diabetes, inflamação e remédios chineses tradicionais

review

article

Diabetes, Obesity and Metabolism 13: 289–301, 2011.© 2011 Blackwell Publishing Ltdreview article

Diabetes is an inflammatory disease: evidence fromtraditional Chinese medicinesW. Xie1 & L. Du2

1Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China2Laboratory of Pharmaceutical Sciences, School of Life Sciences, School of Medicine, Tsinghua University, Beijing, China

Diabetes is usually associated with inflammation. Inflammation contributes to the development of diabetes. Traditional Chinese medicines(TCM) play an important role in lowering blood glucose and controlling inflammation. Many studies show that TCM with hypoglycaemiceffects, for example Radix Astragali, Radix Rehmanniae, Radix Trichosanthis, Panax Ginseng, Fructus Schisandrae, Radix Ophiopogonis, RhizomaAnemarrhenae, Radix Puerariae, Fructus Lycii, Poria, Rhizoma Coptidis, Rhizoma Dioscoreae, Rhizoma Polygonati, Radix Salviae Miltiorrhizae,Radix Glycyrrhizae, Semen Trigonellae, Momordica charantia, Allium sativum, Opuntia stricta, Aloe vera, Cortex Cinnamomi, Rhizoma CurcumaeLongae, and so on, have nearly independent anti-inflammatory action. Antihyperglycaemic compounds, for example berberine, puerarin,quercetin, ferulic acid, astragaloside IV, curcumin, epigallocatechin gallate, resveratrol, tetrandrine, glycyrrhizin, emodin and baicalin, used inTCM also have anti-inflammatory effects. These studies suggest that TCM might exert hypoglycaemic effects that are partly mediated by theanti-inflammatory mechanisms. However, small amounts of TCM with potent anti-inflammatory action does not have any hypoglycaemic effect.This indirectly indicates that diabetes may be a low-grade inflammatory disease and potent regulation of inflammatory mediators may not berequired. Studies of TCM add new evidences, which indicate that diabetes may be an inflammatory disease and slight or moderate inhibition ofinflammation might be useful to prevent the development of diabetes. Through this review, we aim to develop more perspectives to indicatethat diabetes may be an inflammatory disease and diverse TCM may share a common antidiabetic property: anti-inflammatory action. Furtherstudies should focus on and validate inflammation-regulating targets of TCM that may be involved in inhibiting the development of diabetes.Keywords: antidiabetic drug, diabetes, inflammation, traditional Chinese medicines

Date submitted 21 August 2010; date of first decision 23 September 2010; date of final acceptance 4 November 2010

IntroductionDiabetes is a growing health problem across the world. It hasbeen postulated that diabetes is a manifestation of an ongoingchronic low-grade inflammation. Inflammation is defined asa cascade of phenomena induced in response to differentpathological stimuli and tissue injury. Chronic subclinicalinflammation is associated with insulin resistance, a situationof increased risk for developing diabetes [1]. Inflammatoryprocesses seem to play an important role in the developmentof diabetes and its late complications [2].

The role of inflammation in the pathogenesis of type 2diabetes and its vascular complications was confirmed byinterventional studies. It has been shown that metformin,peroxisome proliferator-activated receptor (PPAR)-γ agonist,glyburide and salicylates reduce the incidence of type 2 diabetesand its vascular complications partly via anti-inflammatorymechanisms [3–6]. It is also reported that insulin suppressesfactors of inflammation in humans [7]. These studies indicatethat anti-inflammatory effects of classic hypoglycaemic drugs

Correspondence to: Lijun Du, Laboratory of Pharmaceutical Sciences, School of LifeSciences, School of Medicine, Tsinghua University, Beijing 100084, China.E-mail: [email protected]

may contribute to their antidiabetic action. Conversely, it canbe concluded that diabetes might be an inflammatory disease,although there is no solid evidence at the present time tosupport this conclusion.

Chinese herbal formulas with antidiabetic effects are welldeveloped such that a number of these formulas havecommonly been used in diabetic patients since ancienttimes. Li et al. systemically listed 86 natural medicines withregard to their origin, antidiabetic active principles and/orpharmacological test results in China [8]. Jia et al. havereviewed antidiabetic herbal drugs officially approved in Chinaand showcase eight antidiabetic herbal formulas [9]. Theseauthors believe that polysaccharide-containing herbs restorefunctions of pancreatic tissues and cause an increase in insulinoutput from the functional β cells, while other ingredientsenhance microcirculation, increase the availability of insulinand facilitate metabolism in insulin-dependent processes. Liuet al. have also conducted a systemic review of Chinese herbalmedicines for type 2 diabetes mellitus, and show that 69different herbal medicines lower blood sugar, thereby relievingsymptoms in patients with diabetes [10]. Qi et al. also reporton the most frequently used 10 Chinese herbs in the periodfrom 2004 to 2009, for the treatment of diabetes and itscomplications, that include Radix Astragali, Rhizoma Dioscoreae

review article DIABETES, OBESITY AND METABOLISM

(RD), Radix Rehmanniae, Radix Salviae Miltiorrhizae, RadixPuerariae, Rhizoma Coptidis, Fructys Lycii, Poria, RhizomaAlismatis and Fructus Corni [11]. Wang and Wylie-Rosettselected 23 herbs and 5 herbal formulas in the treatmentof type 2 diabetes for review and indicated that the use ofChinese herbal medicines in diabetes is promising, althoughthey are yet to be proven by further research [12].

