This review article discusses evidence that diabetes may be an inflammatory disease based on studies of traditional Chinese medicines (TCM) with anti-diabetic effects. The article reviews 15 top Chinese herbs commonly used to treat diabetes that have both anti-hyperglycemic and anti-inflammatory properties. Many studies show that the active compounds in these TCMs, such as polysaccharides, terpenoids and flavonoids, lower blood glucose levels and control inflammation, suggesting their anti-diabetic effects may be mediated by anti-inflammatory mechanisms. The article concludes that TCMs provide new evidence that diabetes could be a low-grade inflammatory disease, and that moderate inhibition of inflammation may help prevent diabetes development.

1. review article
Diabetes, Obesity and Metabolism 13: 289–301, 2011.
© 2011 Blackwell Publishing Ltd
article
review
Diabetes is an inflammatory disease: evidence from
traditional Chinese medicines
W. Xie1 & L. Du2
1 Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
2 Laboratory 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 hypoglycaemic
effects, for example Radix Astragali, Radix Rehmanniae, Radix Trichosanthis, Panax Ginseng, Fructus Schisandrae, Radix Ophiopogonis, Rhizoma
Anemarrhenae, 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 Curcumae
Longae, 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 in
TCM also have anti-inflammatory effects. These studies suggest that TCM might exert hypoglycaemic effects that are partly mediated by the
anti-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 be
required. Studies of TCM add new evidences, which indicate that diabetes may be an inflammatory disease and slight or moderate inhibition of
inflammation might be useful to prevent the development of diabetes. Through this review, we aim to develop more perspectives to indicate
that diabetes may be an inflammatory disease and diverse TCM may share a common antidiabetic property: anti-inflammatory action. Further
studies 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
Introduction may contribute to their antidiabetic action. Conversely, it can
be concluded that diabetes might be an inflammatory disease,
Diabetes is a growing health problem across the world. It has although there is no solid evidence at the present time to
been postulated that diabetes is a manifestation of an ongoing support this conclusion.
chronic low-grade inflammation. Inflammation is defined as Chinese herbal formulas with antidiabetic effects are well
a cascade of phenomena induced in response to different developed such that a number of these formulas have
pathological stimuli and tissue injury. Chronic subclinical commonly been used in diabetic patients since ancient
inflammation is associated with insulin resistance, a situation times. Li et al. systemically listed 86 natural medicines with
of increased risk for developing diabetes [1]. Inflammatory regard to their origin, antidiabetic active principles and/or
processes seem to play an important role in the development pharmacological test results in China [8]. Jia et al. have
of diabetes and its late complications [2]. reviewed antidiabetic herbal drugs officially approved in China
The role of inflammation in the pathogenesis of type 2 and showcase eight antidiabetic herbal formulas [9]. These
diabetes and its vascular complications was confirmed by authors believe that polysaccharide-containing herbs restore
interventional studies. It has been shown that metformin, functions of pancreatic tissues and cause an increase in insulin
peroxisome proliferator-activated receptor (PPAR)-γ agonist, output from the functional β cells, while other ingredients
glyburide and salicylates reduce the incidence of type 2 diabetes enhance microcirculation, increase the availability of insulin
and its vascular complications partly via anti-inflammatory and facilitate metabolism in insulin-dependent processes. Liu
mechanisms [3–6]. It is also reported that insulin suppresses et al. have also conducted a systemic review of Chinese herbal
factors of inflammation in humans [7]. These studies indicate medicines for type 2 diabetes mellitus, and show that 69
that anti-inflammatory effects of classic hypoglycaemic drugs different herbal medicines lower blood sugar, thereby relieving
symptoms in patients with diabetes [10]. Qi et al. also report
on the most frequently used 10 Chinese herbs in the period
Correspondence to: Lijun Du, Laboratory of Pharmaceutical Sciences, School of Life
Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. from 2004 to 2009, for the treatment of diabetes and its
E-mail: lijundu@mail.tsinghua.edu.cn complications, that include Radix Astragali, Rhizoma Dioscoreae

2. review article DIABETES, OBESITY AND METABOLISM
(RD), Radix Rehmanniae, Radix Salviae Miltiorrhizae, Radix TCM With Both Hypoglycaemic and
Puerariae, Rhizoma Coptidis, Fructys Lycii, Poria, Rhizoma Anti-inflammatory Activities
Alismatis and Fructus Corni [11]. Wang and Wylie-Rosett
selected 23 herbs and 5 herbal formulas in the treatment TCM are consisted of several herbal formulas, individual herbs
of type 2 diabetes for review and indicated that the use of and active extracts or chemical components. We select the top
15 herbs most commonly prescribed in traditional Chinese
Chinese herbal medicines in diabetes is promising, although
formulas in the treatment of type 2 diabetic patients and are
they are yet to be proven by further research [12].
