig.1.(Continued)

Catalpol (13) (P ＜0.05 and 0.01) could improve IR by regulating glucose consumption and transportation.Berberine (25) (P ＜0.05 and 0.01) could down-regulate expression of PPAR-γ mRNA in adipocyte compared with the model groups[26].

Aucubin (14) could attenuate TNF-α induced inflammatory response and then ameliorate obesity-induced atherosclerosis.Aucubin obviously reduced TNF-α production and mRNA synthesis of the adipocytokine such as plasminogen activator inhibitor type 1 (PAI-1), IL-6, and MCP-1.Further research indicated that aucubin could suppress ERK activation,IκBa degradation,and following NF-κB translocation[27].

Paeoniflorin (PF) (15), a natural active component in roots of peonies, inhibited lipid ectopic deposition via regulating lipid metabolism, and exerting insulin regulating effect via the insulin pathway IRS/Akt/GSK3β and anti-oxidation[28].

Stevioside (16) and rebaudioside A (17) are diterpenoid glycosides which were isolated from Stevia rebaudiana Bertoni leaves.They could enhance glucose utilization in rat fibroblasts through regulating the PI3K/Akt pathway,and then inducing GLUT4 translocation from cytoplasm to the cytomembrane[29].

Fig.2.The structures of active alkaloids.

Ginsenoside Rb1(18)induced translocation of GLUT4 by upregulation of leptin receptors and activation of PI3K,which improved insulin sensitivity and glucose metabolism in skeletal muscle cells[30,31].

Astragaloside IV (20) was isolated from Astragalus membranaceus, showed anti-diabetic effects [32].Astragaloside IV restrained lipolysis by decreasing cAMP (cyclic adenosine monophosphate)accumulation through stimulation of Akt/PDE3B,contributing to reducing hepatic lipid accumulation and suppressing excessive hepatic glycogen disintegration[33].

Eleutheroside E (21), derived from Eleutherococcus senticosus(ES), regulated hepatic glucose homeostasis by upregulating glycolysis and downregulating gluconeogenesis in T2D mice[34].

Phytol (22) is a branched-chain fatty alcohol.It could improve adipocyte number in iWAT and glucose uptake in mice fed by highfat and high fructose diet (HFFD), which was consistent with the promoted differentiation and glucose utilization in 3T3-L1 cells relating with regulation of PI3K/Akt IR signaling pathway[35].

Limonene (23) is a cyclic monoterpene isolated from citrus fruits.Limonene induced osteoblast and C2C12 skeletal muscle cells adipogenesis and glucose uptake via stimulating p38 mitogenactivated protein kinase(MAPK)and Akt pathways[36].

Myrtenal (24) could decrease the levels of plasma glucose,improve the plasma insulin levels,up-regulation of IRS-2,Akt and GLUT2 in liver and IRS-2,Akt and GLUT4 protein synthesis in skeletal muscle with diabetic rat models.The up-regulation of glucose transporters enhanced the glucose uptake in liver and skeletal muscle[37].

2.2.Alkaloids

Seven alkaloids (25-31) (Fig.2) contain isoquinoline alkaloid(25), piperidine alkaloids (26, 30, 31), adenosine (27), pyrrolidine alkaloid (28) and organic amine alkaloids (29).Seven alkaloids were obtained from 6 species,Coptis chinensis Franch(25),Sophora flavescens(26),Grifola gargal(27),Murraya koenigii(28-29),Peganum harmala Linn(30),Morus alba(31).

Berberine (25), an isoquinoline alkaloid isolated from Chinese herbs Coptidis rhizoma or Cortex phellodendri.These results suggested that berberine could improve glucose tolerance via regulating key molecules such as AMPK and PKC (paroxysmal kinesigenic choreoathetosis)and AS160 phosphorylation in insulin signaling pathway and GLUT4 translocation, lead to increase glucose uptake in insulin-resistant cells[38].

Oxymatrine (26), is widely found in Sophora flavescens or Sophora subprostrata.Oxymatrine can protect T2DM rats from IR through the regulation of the KSRP, PETN, and Akt expression in the liver[39].