However, it is unclear whether these hypoglycaemic Chineseherbs would have as potent anti-inflammatory properties asthat of Western hypoglycaemic drugs. The Chinese herbs inves-tigated are mostly qi-invigorating, heat-clearing and detoxify-ing drugs, as described previously in the theory of traditionalChinese medicines (TCM) [13]. Heat-clearing and detoxifyingdrugs usually have anti-inflammatory effects [14]. In particu-lar, the main active compounds, for example polysaccharides,terpenoids, flavonoids and alkaloids, in hypoglycaemic Chineseherbs usually have wide pharmacological effects includinganti-inflammatory action. Therefore, it was not difficult tospeculate that diverse hypoglycaemic TCM might all haveanti-inflammatory effects. These effects might contribute theirbeneficial effects by inhibiting the development of diabetesas diabetes is associated with an inflammatory process. Inthis article, we systemically review anti-inflammatory evi-dences from TCM in the treatment of diabetes. This reviewaims to ascertain whether hypoglycaemic TCM share commonaction pathways in addition to their routine mechanisms ofaction and, further, to understand the inflammatory nature ofdiabetes.

TCM With Both Hypoglycaemic andAnti-inflammatory ActivitiesTCM are consisted of several herbal formulas, individual herbsand active extracts or chemical components. We select the top15 herbs most commonly prescribed in traditional Chineseformulas in the treatment of type 2 diabetic patients and areapproved by the State Food & Drugs Administrator (SFDA)in the mainland of China (unpublished data). These herbsnot only have antihyperglycaemic action but they also haveanti-inflammatory effects (Table 1). In addition to these herbsfrom Chinese formulas, other individual hypoglycaemic herbsalso have anti-inflammatory effects. These anti-inflammatoryeffects do not appear to be the result of hypoglycaemiceffects. These reported studies indicate that Chinese herbsexert a hypoglycaemic effect via their anti-inflammatorymechanism.

Traditional Chinese Medicines

Huang Qi (Radix Astragali). In theories of TCM, RadixAstragali replenishes qi to invigorate yang, has beneficialeffects on lungs to strengthen the body, promotes diuresisand relieves edema, cures skin infection and promotes tissueregeneration. Radix Astragali is the most widely used herbin traditional Chinese formulas in the treatment of diabetes.Astragalus polysaccharides (APS) exerts a hypoglycaemic effectby decreasing the stress on the endoplasmic reticulum andthen inhibiting the expression of protein tyrosine phosphatase1B (PTP1B) in type 2 diabetic rats that have been induced by

Table 1. Antihyperglycaemic and anti-inflammatory effects of the top 15 most frequently prescribed herbs in 30 formulas and other individual herbprescriptions.

No. TCMAntihyperglycaemicactivity (references)

Anti-inflammatoryactivity (references) Active components

1 Huang Qi (Radix Astragali) + [15–17] + [18,19] Polysaccharides2 Di Huang (Radix Rehmanniae) + [20–22] + [23,24] Catalpol, oligosaccharide3 Tian Hua Fen (Radix Trichosanthis) + [25] + [26] Glycans, trichosanthin4 Ren Shen (Radix Ginseng) + [27–29] + [30,31] Saponins5 Wu Wei Zi (Fructus Schisandrae) + [32,33] + [34] Lignans, polysaccharides6 Mai Dong (Radix Ophiopogonis) + [35] + [36] Sapogenin7 Zhi Mu (Rhizoma Anemarrhenae) + [37] + [38] Mangiferin8 Ge Gen (Radix Puerariae) + [39,40] + [41] Puerarin (flavonoids)9 Gou Qi (Fructus Lycii) + [42] + [43] Polysaccharides

10 Fu Ling (Poria) + [44,45] + [46] Triterpene acid11 Huang Lian (Rhizoma Coptidis) + [47–49] + [50] Berberine12 Shan Yao (Rhizoma Dioscoreae) + [51] + [52,53] Saponins13 Huang Jing (Rhizoma Polygonati) + [54,55] + [56] Flavonoids, polysaccharides14 Dan Shen (Radix Salviae Miltiorrhizae) + [57] + [58,59] Tanshinone IIA (lignans)15 Gan Cao (Radix Glycyrrhizae) + [60,61] + [62] Glycyrrhetinic acidI Semen Trigonellae + [63] + [64,65] Diosgenin (saponin)II Momordica charantia + [66–70] + [71] Polypeptide-p, SaponinsIII Allium sativum + [72,73] + [74,75] Volatile oils, sulphur compoundsIV Cactus (Opuntia stricta) + [76] + [77] Polysaccharides, β-SitosterolV Aloe vera + [78] + [79] Aloe vera gelVI Rou Gui (Cortex Cinnamomi) + [80–83] + [84] Cinnamon oilVII Jiang Huang (Rhizoma Curcumae Longae) + [85,86] + [87] Curcuminoids and sesquiterpenoids

The ‘+’ indicates that the compound has that particular activity.

290 Xie and Du Volume 13 No. 4 April 2011

DIABETES, OBESITY AND METABOLISM review articlehigh-fat diets and low-dose streptozotocin (STZ) [15]. APS alsoincreases glucose metabolism by increasing liver glycogenesisand skeletal muscle glucose translocation through activatingAMP kinase (AMPK) in the same type of diabetic rats [16]. APSimproves insulin sensitivity and exerts a hypoglycaemic effectin KK-Ay mice by regulating protein kinase B (PKB)/glucosetransporter (GLUT)4 signalling in skeletal muscle [17]. APSmay be effective in the attenuation of insulitis and prevents β

cells from undergoing apoptosis in type 1 diabetic mice [18].Radix Astragali exhibits anti-inflammatory effects in Zymosanair-pouch mice by inhibiting the expression of induciblenitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2),interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumournecrosis factor (TNF)-α while also reducing the production ofnitric oxide (NO) [19]. Its anti-inflammatory effect is attributedto the inactivation of p38 and extracellularly regulated kinase1/2(ERK1/2) and the inhibition of nuclear factor-κB (NF-κB)-mediated transcription.