approved by the State Food & Drugs Administrator (SFDA)
However, it is unclear whether these hypoglycaemic Chinese
in the mainland of China (unpublished data). These herbs
herbs would have as potent anti-inflammatory properties as
not only have antihyperglycaemic action but they also have
that of Western hypoglycaemic drugs. The Chinese herbs inves- anti-inflammatory effects (Table 1). In addition to these herbs
tigated are mostly qi-invigorating, heat-clearing and detoxify- from Chinese formulas, other individual hypoglycaemic herbs
ing drugs, as described previously in the theory of traditional also have anti-inflammatory effects. These anti-inflammatory
Chinese medicines (TCM) [13]. Heat-clearing and detoxifying effects do not appear to be the result of hypoglycaemic
drugs usually have anti-inflammatory effects [14]. In particu- effects. These reported studies indicate that Chinese herbs
lar, the main active compounds, for example polysaccharides, exert a hypoglycaemic effect via their anti-inflammatory
terpenoids, flavonoids and alkaloids, in hypoglycaemic Chinese mechanism.
herbs usually have wide pharmacological effects including
anti-inflammatory action. Therefore, it was not difficult to Traditional Chinese Medicines
speculate that diverse hypoglycaemic TCM might all have
Huang Qi (Radix Astragali). In theories of TCM, Radix
anti-inflammatory effects. These effects might contribute their Astragali replenishes qi to invigorate yang, has beneficial
beneficial effects by inhibiting the development of diabetes effects on lungs to strengthen the body, promotes diuresis
as diabetes is associated with an inflammatory process. In and relieves edema, cures skin infection and promotes tissue
this article, we systemically review anti-inflammatory evi- regeneration. Radix Astragali is the most widely used herb
dences from TCM in the treatment of diabetes. This review in traditional Chinese formulas in the treatment of diabetes.
aims to ascertain whether hypoglycaemic TCM share common Astragalus polysaccharides (APS) exerts a hypoglycaemic effect
action pathways in addition to their routine mechanisms of by decreasing the stress on the endoplasmic reticulum and
action and, further, to understand the inflammatory nature of then inhibiting the expression of protein tyrosine phosphatase
diabetes. 1B (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 herb
prescriptions.
Antihyperglycaemic Anti-inflammatory
No. TCM activity (references) activity (references) Active components
1 Huang Qi (Radix Astragali) + [15–17] + [18,19] Polysaccharides
2 Di Huang (Radix Rehmanniae) + [20–22] + [23,24] Catalpol, oligosaccharide
3 Tian Hua Fen (Radix Trichosanthis) + [25] + [26] Glycans, trichosanthin
4 Ren Shen (Radix Ginseng) + [27–29] + [30,31] Saponins
5 Wu Wei Zi (Fructus Schisandrae) + [32,33] + [34] Lignans, polysaccharides
6 Mai Dong (Radix Ophiopogonis) + [35] + [36] Sapogenin
7 Zhi Mu (Rhizoma Anemarrhenae) + [37] + [38] Mangiferin
8 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 acid
11 Huang Lian (Rhizoma Coptidis) + [47–49] + [50] Berberine
12 Shan Yao (Rhizoma Dioscoreae) + [51] + [52,53] Saponins
13 Huang Jing (Rhizoma Polygonati) + [54,55] + [56] Flavonoids, polysaccharides
14 Dan Shen (Radix Salviae Miltiorrhizae) + [57] + [58,59] Tanshinone IIA (lignans)
15 Gan Cao (Radix Glycyrrhizae) + [60,61] + [62] Glycyrrhetinic acid
I Semen Trigonellae + [63] + [64,65] Diosgenin (saponin)
II Momordica charantia + [66–70] + [71] Polypeptide-p, Saponins
III Allium sativum + [72,73] + [74,75] Volatile oils, sulphur compounds
IV Cactus (Opuntia stricta) + [76] + [77] Polysaccharides, β-Sitosterol
V Aloe vera + [78] + [79] Aloe vera gel
VI Rou Gui (Cortex Cinnamomi) + [80–83] + [84] Cinnamon oil
VII 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

3. DIABETES, OBESITY AND METABOLISM review article
high-fat diets and low-dose streptozotocin (STZ) [15]. APS also Ren Shen (Radix Ginseng). In TCM, Ginseng is claimed to
increases glucose metabolism by increasing liver glycogenesis invigorate renal qi, strengthen qi of the spleen and lung,
and skeletal muscle glucose translocation through activating promote production of the body fluids to quench thirst and
AMP kinase (AMPK) in the same type of diabetic rats [16]. APS calm the mind to promote intelligence. Ginseng has been
improves insulin sensitivity and exerts a hypoglycaemic effect reported effective, in many ancient Chinese medical literatures,