Adenosine (27) was isolated and identified in Grifola gargal (GLF), an edible mushroom widely distributed in southern Argentina and Chile.Adenosine and GLF increased GLUT4 translocation from cytoplasm to the cytomembrane through modulation of PI3K/Akt signal molecules and AMPK phosphorylation in L6 myotubes to prevent post-prandial hyperglycaemia and T2DM[40].

Mahanine (28) has been reported to be a major bioactive carbazole alkaloid.Mahanine (5-10 μmol/L) could improve glucose metabolism in L6 myotubes and adipocyte cells via modulation of the Akt signaling pathway and then raised plasma membrane GLUT4 content[41].

Capsaicin(29)is a pungent principal compound of hot chili peppers.It was demonstrated promoted glucose utilization in C2C12 muscle cells by modulating AMPK, ROS (reactive oxygen species)and p38 MAPK signaling pathway[42-44].

4-Hydroxypipecolicacid (4-HPA) (30) has an analogous structure with insulinotropic and insulin sensitizing, such as 4-hydroxyisoleucine and fagomine.Treatment with 4-HPA (2.5-50 μmol/L) increased glucose utilization and GLUT4 translocation to cytomembrane in skeletal muscle cells in a dosage-dependent manner[43].

1-Deoxynojirimycin (DNJ) (31) is a glucose analogue with an oxygen atom replacing by amidogen of the pyranose ring.DNJ is normally identified as a competitive inhibitor of small intestinal cell α-glucosidase[14-16].Liu reported that DNJ dramatically improved IR via activating PI3K/Akt insulin pathway in skeletal muscle of db/db mice[44].

Fig.3.The structures of active quinones.

2.3.Quinones

Four quinones(32-35)(Fig.3)were isolated from four different plants.Compounds 32 and 33 are anthraquinones,and compound 34 is a phenanthraquinone,while 35 is a naphthoquinone.

Alizarin (AZ) (32), was isolated from Rubia cordifolia, showed that AZ could obviously promote the glucose metabolism of 3T3-L1 adipocytes,GLUT4 protein translocation,the phosphorylation of IRS-1 and Akt protein to improve IR[45].

Emodin (33) is a powerful inhibitor of 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1) isolated from the root and rhizome of Rheum palmatum.Emodin suppressed the 11β-HSD1 activity in 3T3-L1 adipocytes with a dosage and time-dependent manner and improved glycemic level in ob/ob mice[46].

As an antagonist of PPARγ, tanshinone IIA (34) could activate AMPK and Akt pathway that related to promoted glucose transport in mice[47].

Arnebin-1 (35), a bioactive compound isolated from Arnebia nobilis, stimulated glucose utilization, mediated the translocation of GLUT4 to cytomembrane.Moreover, Arnebin-1 (100 mg/kg)attenuated postprandial glycemic levels in streptozotocin-induced diabetic rats[48].

2.4.Phenylpropanoids

Twelve phenylpropanoids(36-47)(Fig.4)have shown promising IR and glucose metabolism activity.They were obtained from eight species (Magnolia officinalis, Pongamia pinnata, Myristica fragrans, Aronia melanocarpa, Angelica gigas, Forsythia suspense,Broussonetia kazinoki and Salvia miltiorrhiza).

Magnolol (36), is a principal compound isolated from Magnolia officinalis,could modulate insulin homeostasis through activate the ligand of PPARγ.In the early stage of adipogenesis, magnolol showed binding affinity to PPARγ, however its effect was weaker than rosiglitazone.In differential 3T3-L1 adipocytes, it improved insulin-activated glucose utilization coincident with the increase of mRNA and protein level of GLUT4[49].

Pongamol (37) from Pongamia pinnata induced glucose uptake in L6 myotubes.Pongamol could promote the transfer of GLUT4 from cytoplasm to the cytomembrane, which was driven by the PI3K/Akt molecular mechanism[50].

Licarin B (LB) (38) isolated from Myristica fragrans Houtt (nutmeg)that an aromatic evergreen plant of the family Myristicaceae.LB increased glucose tolerance via upregulating the GLUT4 synthesis and translocation by IRS-1/PI3K/Akt insulin pathway,stimulated adiponectin production and regulated mRNA expression profile of PPARγ target genes,LPL,IRS-2,and C/EBPα[51].