Di Huang (Radix Rehmanniae). In theories of TCM, RadixRehmanniae (RR) is used to clear away heat and cool theblood, nourish yin and promote the production of the bodyfluids. RR has a very long history of use in TCM and isusually one of the principal herbs in many herbal formulasused in the treatment of diabetes. RR has been reported tocontain more than 70 compounds and has a broad range ofpharmacological effects [20]. Catalpol, with its hypoglycaemiceffects, is one of the most important compounds in RR [21].Next, oligosaccharides exert a significant hypoglycaemic effectin normal and alloxan-induced diabetic rats [22]. The mecha-nism of RR for regulating glucose metabolism has a correlationwith the regulation of the neuroendocrine system, stimulatesthe secretion of insulin, improves insulin resistance, enhancesactivity of liver glucokinase and glucose-6-phosphate dehy-drogenase, decreases hepatic glycogen content and stimulatesglucose uptake [20]. Treatment with RR brings about decreasedplasma C-reactive protein (CRP) levels compared with diabeticcontrols [23]. RR injections inhibit increase in total white bloodcell and neutrophil counts and attenuate the increase in TNF-α,O2−, myeloperoxidase induced by lipopolysaccharides (LPS),and minimize pathophysiologic changes including neutrophilinfiltration and mucosal edema in the tracheae in a rat modelof lung inflammation, induced by LPS [24].

Tian Hua Fen (Radix Trichosanthis). In the theory of TCM,Radix Trichosanthis has actions such as clearing of heat, pro-motion of production of body fluids, resolution of swellingand drainage of pus. This herb is used in the treatment ofdiabetes and increased thirst. The water extract of the rootsof Trichosanthes kirilowii is found to reduce plasma glucoselevels in mice [25]. Five glycans, called trichosans A, B, C,D and E, have been isolated from the water extract of theroots of Trichosanthes kirilowii, and have manifested hypogly-caemic effects in normal mice. The main glycan, trichosan A,also exhibits activity in alloxan-induced diabetic mice. Tri-chosanthes inhibits TNF-α and IL-1β production in peripheralblood mononuclear cells stimulated by LPS, indicating definiteanti-inflammatory activity [26].

Ren Shen (Radix Ginseng). In TCM, Ginseng is claimed toinvigorate renal qi, strengthen qi of the spleen and lung,promote production of the body fluids to quench thirst andcalm the mind to promote intelligence. Ginseng has beenreported effective, in many ancient Chinese medical literatures,to treat emaciation and symptoms such as thirst [27]. Ginsengtherapy significantly reduces fasting blood glucose (FBG)and homeostatic model assessment of insulin resistance intype 2 diabetic subjects compared with placebo [28]. Ginsengreduces hyperglycaemia in the diabetic mouse model, inducedby STZ [29]. However, ginseng has no effect on glucoseregulation during acute or chronic administration in healthyvolunteers [88]. Its effects include increased insulin secretion,prevention of β-cell apoptosis, enhanced insulin sensitivityand promotion of thermogenesis [27]. Commonly, the activecomponents of ginseng are considered to be ginsenosides.Ginsenoside Re inhibits intracellular inflammatory moleculesincluding c-Jun N-terminal kinase (JNK) and NF-κB andenhances insulin sensitivity in 3T3-L1 adipocytes and high-fatdiet rats [30]. Ginsenoside Ro inhibits vascular permeabilityin mice that have been induced by acetic acid and reducesacute paw edema in rats induced by the compound 48/80 orcarrageenan [31].

Wu Wei Zi (Fructus Schisandrae). Fructus Schisandrae, inTCM, is used as an astringent of the lung to treat coughand asthma, nourish the kidney, promote the production ofbody fluid and inhibit perspiration, condense the essence andstop diarrhoea, nourish the heart and calm the mind. FructusSchisandrae lowers blood glucose and improves insulin resis-tance in 90% pancreatectomized diabetic rats maintained onhigh-fat diets and may have been mediated by the mechanismof increased insulin sensitivity [32]. Dibenzocyclooctadienelignans, the active principle isolated from Fructus Schisan-drae, reduces the level of blood glucose by stimulating glucoseuptake into peripheral tissues [33]. Schisandrin is the mainactive ingredient isolated from the fruit of Schisandra chinensisBaill. Schisandrin significantly inhibits carrageenan-inducedpaw edema and acetic acid-induced vascular permeability inmice. Further, schisandrin has a protective effect on LPS-induced sepsis [34]. Schisandrin also inhibits the production ofNO and prostaglandin E2 (PGE2), and attenuates the expres-sion of COX-2 and iNOS, which may be mediated by theinhibition of NF-κB, JNK and p38 mitogen-activated proteinkinase (MAPK) activities in RAW 264.7 macrophage cells.

Mai Dong (Radix Ophiopogonis). Radix Ophiopogonis (RO),another top herb used in TCM, nourishes yin and increases lungsecretions, benefits the stomach and regenerates body fluids,clears away heart-heat and relieves anxiety. Intraperitonealadministration of the n-butanol extract of RO decreases bloodglucose levels in normal and STZ-induced diabetic mice [35].RO also tends to suppress epinephrine-induced hyperglycaemiain mice. Aqueous extract from RO significantly inhibits xylene-induced ear swelling and carrageenan-induced paw edema inmice following oral administration [36]. RO also remarkablysuppresses carrageenan-induced pleural leucocyte migrationin rats and Zymosan A-evoked peritoneal total leucocyte and

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neutrophil migration in mice. Ruscogenin and ophiopogoninD are two of the active components of this herb.

Zhi Mu (Rhizoma Anemarrhenae). In TCM, Rhizoma Anemar-rhenae (RA) is used to clear away heat and purge fire, nourishyin and aid moisturization. The aqueous extract of RA reducesblood glucose levels following oral administration and alsotends to reduce serum insulin levels in KK-Ay mice [37]. RA-treated KK-Ay mice have shown significantly lowered bloodglucose levels in an insulin tolerance test. The antidiabeticaction of RA may be due to decreased insulin resistance. Fur-ther, mangiferin and its glucoside have been confirmed as activecomponents of RA. It is reported that the total polysaccharideextracts from RA may inhibit inflammatory responses in var-ious models [38]. Timosaponin B-II, derived from a purifiedextract of RA, significantly inhibits the increase in IL-1β, TNF-α and IL-6, on both mRNA and protein levels from BV2 cellsstimulated by LPS in a dose-dependent manner.