in KK-Ay mice by regulating protein kinase B (PKB)/glucose to treat emaciation and symptoms such as thirst [27]. Ginseng
transporter (GLUT)4 signalling in skeletal muscle [17]. APS therapy significantly reduces fasting blood glucose (FBG)
may be effective in the attenuation of insulitis and prevents β and homeostatic model assessment of insulin resistance in
cells from undergoing apoptosis in type 1 diabetic mice [18]. type 2 diabetic subjects compared with placebo [28]. Ginseng
Radix Astragali exhibits anti-inflammatory effects in Zymosan reduces hyperglycaemia in the diabetic mouse model, induced
air-pouch mice by inhibiting the expression of inducible by STZ [29]. However, ginseng has no effect on glucose
nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), regulation during acute or chronic administration in healthy
interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumour volunteers [88]. Its effects include increased insulin secretion,
necrosis factor (TNF)-α while also reducing the production of prevention of β-cell apoptosis, enhanced insulin sensitivity
nitric oxide (NO) [19]. Its anti-inflammatory effect is attributed and promotion of thermogenesis [27]. Commonly, the active
to the inactivation of p38 and extracellularly regulated kinase1/2 components of ginseng are considered to be ginsenosides.
(ERK1/2) and the inhibition of nuclear factor-κB (NF-κB)- Ginsenoside Re inhibits intracellular inflammatory molecules
mediated transcription. including c-Jun N-terminal kinase (JNK) and NF-κB and
enhances insulin sensitivity in 3T3-L1 adipocytes and high-fat
Di Huang (Radix Rehmanniae). In theories of TCM, Radix diet rats [30]. Ginsenoside Ro inhibits vascular permeability
Rehmanniae (RR) is used to clear away heat and cool the in mice that have been induced by acetic acid and reduces
blood, nourish yin and promote the production of the body acute paw edema in rats induced by the compound 48/80 or
fluids. RR has a very long history of use in TCM and is carrageenan [31].
usually one of the principal herbs in many herbal formulas
used in the treatment of diabetes. RR has been reported to Wu Wei Zi (Fructus Schisandrae). Fructus Schisandrae, in
contain more than 70 compounds and has a broad range of TCM, is used as an astringent of the lung to treat cough
pharmacological effects [20]. Catalpol, with its hypoglycaemic and asthma, nourish the kidney, promote the production of
effects, is one of the most important compounds in RR [21]. body fluid and inhibit perspiration, condense the essence and
Next, oligosaccharides exert a significant hypoglycaemic effect stop diarrhoea, nourish the heart and calm the mind. Fructus
in normal and alloxan-induced diabetic rats [22]. The mecha- Schisandrae lowers blood glucose and improves insulin resis-
nism of RR for regulating glucose metabolism has a correlation tance in 90% pancreatectomized diabetic rats maintained on
with the regulation of the neuroendocrine system, stimulates high-fat diets and may have been mediated by the mechanism
the secretion of insulin, improves insulin resistance, enhances of increased insulin sensitivity [32]. Dibenzocyclooctadiene
activity of liver glucokinase and glucose-6-phosphate dehy- lignans, the active principle isolated from Fructus Schisan-
drogenase, decreases hepatic glycogen content and stimulates drae, reduces the level of blood glucose by stimulating glucose
glucose uptake [20]. Treatment with RR brings about decreased uptake into peripheral tissues [33]. Schisandrin is the main
plasma C-reactive protein (CRP) levels compared with diabetic active ingredient isolated from the fruit of Schisandra chinensis
controls [23]. RR injections inhibit increase in total white blood Baill. Schisandrin significantly inhibits carrageenan-induced
cell and neutrophil counts and attenuate the increase in TNF-α, paw edema and acetic acid-induced vascular permeability in
O2− , myeloperoxidase induced by lipopolysaccharides (LPS), mice. Further, schisandrin has a protective effect on LPS-
and minimize pathophysiologic changes including neutrophil induced sepsis [34]. Schisandrin also inhibits the production of
infiltration and mucosal edema in the tracheae in a rat model NO and prostaglandin E2 (PGE2), and attenuates the expres-
of lung inflammation, induced by LPS [24]. sion of COX-2 and iNOS, which may be mediated by the
inhibition of NF-κB, JNK and p38 mitogen-activated protein
Tian Hua Fen (Radix Trichosanthis). In the theory of TCM, kinase (MAPK) activities in RAW 264.7 macrophage cells.