Three anti-adipogeniccompounds (39-41) (100 or 200 mg/kg/day), isolated from Aronia melanocarpa methanol extract, could significantly decrease the body weight, serum triglyceride, and low-density lipoprotein cholesterol levels and increase glucose tolerance compared with HFFD controls in the model of HFFD-induced obese mice[52].

Decursin(42),a coumarin,is abundant in Angelica gigas.Experiment results proved that decursin promoted glucose utilization in mice fed with HFFD.In addition,administration of decursin could significantly weaken the secretion of HFFD-induced adipocytokines like resistin,IL-6,leptin and MCP-1[53].

Chlorogenic acid (CGA) (43) is one of the phenols in coffee formed from quinicacid and cinnamic acids.Khang [54] have demonstrated that CGA reduced the level of fasting glycemic level in db/db mice.Also, CGA promoted glucose transport in skeletal muscle through the translocation of GLUT4 and the activation of AMPK.

Caffeic acid phenethyl ester (CAPE) (44) is a major active phenolic compound in honeycomb.Kim [55] researched the efficacy and functional mechanism of CAPE in a T2D mouse of HFFDinduced obesity and MetS.Results reflected that 0.05% CAPE induced PPARγ activity,leading to more equilibrium distribution of adipocytes,attenuated inflammation andimmune cell penetration and decreased adipokine secretion.

Phillyrin(45)was isolated from Forsythia suspensa.Results indicated that three lignans could promote the insulin sensitizing in 3T3-L1 adipocytes under IR.Phillyrin (100-200 μmol/L) demonstrated more significantly activity toimprove glucose utilization as it could increase the protein phosphorylation of IRS-1,Akt and the translocation of GLUT4 protein(P ＜0.001)[56].

Kazinol B (46) isolated from Broussonetia kazinoki Siebold (BK)could increase glucose tolerance by upregulating the expression and translocation of GLUT4 into the plasma membrane in 3T3-L1 adipocytes at the concentration of 2-20 μmol/L.BK was proved that it could enhance insulin sensitivity via the activation of the Akt and AMPK signaling pathway[57].

Salvianolic acid B (Sal B) (47), a water-soluble compound derived from the root of Salvia miltiorrhiza (Danshen), reduced obesity and obesity-related metabolic disorders by inhibiting adipogenesis which was verified in vivo and in vitro.The effects of Sal B in adipose tissue may be connected with its action on PPARγ,C/EBPα,GATA-2 and GATA-3[58].

2.5.Flavonoids

Flavonoids widely existed in natural plants and they have powerful treatment effect such as antioxidant,anticancer,antibacterial,antiviral and anti-inflammatory[59].Thirty-seven flavonoids(48-84) (Fig.5) had the improving activity of IR, including xanthones,flavanones, flavans, anthocyanins and chalcones.They were isolated from twenty species of different plants(Scutellaria baicalensis,Hippophae rhamnoides,Psoralea corylifolia,Amorpha fruticose,Cleistocalyx operculatus, Glycyrrhiza uralensis, Lycopersicon esculentum,Angelica keiskei, Silybum marianum, Garcinia mangostana, Broussonetia kazinoki, Camellia ptilophylla, Camellia sinensis, Trigonella foenum-graecum, Cinnamomum cassia, Osmophloeum kaneh, Pueraria lobate, Abelmoschus manihot, Averrhoa carambola, Aronia melanocarpa and Ligustrum lucidum).

Fig.4.The structures of active phenylpropanoids.

Wogonin(5,7-dihydroxy-8-methoxyflavone)(48)isolated from the root of S.baicalensis.Gerogi [60] evaluated the therapeutic effects of wogonin using db/db mice.Results indicated that wogonin may have a beneficial effect on glucose and lipid metabolism related to increased adiponectin and PPARα secretion via activate AMPK signaling pathway.