Ge Gen (Radix Puerariae). In TCM, Radix Puerariae is usedto expel pathogenic factors in the muscles to abate heat,expel skin eruptions, promote the production of body fluid todecrease thirst, uplift yang and to relieve diarrhoea. Intravenousinjection of puerarin, purified from Radix Puerariae, decreasesplasma glucose levels in a dose-dependent manner in STZ-induced diabetic rats [39]. Radix Puerariae increases glucoseutilization in diabetic rats with insulin deficiency. Moreover,the mRNA and protein levels of GLUT4 in soleus muscleare increased after intravenous administration of puerarinin STZ-induced diabetic rats. Puerarin may activate α1-adrenoceptors in the adrenal gland to enhance the secretion ofβ-endorphin, with resultant reduction in plasma glucose levelsin STZ-induced diabetic rats. Puerarin can protect islets againstoxidative stress induced by H2O2 probably by its mechanismof action increasing catalase and superoxide dismutaseactivities [40]. Puerarin also acts as an anti-inflammatory agent.Puerarin inhibits the expression of the protein and mRNAlevels of CRP in LPS-induced peripheral blood mononuclearcells [41]. The inhibition of CRP expression is due to a dose-dependent inhibition of phosphorylation and degradation ofinhibitor-κB (I-κB), which results in a reduction of p65 NF-κBnuclear translocation.

Gou Qi (Fructus Lycii). In TCM, Fructus Lycii (FL) is claimed totone the kidney and benefit essence, while nourishing the liverand improving eyesight. Polysaccharides extracted followingtreatment of FL for 28 days bring about a significant decreasein concentrations of FBG, total cholesterol and triglycerides(TG) in alloxan-induced diabetic mice [42]. Further, FLpolysaccharides significantly increase body weight in thisanimal model. FL polysaccharides are effective in the protectionof liver and kidney tissue from damage as shown in STZ-induced diabetic rat; this implies that FL polysaccharides maybe of use as antihyperglycaemic agents. FL polysaccharides havebeen identified as one of the active ingredients responsible forFL’s biological properties. FL polysaccharides can attenuate theinflammatory reaction in endothelial cells and this is mediatedby inhibition of the CRP and NO production [43].

Fu Ling (Poria). In TCM, Poria is utilized to promotediuresis to resolve dampness from the lower energizer,invigorate the spleen and tranquilize the mind. Poria extract,and triterpenes therein, lowers postprandial blood glucoselevels in db/db mice via enhanced insulin sensitivity [44].The triterpene acid compound dehydrotrametenolic acid,isolated from Poria, can reduce hyperglycaemia in db/dbmice and act as an insulin sensitizer [45]. Poria extract iseffective in mitigating inflammation in different in vivo modelsof inflammation induced by 12-O-tetradecanoyl-phorbol-13-acetate, ethyl phenylpropiolate and phospholipase A2 [46].Active components in this herb are lanostane triterpenes.

Huang Lian (Rhizoma Coptidis). In TCM, Rhizoma Coptidisis used to clear away heat and remove dampness, purge thesthenic fire and eliminate toxic materials. Rhizoma Coptidishas been used to treat diabetes for more than 1400 yearsin China. Berberine is one of the main active alkaloidspresent in Rhizoma Coptidis. Berberine reduces weight gain,enhances insulin sensitivity and decreases blood glucose inboth dietary and genetic animal models of type 2 diabetes [47].Berberine activates AMPK via the inhibition of mitochondriafunction [48]. Berberine has protective effects on β cells inSTZ- and high-carbohydrate/high-fat diet-induced diabeticrats [47]. Berberine reduces glucose absorption in the intestineby inhibiting intestinal disaccharidases [49]. Rhizoma Coptidisis well known for its anti-inflammatory activity. Incubationwith Rhizoma Coptidis and berberine strongly inhibitedLPS-induced monocyte chemoattractant protein (MCP)-1production in RAW 264.7 cells [50]. The increase in thetranscription factors activator protein-1 (AP-1) and NF-κB isinhibited by Rhizoma Coptidis in a dose- and time-dependentmanner.

Shan Yao (Rhizoma Dioscoreae). In TCM, RD invigoratesthe spleen and stomach, promotes production of the bodyfluids and benefits lungs, invigorates kidneys and preservesthe essence. RD is a common food ingredient in China. RDimproves fructose-induced decrease in the insulin-stimulatedglucose disposal rate after 3 days of treatment [51]. In addition,oral administration of RD into STZ-induced diabetic ratsfor 10 days increases sensitivity to exogenous insulin. RDsignificantly inhibited TNF-α and IL-1β production anddownregulated COX-2 and iNOS expression in humanfibroblast-like synovial cells that were stimulated by IL-1β andTNF-α. Further, RD effectively reduced the level of reactiveoxygen species (ROS) in these cells [52]. The extract of RD hasbeen shown to decrease damage in renal tubules, inflammationin the central vein and necrosis in the liver tissue of rats [53].

Huang Jing (Rhizoma Polygonati). In TCM, Rhizoma Polygo-nati (RP) is used to increase secretions in the lung, nourish andinvigorate the kidney and benefit qi. Intraperitoneal admin-istration of the methanol extract of RP lowers blood glucoselevels in normal and STZ-induced diabetic mice [54]. How-ever, the hypoglycaemic effects are not accompanied by anyalteration in serum insulin in these mice. RP decreased hepaticglucose output and exerted a hypoglycaemic effect, presumablybecause of the reduction of GLUT2 expression in the total


DIABETES, OBESITY AND METABOLISM review articlemembrane of the liver [55]. One of the active components ofRP is identified as a spirostanol glycoside. In addition, pharma-cological research indicates that Polygonatum polysaccharidihas anti-inflammatory effects [56].