Radix Trichosanthis has actions such as clearing of heat, pro-
motion of production of body fluids, resolution of swelling Mai Dong (Radix Ophiopogonis). Radix Ophiopogonis (RO),
and drainage of pus. This herb is used in the treatment of another top herb used in TCM, nourishes yin and increases lung
diabetes and increased thirst. The water extract of the roots secretions, benefits the stomach and regenerates body fluids,
of Trichosanthes kirilowii is found to reduce plasma glucose clears away heart-heat and relieves anxiety. Intraperitoneal
levels in mice [25]. Five glycans, called trichosans A, B, C, administration of the n-butanol extract of RO decreases blood
D and E, have been isolated from the water extract of the glucose levels in normal and STZ-induced diabetic mice [35].
roots of Trichosanthes kirilowii, and have manifested hypogly- RO also tends to suppress epinephrine-induced hyperglycaemia
caemic effects in normal mice. The main glycan, trichosan A, in mice. Aqueous extract from RO significantly inhibits xylene-
also exhibits activity in alloxan-induced diabetic mice. Tri- induced ear swelling and carrageenan-induced paw edema in
chosanthes inhibits TNF-α and IL-1β production in peripheral mice following oral administration [36]. RO also remarkably
blood mononuclear cells stimulated by LPS, indicating definite suppresses carrageenan-induced pleural leucocyte migration
anti-inflammatory activity [26]. in rats and Zymosan A-evoked peritoneal total leucocyte and
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4. review article DIABETES, OBESITY AND METABOLISM
neutrophil migration in mice. Ruscogenin and ophiopogonin Fu Ling (Poria). In TCM, Poria is utilized to promote
D are two of the active components of this herb. diuresis to resolve dampness from the lower energizer,
invigorate the spleen and tranquilize the mind. Poria extract,
Zhi Mu (Rhizoma Anemarrhenae). In TCM, Rhizoma Anemar- and triterpenes therein, lowers postprandial blood glucose
rhenae (RA) is used to clear away heat and purge fire, nourish levels in db/db mice via enhanced insulin sensitivity [44].
yin and aid moisturization. The aqueous extract of RA reduces The triterpene acid compound dehydrotrametenolic acid,
blood glucose levels following oral administration and also isolated from Poria, can reduce hyperglycaemia in db/db
tends to reduce serum insulin levels in KK-Ay mice [37]. RA- mice and act as an insulin sensitizer [45]. Poria extract is
treated KK-Ay mice have shown significantly lowered blood effective in mitigating inflammation in different in vivo models
glucose levels in an insulin tolerance test. The antidiabetic of inflammation induced by 12-O-tetradecanoyl-phorbol-13-
action of RA may be due to decreased insulin resistance. Fur- acetate, ethyl phenylpropiolate and phospholipase A2 [46].
ther, mangiferin and its glucoside have been confirmed as active Active components in this herb are lanostane triterpenes.
components of RA. It is reported that the total polysaccharide
extracts from RA may inhibit inflammatory responses in var- Huang Lian (Rhizoma Coptidis). In TCM, Rhizoma Coptidis
ious models [38]. Timosaponin B-II, derived from a purified is used to clear away heat and remove dampness, purge the
extract of RA, significantly inhibits the increase in IL-1β, TNF- sthenic fire and eliminate toxic materials. Rhizoma Coptidis
α and IL-6, on both mRNA and protein levels from BV2 cells has been used to treat diabetes for more than 1400 years
stimulated by LPS in a dose-dependent manner. in China. Berberine is one of the main active alkaloids
present in Rhizoma Coptidis. Berberine reduces weight gain,
Ge Gen (Radix Puerariae). In TCM, Radix Puerariae is used enhances insulin sensitivity and decreases blood glucose in
to expel pathogenic factors in the muscles to abate heat, both dietary and genetic animal models of type 2 diabetes [47].