Luteolin(LU,3,4,5,7-tetrahydroxyflavone)(49)can be found in leaves, fruits of many natural plants and herbal drugs.Luteolin mediated and normalized pancreatic islet dysfunction by differentially regulating plasma GIP and GLP-1, which was conducive to improvement of IR, lipotoxicity and fibrosis.Morever, it suppressed fibrosis by reduce cathepsin gene expression and extra cellular matrix accumulation.Overall,these studies showed novel insights into the effect of luteolin on the relation among fibrosis,hepatic steatosis,adiposopathy and IR[61].

Quercetin (50) is a major bioflavonoid and common in dietary plants.A series of in vitro studies suggested a possible therapeutic effect of quercetin on obesity and IR and its action mechanism could connect to the activation of FGF21/MAPK signaling pathway[62,63].

Pentamethyl quercetin (PMQ) (51), a typical compound of the polymethoxylated flavone family, could activate AMPK signaling pathway and increase ACC (acetyl-CoA carboxylase) phosphorylation and translocating of GLUT4 in MSG mice (5, 10, 20 mg/kg daily).In addition, PMQ upregulated the expression of some key genes associated with fatty acid oxidation in C2C12 myotubes(10 μmol/L)[64].

Tricin(5,7,4′-trihydroxy-3′,5′-dimethoxyflavone)(52),a methylated flavone, widely existed in cereals.After tricin (20 μmol/L)treatment in C2C12 myotubes, glucose uptake level was significantly increased and the insulin-dependent signaling pathway was activated, including IRS-1, PI3K, Akt, and AS160[65].

Li [66] investigated the effects of tectorigenin (53) on 3T3-L1 preadipocyte differentiation and adipocytokines secretion.Tectorigenin(10-75 mmol/L)inhibited 3T3-L1 adipogenesis and involved in genes transcription.Tectorigenin may improve hyperglycemia by blocking preadipocyte differentiation and adipocytokines secretion in which related to PPARγ and NF-κB signaling pathways.

Daidzein(54)is one of the main components of soy isoflavones.3T3-L1 adipocytes and C57BL/6 J mice fed on HFFD were treated with daidzein.Results showed that daidzein promote dadipocytes differentiation,improved insulin sensitivity with the activation of PPARγ and upregulated adiponectin expression and downregulated MCP-1 expression in vivo and in vitro[67].

Eriodictyol(55)could improve insulin-induced glucose uptake in HepG2 cells and 3T3-L1 adipocytes and increase PPARγ2 expression in differentiated 3T3-L1 adipocytes which may related to activate the PI3K/Akt signal pathway[68].

Naringenin(56),widely found in Citrus fruits,reduced the ROS accumulation,decreased the SH-SY5Y cell death and IR.It involved the activation of mTOR/p70S6K signal pathway[69].

Bavachinin(BVC)(57),a novel natural pan-PPAR agonist derived from the fruit of the traditional herb malaytea scurfpea, showed a glucose-lowering property without hepatotoxicity or inducing weight gain.Li [70] reported a synergistic glucose- and lipidlowering effect of BVC and synthetic agonist activated by unique binding with PPAR-α/γ.BVC could adjunctively treat the metabolic syndrome.

Bavachin(58)obtained from Psoralea corylifolia,most potently lipids deposition during adipocyte differentiation.Bavachin enhanced glucose uptake through GLUT4 translocation to plasma membrane by activating the Akt and AMPK pathway in the presence or absence of insulin[71].

5,7-Dihy-droxy-6-geranylflavanone (DGF) (59) isolated from Amorpha fruticosa is a novel PPARα/γ dual agonist could increase glucose uptake in muscle cells which may be used to stimulate insulin sensitivity[72].

2,4-Dihydroxy-6-methoxy-3,5-dimethylchalcone(DMC)(60)is a natural compound from Cleistocalyx operculatus that is widely distributed in southern Asia.DMC showed anti-diabetic effects in 3T3-L1 cell to stimulate phosphorylation of AMPK alpha subunit(T172)by directly binding to AMPK,which resulted in the activation of AMPK[73].

Isoliquiritigenin (ILG) (61) is a component with a chalcone skeleton derived from Glycyrrhiza uralensis.Previous studies have confirmed that ILG potently limited the activation of the NLRP3 inflammasome ILG inhibited adipose tissue inflammation and fibrosis by affecting the paracrine loop composing of TNF-α and saturated fatty acids by a co-culture consisting of adipocytes and macrophages.[74].