Dan Shen (Radix Salviae Miltiorrhizae). In TCM, Radix SalviaeMiltiorrhizae promotes blood circulation to remove bloodstasis, regulates menstruation to relieve pain, cools the bloodto relieve carbuncle and clears away heat from the bodyand tranquilizes the mind. Tanshinone IIA, an importantcomponent extracted from Salvia miltiorrhiza, can improveglucose tolerance and inhibits adipogenesis in rats fed on a high-fat diet, and might be beneficial in the treatment of diabeticpatients with complex metabolic disorders [57]. TanshinoneIIA has protective effects on several pharmacological targetsin the progression of diabetic nephropathy [89]. TanshinoneIIA restores impaired neural functions in the experimentaldiabetic rats [90] and also protects the myocardium againstischaemia/reperfusion injury [91]. Danshen is used to treatacute pancreatitis and its mechanisms of action includeimprovement of microcirculatory disturbances, eliminationof oxygen free radicals, modulation of the metabolism of lipidinflammatory mediator and blocking of calcium inflow withsubsequent prevention of calcium overload [58]. TanshinoneIIA exerts anti-inflammatory effects mediated by inhibition ofiNOS gene expression and NO production, as well as inhibitionof inflammatory cytokine (IL-1β, IL-6 and TNF-α) expressionvia the endoplasmic reticulum-dependent pathway in LPS-induced RAW 264.7 cells [59].

Gan Cao (Radix Glycyrrhizae). In TCM, Radix Glycyrrhizaefunctions by enriching qi and invigorating the stomach andspleen, moistening the lung and clearing away phlegm, clearingaway heat and toxins and relieving spasm and alleviatingpain. Roasted Glycyrrhizae Radix, containing glycyrrhetinic acid(GA), improves glucose tolerance better than raw GlycyrrhizaeRadix extract by enhancing insulinotropic action in partiallypancreatectomized diabetic mice [60]. Glycyrin, one of themain PPAR-γ ligands of licorice, significantly lowers the bloodglucose level [61]. GA inhibits TNF-α-stimulated intercellularadhesion molecule-1 (ICAM-1) expression, leading to adecrease in monocytes adhering to human umbilical veinendothelial cells [62]. This inhibition is attributed to GAinterruption of both JNK/c-Jun and I-κB/NF-κB signallingpathways, which decrease AP-1 and NF-κB-mediated ICAM-1expressions. The results imply that GA may manifest anti-inflammatory effects.

Semen Trigonellae. Oral administration of Semen Trigonellae(fenugreek) seeds soaked in hot water significantly decreasedFBG levels in patients with type 2 diabetes mellitus [63].4-Hydroxyisoleucine, an unusual amino acid isolated fromfenugreek seeds, when administered orally in mice significantlyinhibits elevation of blood glucose and plasma insulin levels indb/db diabetic mice, which is evidenced by the enhancementof insulin sensitivity and glucose uptake in peripheraltissues. Fenugreek also inhibits macrophage infiltration intoadipose tissues and decreases the mRNA expression levelsof inflammatory genes [64]. In addition, diosgenin, a major

aglycone of saponins, in fenugreek has been identified topromote adipocyte differentiation and to inhibit expressions ofseveral molecular candidates associated with inflammationin 3T3-L1 cells. Diosgenin has been shown to suppressinflammation mediated by its inhibition of TNF-induced NF-κB activation in tumour cells [65].

Momordica Charantia. Momordica charantia (bitter melon) isa popular fruit used for the treatment of diabetes and relatedconditions amongst the indigenous populations of Asia, SouthAmerica, India and East Africa. Many animal and humanstudies have proved the potential role of Momordica charantiain glycaemic control [66]. Momordica charantia reduces bloodglucose levels and also significantly lowers the serum insulinlevels in KK-Ay mice after 3 weeks of oral administration [67].The hypoglycaemic mechanisms are related to its inhibitionof PTP1B [68], activation of AMPK [69], increase in GLUT4protein content in the plasma membrane [67] and promotionof the recovery of β cells [92]. Major active compounds inthis herb include cucurbitane triterpenoids [93], polypeptide-p [70], saponins, and so on. The butanol soluble fraction ofbitter gourd placenta extract strongly suppresses LPS-inducedTNF-α production and expression of various LPS-inducedinflammatory genes in RAW 264.7 cells [71]. The butanolfraction significantly suppresses NF-κB DNA-binding activityand phosphorylation of p38, JNK and ERK MAPKs.

Allium Sativum. Garlic (Allium sativum), which is a com-mon cooking spice and has a long history of use as afolk remedy, has been reported to have antidiabetic activity.Antioxidant, anti-inflammatory and antiglycative propertiesof garlic play an important role in preventing progres-sion of diabetes and the development of diabetes-relatedcomplications [72]. Both garlic oil and diallyl trisulphideimprove glycaemic control in STZ-induced diabetic ratsthrough increased insulin secretion and sensitivity [73]. Sul-phur compounds isolated from garlic exert anti-inflammatoryproperties. S-Allyl-l-cysteine sulphoxide can control TNF-α-mediated inflammation and mediate vascular disease [74].Thiacremonone, another novel sulphur compound from gar-lic, suppresses 12-O-tetradecanoylphorbol-13-acetate-induced(1 μg/ear) ear edema [75]. Thiacremonone (1–10 mg/kg)administered directly onto the plantar surface of hind pawalso suppresses carrageenan (1.5 mg/paw) and Mycobacteriumbutyricum (2 mg/paw)-induced inflammatory and arthriticresponses, which may be related to the inhibition of expressionof iNOS and COX-2.