Fig.5.The structures of active flavonoids.

Fig.5.(Continued)

Fig.6.The structures of active sterides.

Naringenin chalcone(62)is mainly found in tomatoes,and accumulates almost exclusively in the tomato peel.Naringenin chalcone could upregulate the adiponectin pathway through the elevation of both the ligand and its receptor[75].

4-Hydroxyderricin (4-HD) (63) was isolated from Angelica keiskei that a Japanese herb.Experiment results demonstrated that 4-HD promoted adipocyte TG deposition by activating PPARγ receptors and inducing PPARγ gene and protein expression levels.Moreover,it improved insulin-dependent glucose utilization in 3T3-L1 mature adipocytes,Akt phosphorylation and GLUT4 mRNA expression.[76].

Silibinin (64), the major flavonoid contained in silymarin, a mixture of flavonolignans obtained from Silybum marianum seeds.Results of H.B.Li[77]exhibited that silibinin activation of the IRS-1/PI3K/Akt pathway, therefore mediating palmitate-induced IR in C2C12 myotubes.

α-Mangostin (65), a principal xanthone component derived from the stem bark of G.malaccensis, improved glucose uptake and inhibited adipocytes differentiation in 3T3-L1 adipocytes via PPARγ, GLUT4, and leptin expression.α-Mangostin significantly stimulated the glucose uptake (P ＜0.05) with the highest activity at 25 mmol/L[78].

Lee [79] estimated the insulin-sensitizing effect of flavans isolated from Broussonetia kazinoki Siebold(BK)on 3T3-L1 adipocytes.They found kazinol B (66) increased intracellular lipid accumulation, gene expression of PPARγ and C/EBPα, and consistently induced PPARγ transcriptional activation.Meanwhile,they proved kazinol B promoted insulin sensitivity through improve glucose uptake via the insulin-Akt phosphorylation and AMPK activation.

Epigallocatechin gallate (EGCg) (67) is a main polyphenol in green tea.EGCg(75 mg/kg)could improve GLUT4 translocation in skeletal muscle of rats.Similarly,it significantly improved glucose uptake related to GLUT4 transfer in L6 myotubes at 1 nmol/L.These all proved EGCg could improve hyperglycemia by increasing GLUT4 translocation in skeletal muscle,which was partially different from the mechanism of insulin[80].

Gallocatechin-(4→8)-gallocatechin-3-O-gallate (GC-(4→8)-GCG) (68) is the major oligomeric proanthocyanidin in cocoa tea(Camellia ptilophylla).Peng [81] demonstrated GC-(4→8)-GCG have a strong anti-adipogenic potential in 3T3-L1 preadipocyte by suppressing the expression of key adipogenic transcription factors and downregulating the secretion of proinflammatory cytokines by restraining the activation of the NF-κB, JAK/STAT3 and MAPK signal pathways.

Mangiferin(69),a polyphenol extracted from Rhizome anemarrhenae, substantially inhibited the expression of HIF-1α, lactate acid and lipolysis in insulin resistance state.Yang[82]proved that mangiferin could not only repaired the damaged insulin signaling pathway in hypoxic adipocytes,but also improve inflammatory reactionand IR caused by hypoxia.

Fenugreek(Trigonella foenum-graecum)is a well-known annual plant of Legume family.Flavonoid glycosides(70-73)derived from fenugreek seeds could improve glucose uptake and lipid deposition in 3T3-L1 adipocytes.Isoorientin (73) demonstrated a significant activity among them.Firstly, it reduced the accumulation of lipid droplets through inhibiting the expression of adipokines such as C/EBPα, FAS, and PPARγ.Secondly, isoorientin impaired insulinstimulated glucose metabolism in DEX induced IR in adipocytes via reactivating AMPK and Akt signaling.Finally, isoorientin and vitexin (73) also reversed DEX induced attenuation in mitochondrial membrane potential(MMP)and intracellular ATP generation,decreased production of intracellular ROS, and prevented mitochondrial DNA(mtDNA)from oxidative damage[83].

Kaempferitrin (74), a 3,7-diglycosylflavone, was provided evidence of the dual effects of improve IR by Tzeng.Kaempferitrin showed an increased level of phosphorylation on insulin receptor beta and IRS-1, and ser473 site in PKB/Akt.Translocation of GLUT4 to membrane and corresponding protein expression level were increased under kaempferitrin activation[84][85].

Daidzin(75),mainly found in the roots of Pueraria lobata(Willd)Ohwi, enhanced adipocytes differentiation in 3T3-L1 cells with the activation of PPARγ, upregulated adiponectin expression and downregulated MCP-1 expression[86].

Puerarin(Pue)(76)is a kind of isoflavone extracted from dried root of pueraria lobata.Pue could significantly improve the IR of 3T3-L1 lipocyte, which is realized possibly by way of inactivating CAP path,promoting GLUT4 transfer to plasma membrane and enhance the utilization of glucose[87].

Hesperidin (5,7,3′-trihydroxy-4′-methoxy-flavanone-7-rhamnoglucoside, HES) (77) is a flavanone glycoside that is widely distributed in citrus fruits and vegetables.A potential mechanism of HES regulating IR may relate to the IRS-1-GLUT2 pathway viaTLR4 represents in HepG2 cells[88].

Aspalathin (78), a new natural compound, was found only in South African red bush tea.3T3-L1 adipocytes were cultured in medium containing 0.75 mmol/L palmitate for 16 h to induce IR before treatment for 3 h with ASP(10 μmol/L).ASP inhibited NF-κB,IRS-1 (Ser307) and AMPK phosphorylation.In addition, ASP could also increase the expression of CPT1 and Akt activation[89].

Two flavonoids, apigenin-6-C-β-fucopyranoside (79) and apigenin-6-C-(2′′-O-α-rhamnopyranosyl)-β-fucopyranoside (80)isolated from the Averrhoa carambola leaves showeda potential hypoglycemic effect.Both flavonoids obviously improved uscle and liver glycogen synthesis after an acute treatment.Additionally,apigenin-6-C-β-fucopyranoside could improve glucose utilization in soleus muscle acting via MEK,PI3K and atypical PKCs signaling pathways[90].

Cyanidin-3-rutinoside (C3R) (81) is an anthocyanin derivative and mainly derived from mulberry fruit.C3R could improve glucose uptake and PM-GLUT4 translocation in 3T3-L1 adipocytes via stimulating the PI3K/Akt pathways[91].

Cyanidin-3-O-β-glucoside (C3G) (82) and Cyanidin-3-xyloside(83) are a typical anthocyanin.Guo proved a novel mechanism by which anthocyanin regulated FoxO1-mediated transcription of ATGL and thus inhibited adipocyte lipolysis.In addition,C3G upregulated GLUT4 and downregulated RBP4 in white adipose tissue significantly[52].

2.6.Steriodes

Three active compounds (Fig.6) reported are presented here.Ergosterol(ERG)(85),a phytosterol isolated from the edible mushroom Pleurotus ostreatus.Xiong[92]proved ERGcouldbea potential hypoglycemic agent for the treatment of T2DM with the probable mechanism of promoting GLUT4 translocation and expression modulated by the PI3K/Akt pathway and PKC pathway.

Experiment results proved high-dose testosterone (86)(100 nmol/L) and testosterone-BSA could improve GLUT4-dependent glucose uptake in 3T3-L1 adipocytes via regulating the LKB1/AMPK signaling pathway[93].

4β-Hydroxywithanolide E (87) derived from Physalis pruinosacalyx could decrease inflammatory responses through suppressing the NF-κB signaling in adipose tissue of diabetic mouse.In addition, 4β-Hydroxywithanolide E led to the amelioration of inflammation in adipocyte which may also have an effect on the inhibition of macrophage recruitment in obese adipose tissue[94].

2.7.Phenols

Resveratrol (RSV) (88), 3,5,4′-trihydroxy-trans-stilbene, and its derivatives, 3-hydroxy-trans-stilbene (3(OH)ST) (89) and 3,4′-dihydroxy-trans-stilbene(3,4′(OH)2 ST)(90), particularly-38 suppressed adipocyte differentiation and increased glucose utilization in the myotubes, leading to an improvement in glucose utilization and a reduction of obesity[95](Fig.7).