Opuntia Stricta. Opuntia stricta (cactus) has an effect onlowering blood glucose levels in patients with type 2 diabetesmellitus. Blood glucose and glycated haemoglobin (HbA1c)levels are reduced to normal values by a combined treatment ofinsulin and Opuntia extract in STZ-induced diabetic rats [76].When insulin is withdrawn from this combined therapy,Opuntia stricta extract alone can maintain normoglycaemicstate in diabetic rats. Rats receiving combination treatment ofinsulin and Opuntia extract for 7 weeks followed by Opuntiaextract alone have shown rapid return of blood glucoselevels than those of non-diabetic rats after being challengedwith exogenous glucose administration. Polysaccharides may



be responsible for this hypoglycaemic activity. The ethanolextract of Opuntia stricta manifests potent anti-inflammatoryaction [77]. In adjuvant-induced chronic inflammation modelin mice, the active anti-inflammatory principle has beenisolated and identified as β-sitosterol.

Aloe Vera. Oral administration of processed Aloe vera gel(PAG) for 8 weeks reduces blood glucose concentrations toa normal level in these diet-induced obese mice [78]. Inaddition, PAG significantly decreases plasma insulin. Theantidiabetic effects of PAG are also confirmed by intraperitonealglucose tolerance testing. PAG appears to lower blood glucoseconcentrations by decreasing insulin resistance. Phytosterolsderived from Aloe vera gel may act as active compounds in thisaction [94]. However, Aloe vera used topically, administeredintraperitoneally or by a combination delivery modulatesinflammatory responses [79]. The maximal effect is observedwith the combined delivery, indicating modulation at local aswell as systemic levels. This modulation could result from thepotential of Aloe vera to attenuate peroxidative damage by adecrease in the levels of TNF-α, IL-1 and IL-6, and an increasein the level of superoxide dismutase.

Rou Gui (Cortex Cinnamomi). In TCM, Cortex Cinnamomifunctions by supplementing fire and strengthening yang,expelling cold and alleviating pain and warming channelsto promote blood circulation. Intake of 2 g of cinnamonfor 12 weeks significantly reduces the HbA1c among patientswith poorly controlled type 2 diabetes [80]. Cinnamon oil(CO), when administered for 35 days, significantly decreasesFBG levels in an animal model of type 2 diabetes (KK-Ay mice) [81]. Meanwhile, glucose tolerance is improved,and the immunoreactive capacity of pancreatic islets β cellsis enhanced. Indeed, it is evident that Cortex cinnamomiextract prevents STZ- and cytokine-induced β-cell damageby inhibition of NF-κB [82]. Further, cinnamon extractsincrease GLUT1 mRNA and decrease the expression of furthergenes encoding insulin signalling pathway proteins [83]. Themain component of CO is cinnamaldehyde. Twig essentialoil and its major constituents such as trans-cinnamaldehyde,caryophyllene oxide, l-borneol, l-bornyl acetate, eugenol, β-caryophyllene, E-nerolidol and cinnamyl acetate significantlyinhibit NO and PGE2 production in LPS-activated RAW 264.7cells [84].

Jiang Huang (Rhizoma Curcumae Longae). In TCM, Rhi-zoma Curcumae Longae is traditionally used to promotecirculation of blood and qi, dredge the meridian passage toalleviate pain. The ethanol extract of turmeric significantlyinhibits increase in blood glucose levels in type 2 diabeticKK-Ay mice [85]. In an in vitro evaluation, the extract stim-ulated human adipocyte differentiation in a dose-dependentmanner and showed human PPAR-γ ligand-binding activ-ity. The main constituents of the extract are identified ascurcumin, demethoxycurcumin, bisdemethoxycurcumin andar-turmerone, and it also has PPAR-γ ligand-binding activity.Curcumin increased GLUT4 expression and glucose uptakeinto skeletal muscle, isolated from Wistar rats, through thephospholipase C (PLC)–phosphoinositide 3 kinase (PI3K)

pathway [86]. A turmeric preparation depleted of essential oilsprofoundly inhibits joint inflammation and periarticular jointdestruction in a dose-dependent manner. In vivo treatmentprevents local activation of NF-κB and the subsequent expres-sion of NF-κB-regulated genes that mediate joint inflammationand destruction, including chemokines, COX-2 and receptoractivator of NF-κB ligand [87]. Further, inflammatory cellinflux, levels of PGE2 within a joint and periarticular osteoclastformation are inhibited by treatment with turmeric extract.

Compounds Derived From TCM

Active components of TCM mainly contain polysaccharides,flavonoids, terpenoids, alkaloids and so on. It is hypothesizedthat these common chemical components might share similarmechanisms of action within different herbs. In addition tothe well-defined berberine and puerarin described above, someother active components from Chinese herbal medicines arefound to have significant or moderate hypoglycaemic effects aswell as anti-inflammatory action (figure 1).

Quercetin. Quercetin, a bioflavonoid widely used in TCM,is a food component that may ameliorate diabetic symp-toms. Diets containing 0.1 or 0.5% quercetin lowered theSTZ-induced increase in blood glucose levels and enhancedplasma insulin levels [95]. Dietary quercetin may improvehepatic and pancreatic functions by facilitating cell prolif-eration through inhibition of Cdkn1a expression. Quercetinpromotes glucose- and glibenclamide-induced insulin secre-tion and protects β cells against oxidative damage through theERK1/2 pathway [96]. Quercetin enhances glucose metabolismthrough activation of both silent mating type information reg-ulation 2 homolog 1 (SIRT1) and AMPK in HepG2 cells [97].Quercetin affects inflammation by modulating several intra-cellular signalling kinases, phosphatases, enzymes and mem-brane proteins that are often crucial for a specific cellularfunction [98]. Quercetin attenuates lethal systemic inflamma-tion caused by endotoxaemia [99]. In macrophage cultures,quercetin limits the activation of MAPK and NF-κB.