Fig.7.The structures of active phenols.

Fig.8.The structures of other active compounds.

Gallic acid(3,4,5-trihydroxybenzoicacid)(91),a main bioactive polyphenol distributed in C.tetragonoloba.Gallic acid (20 mg/kg)was given to HFFD fed-streptozotocin-induced rats and results showed that it could increase GLUT4translocation and glucose uptake which was related to atypical protein kinase Cζ/λ[96,97].

Park demonstrated the insulin sensitizing effect of 3-hydroxy-2-naphthoic acid (3-HNA) (92) in3T3-L1 adipocytes, which could increase insulin signaling and GLUT4 membrane translocation.Upon 3-HNA treatment to ob/ob mice (150 mg/kg/day), the diabetic parameters such as systemic insulin sensitivity and glucose tolerance were significantly improved[98].

Aloe emodin-8-O-glycoside (AEG) (93) has been derived from rhizome of Rheum palmatum (L.) and Aloe vera the root and leaf.Immunoblot analysis revealed AEG could activate key markers involved in IRβ,IRS-1,PI3K and PKB.In all,AEG enhanced glucose transport by modulating the proximal and distal markers involved in glucose uptake and its transformation into glycogen[99].

In addition,Cui[85]found that compound 74,84 and 94 could increase glucose uptake on 3T3-L1 adipocytes and indicated that they possessed potential hypoglycemic effect.

2.8.Miscellaneous

Four natural compounds (Fig.8) are reported had the effect of improve IR and glucose metabolism.13-oxo-9,11-octadecadienoic acid(13-oxo-ODA)(95)is present only in tomato juice.It acted asa potent PPARα agonist,indicating a possibility to promote obesityinduced dyslipidemia and hepatic steatosis[100].

Farnesol(96),an isoprenoid,is contained in herbal plants and in dietary fruits.Farnesol could ameliorate metabolic abnormalities in mice through both PPARγ-dependent and-independent pathways.In addition,activate the FXR might partially attribute to the PPARγindependent pathways[101].

Bixin (97), one of isoprenoids of natural products, acts as a food-originated agonist of PPARα.In obese KK-Ay mice, bixin(70 μmol/L) could suppresse the development of hyperlipidemia and hepatic lipid deposition[102].

Cinnamaldehyde (CA) (98) is one of the bioactive constituents of cinnamon.Firstly, CA obviously decreased lipid deposition and decreased the expression of PPAR-γ,C/EBPα,and SREBP1 in dosagedependent manners.Secondly,CA could upregulate the expression of AMPK and ACC significantly.These results exhibited that CA could inhibit adipogenic effects by regulation of the PPAR-γ and AMPK signal pathways[103].

3.Conclusion

This paper summarizes the literature about the years from 2009 to 2019.We found that natural products are still considered as the most potential resources for drug discovery and development.From the above literature, 96 compounds have potential therapeutic effects on improving glucose metabolism and IR.They have different structural characteristics and present in many different plants, fruits and herbs.Among them, flavonoids, terpenes and phenylpropanoids are the major categories, involving 36, 24 and 15 respectively.Our unremitting goal is to select more effective compound for clinical treatment according to these different mechanism of action, so it is very important to understand these mechanism.

Above all, IRS-RaS-MAPK and IRS-1-PI3K-Akt signaling pathways play an important role in improving glucose metabolism and IR.Genes associated with the insulin signaling pathway regulate the expression levels of the corresponding proteins,thus affecting the translocation of GLUT4 from the cytoplasm to the cell membrane,and finally play a role in increasing glucose uptake and improving IR.Moreover,it also involved in other signaling pathways,such as AMPK independent pathway etc.These researches will provide a most effective help for the clinical drug screening of T2D.

Declaration of Competing Interest

All the authors declare no conflict of interest.

Acknowledgements

This work was supported by National Natural Science Foundation of China (31900292), Science and Technology Development Program of Henan Province (202102110149, 192102110112, and 182102410083) and Science and Technology Project of Kaifeng(1908005,and 1803010).