Ferulic Acid. Ferulic acid (FA), a phenolic compound, is astrong membrane antioxidant and is reported to have positiveeffects on human health. FA at 0.01 and 0.1% of t basal dietsignificantly suppresses blood glucose levels in STZ-induceddiabetic mice [100]. In KK-Ay mice, 0.05% FA suppressesblood glucose levels effectively. FA also stimulates insulinsecretion from pancreatic β cells [101], protects against cellularredox disruption and several oxidative stress-related diseases,including inflammation in animal studies [102], suppressesNF-κB activation and modulates the expression of NF-κB-induced, proinflammatory COX-2, iNOS, vascular celladhesion molecule-1 (VCAM-1) and ICAM-1 [102]. Further,FA prevents the induction of ICAM-1 and VCAM-1 expressionin a concentration-dependent manner after being stimulatedby radiation [103]. The inhibitory effect of FA on adhesionmolecule expression is mediated by blockade of JNK.

Astragaloside IV. Astragaloside IV, a new cycloartane-typetriterpene glycoside extract of Radix Astragalus membranaceus


DIABETES, OBESITY AND METABOLISM review article

Figure 1. Antihyperglycaemic and anti-inflammatory compounds from traditional Chinese medicines (TCM) (structures were sourced fromhttp://www.pubchem.ncbi.nlm.nih.gov/).

Bunge, at doses of 25 and 50 mg/kg, significantly decreasesblood glucose, TG and insulin levels, and inhibits mRNA andprotein expression as well as enzymatic activity of glycogenphosphorylase (GP) and glucose-6-phosphatase (G-6-Pase) indiabetic mice, induced by a high-fat diet and STZ [104]. Thehypoglycaemic effect of this compound may be explained, inpart, by its inhibition of hepatic GP and G-6-Pase activities.

AS-IV improved TNF-α-induced insulin resistance in 3T3-L1adipocytes [105]. AS-IV has been reported to have anti-inflammatory effects in vivo [106]. AS-IV inhibits cytokine-and LPS-stimulated expression of adhesion molecules in, andleucocyte adhesion to, endothelial cells. AS-IV’s inhibitionof the NF-κB pathway might be one underlying mechanismcontributing to its anti-inflammatory potential in vivo.



Curcumin. Curcumin, an antioxidant compound, lowersblood glucose levels and ameliorates the long-term com-plications of diabetes in animal models of diabetes [107].Curcumin increases the phosphorylation of AMPK and itsdownstream target acetyl-CoA carboxylase (ACC) in cells with400 times the potency of metformin. Curcumin suppresseshepatic gluconeogenesis. Curcumin inhibits proinflammatorycytokine concentrations in the serum and pancreas of STZ-treated animals [108]. Curcumin, in combination with aspirinor rofecoxib, causes a further decrease in serum TNF-α lev-els that could possibly be mediated by inhibition of theCOX enzyme [109]. Curcumin attenuates the developmentof allergic airway inflammation and hyper-responsivity, pos-sibly through inhibition of NF-κB activation in the asthmaticlung tissue [110].

Epigallocatechin Gallate. Epigallocatechin gallate (EGCG) isone of the main compounds derived from green tea. EGCG canprevent abnormal changes in blood glucose and lipid profile andattenuate hepatic lipid peroxidation in STZ-induced diabeticrats [111]. EGCGs have protective effect on the insulinoma-1(INS-1) beta cells against oxidative stress both through antiox-idant effect and antiapoptotic signalling [112]. EGCG inhibitsERK and activates AMPK [113]. Pretreatment with EGCG sup-presses the secretion of monocyte chemoattractant protein-1and the activation of AP-1 in porcine aortic endothelial cellsstimulated by TNF-α [114]. EGCG attenuates LPS-inducedlung injury by inhibition of the macrophage inflammatoryprotein-2 and TNF-α production, as well as ERK1/2 and JNKactivation in macrophages stimulated by LPS [115].

Resveratrol. Resveratrol, a polyphenolic SIRT1 activator,showed a significant antihyperglycaemic effect in type 2 diabeticob/ob mice [116]. The STZ–nicotinamide-induced diabeticrats, when orally treated with resveratrol, exhibit significantdecrease in the levels of blood glucose and glycosylatedhaemoglobin [117]. Its antidiabetic properties may be mediatedby enhanced insulin secretion and antioxidant competence inpancreatic β cells of diabetic rats [118]. Further, resveratrolactivates APMK and increases energy metabolism. Resveratrolsignificantly inhibits airway inflammation in respiratorydisease [119]. Resveratrol treatment decreases the expression ofp65 and I-κB−α and ameliorates elevation in levels of TNF-α,IL-6 and COX-2 in treated rats [120].

Tetrandrine. Tetrandrine, an active plant alkaloid derivedfrom Stephaniae tetrandrae, significantly decreases the plasmaglucose levels in a dose-dependent manner in STZ-induceddiabetic rats [121]. Tetrandrine prevents the spontaneousdevelopment of diabetes mellitus in biobreeding (BB)rats [122]. Tetrandrine has the ability to enhance glucoseutilization in peripheral tissue and protect islet β cells frominjury induced by alloxan. Tetrandrine, remarkably, suppressesthe LPS induction of NO release and PGE2 generation [123].It also significantly attenuates LPS-induced transcription ofproinflammatory cytokines (TNF-α, IL-4 and IL-8) in a dose-dependent manner. Further, tetrandrine significantly blocksthe LPS induction of iNOS and COX-2 expression, which mayaccount for its anti-inflammatory mechanisms.

Glycyrrhizin. Glycyrrhizin treatment significantly lowers bloodinsulin level in diabetic KK-Ay mice [124]. The mice fedon a glycyrrhizin diet also have improved tolerance to oralglucose loading 9 weeks after the beginning of test feeding.Glycyrrhizin inhibits the LPS/d-galactosamine-induced hepaticinjury through prevention of inflammatory responses and IL-18production [125]. Further, it appears that glycyrrhizin preventsIL-18-mediated inflammation in hepatic injury.

Emodin. Emodin, a natural product and active ingredient ofvarious Chinese herbs, significantly decreases blood glucoselevels in high-fat diet-fed- and low-dose STZ-induced diabeticmice [126]. The glucose tolerance and insulin sensitivityin the emodin-treated group were significantly improvedcompared with the controls. The activation of PPAR-γ andthe modulation of metabolism-related genes likely mediate theantidiabetic effects of emodin. Further, emodin is considereda potent and selective inhibitor of 11β-hydroxysteroiddehydrogenase type 1 [127]. Emodin can inhibit the activationof NF-κB and the expression of ICAM-1 induced by LPSin corneas, protect against acute corneal injury and improvesymptoms in rats [128].

Baicalin. Baicalin, a flavonoid known for its radical scavengingactivity, significantly decreases plasma glucose levels in a dose-dependent manner in nicotinamide–STZ-induced diabeticrat [129]. Administration of baicalin results in a significantincrease in hepatic glycogen content and glycolysis, and areduction in serum TNF-α level. Baicalin significantly alleviatedthe morphological injury to the pancreas caused by STZ.Baicalin inhibits macrophage activation and protects mice frommacrophage-mediated endotoxic shock. It also suppresses theincreased generation of NO and expression of iNOS inducedby LPS or interferon-γ without directly affecting iNOS activityin RAW264.7 cells and peritoneal macrophages [130].

TCM With Anti-inflammatory Effects OnlyHowever, many of the classic or potent anti-inflammatorycomponents in herbs, for example daphnetin [131], sinome-nine [132], tripterysium glucosides [133], decanoylacetalde-hyde [134], oxymatrine [135], phthalide lactones [136] andtetramethylpyrazine [137] have no reported hypoglycaemicactivities. Frequently used anti-inflammatory drugs are clas-sified as: non-steroidal anti-inflammatory and steroidalanti-inflammatory drugs. Non-steroidal anti-inflammatorydrugs include salicylates, acetaminophen, phenylbutazone,indomethacin, ibuprofen, colchicines, and so on. With theexception of salicylates [138,139], these drugs have no antidi-abetic effects. Of note, most patients requiring non-steroidalanti-inflammatory drugs for pain control show a high inci-dence of gastrointestinal and cardiovascular risk factors [140].Steroidal anti-inflammatory drugs increase blood glucose lev-els, for example dexamethasone [141]. Therefore, it may beinappropriate to use potent anti-inflammatory drugs to pre-vent the development of diabetes. In turn, these results indicatethat diabetes is a low-grade inflammatory disease. Only thosedrugs with slight or mild anti-inflammatory activities may beable to prevent the development of diabetes.


DIABETES, OBESITY AND METABOLISM review articleDiscussion and PerspectivesThis review, firstly, indicates that most of TCM with hypo-glycaemic activities usually have separate anti-inflammatoryeffects, although their anti-inflammatory effects are weakas compared with the classic anti-inflammatory drugs. Inaddition to routinely used hypoglycaemic Western/allopathicdrugs, there are several Chinese hypoglycaemic herbs thathave anti-inflammatory properties; this implies that weneed to reunderstand the mechanism of action of thesehypoglycaemic drugs, apart from the routine hypoglycaemicmechanisms. In actuality, the aetiology of diabetes is stillfar from fully proven. Indeed, diabetes is associated with a

Figure 2. Hypoglycaemic effects of traditional Chinese medicines (TCM)mediated by mechanisms of anti-inflammatory action. ∗Parts of the figurewere sourced from http://en.wikipedia.org/wiki.

chronic low-grade inflammation or preinflammatory state.Inflammatory cytokines, for example TNF-α, IL-1β, IL6,NO, and so on, are released from macrophages and orother tissues during a state of inflammation (figure 2). Thesefactors can activate the IκB kinase (IKK)/JNK pathway,which results in the inhibition of insulin-receptor substrate(IRS)/phosphatidylinositide 3-kinase (PI3K) pathway andbrings about insulin resistance. The action of the IKK/JNKpathway also inhibits the production of pancreatic andduodenal homeobox-1 (PDX-1)/MafA in pancreatic tissues andresults in decreased insulin secretion. Therefore, inflammationmay promote the development of diabetes. Active componentsamong traditional Chinese herbs with hypoglycaemic activitiesmainly comprise polysaccharides, terpenoids, flavonoids, andso on. Generally, these components have anti-inflammatoryeffects by their inhibition of TNF-α, IL-1β, IL-6, NO, and soon, release. The slight or moderate anti-inflammatory effects ofTCM may be responsible for their hypoglycaemic mechanisms.This may contribute new evidences indicating that slight ormoderate regulatory modulation by TCM on inflammationmay be an effective tactic to prevent the development ofdiabetes. This review has provided different perspectives thatreveal that diabetes may be an inflammatory disease and diverseTCM may share a common antidiabetic mechanism: anti-inflammatory action. Further research focusing on TCM indiabetes is required to validate these inflammation-regulatingtargets of TCM that may inhibit the development of diabetes.

AcknowledgementThis study was supported by the National Natural ScienceFoundation of China (81072680), Natural Science Foundationof Guangdong Province (2010), Tertiary College ScienceFoundation of Nanshan, Shenzhen (2008028) and the ScienceSeed Foundation (2008) of the Graduate School at Shenzhen,Tsinghua University, China.

Conflict of InterestW. X. helped in data collection, analysis and paper writing. L. D.helped in design, data analysis and discussion. The authors havenothing to disclose.

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