expel skin eruptions, promote the production of body fluid to Berberine activates AMPK via the inhibition of mitochondria
decrease thirst, uplift yang and to relieve diarrhoea. Intravenous function [48]. Berberine has protective effects on β cells in
injection of puerarin, purified from Radix Puerariae, decreases STZ- and high-carbohydrate/high-fat diet-induced diabetic
plasma glucose levels in a dose-dependent manner in STZ- rats [47]. Berberine reduces glucose absorption in the intestine
induced diabetic rats [39]. Radix Puerariae increases glucose by inhibiting intestinal disaccharidases [49]. Rhizoma Coptidis
utilization in diabetic rats with insulin deficiency. Moreover, is well known for its anti-inflammatory activity. Incubation
the mRNA and protein levels of GLUT4 in soleus muscle with Rhizoma Coptidis and berberine strongly inhibited
are increased after intravenous administration of puerarin LPS-induced monocyte chemoattractant protein (MCP)-1
in STZ-induced diabetic rats. Puerarin may activate α1- production in RAW 264.7 cells [50]. The increase in the
adrenoceptors in the adrenal gland to enhance the secretion of transcription factors activator protein-1 (AP-1) and NF-κB is
β-endorphin, with resultant reduction in plasma glucose levels inhibited by Rhizoma Coptidis in a dose- and time-dependent
in STZ-induced diabetic rats. Puerarin can protect islets against manner.
oxidative stress induced by H2 O2 probably by its mechanism Shan Yao (Rhizoma Dioscoreae). In TCM, RD invigorates
of action increasing catalase and superoxide dismutase the spleen and stomach, promotes production of the body
activities [40]. Puerarin also acts as an anti-inflammatory agent. fluids and benefits lungs, invigorates kidneys and preserves
Puerarin inhibits the expression of the protein and mRNA the essence. RD is a common food ingredient in China. RD
levels of CRP in LPS-induced peripheral blood mononuclear improves fructose-induced decrease in the insulin-stimulated
cells [41]. The inhibition of CRP expression is due to a dose- glucose disposal rate after 3 days of treatment [51]. In addition,
dependent inhibition of phosphorylation and degradation of oral administration of RD into STZ-induced diabetic rats
inhibitor-κB (I-κB), which results in a reduction of p65 NF-κB for 10 days increases sensitivity to exogenous insulin. RD
nuclear translocation. significantly inhibited TNF-α and IL-1β production and
downregulated COX-2 and iNOS expression in human
Gou Qi (Fructus Lycii). In TCM, Fructus Lycii (FL) is claimed to fibroblast-like synovial cells that were stimulated by IL-1β and
tone the kidney and benefit essence, while nourishing the liver TNF-α. Further, RD effectively reduced the level of reactive
and improving eyesight. Polysaccharides extracted following oxygen species (ROS) in these cells [52]. The extract of RD has
treatment of FL for 28 days bring about a significant decrease been shown to decrease damage in renal tubules, inflammation
in concentrations of FBG, total cholesterol and triglycerides in the central vein and necrosis in the liver tissue of rats [53].
(TG) in alloxan-induced diabetic mice [42]. Further, FL
polysaccharides significantly increase body weight in this Huang Jing (Rhizoma Polygonati). In TCM, Rhizoma Polygo-
animal model. FL polysaccharides are effective in the protection nati (RP) is used to increase secretions in the lung, nourish and
of liver and kidney tissue from damage as shown in STZ- invigorate the kidney and benefit qi. Intraperitoneal admin-
induced diabetic rat; this implies that FL polysaccharides may istration of the methanol extract of RP lowers blood glucose
be of use as antihyperglycaemic agents. FL polysaccharides have levels in normal and STZ-induced diabetic mice [54]. How-
been identified as one of the active ingredients responsible for ever, the hypoglycaemic effects are not accompanied by any
FL’s biological properties. FL polysaccharides can attenuate the alteration in serum insulin in these mice. RP decreased hepatic
inflammatory reaction in endothelial cells and this is mediated glucose output and exerted a hypoglycaemic effect, presumably
by inhibition of the CRP and NO production [43]. because of the reduction of GLUT2 expression in the total
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5. DIABETES, OBESITY AND METABOLISM review article
membrane of the liver [55]. One of the active components of aglycone of saponins, in fenugreek has been identified to
RP is identified as a spirostanol glycoside. In addition, pharma- promote adipocyte differentiation and to inhibit expressions of
cological research indicates that Polygonatum polysaccharidi several molecular candidates associated with inflammation
has anti-inflammatory effects [56]. in 3T3-L1 cells. Diosgenin has been shown to suppress
inflammation mediated by its inhibition of TNF-induced NF-
Dan Shen (Radix Salviae Miltiorrhizae). In TCM, Radix Salviae κB activation in tumour cells [65].
Miltiorrhizae promotes blood circulation to remove blood
stasis, regulates menstruation to relieve pain, cools the blood Momordica Charantia. Momordica charantia (bitter melon) is
to relieve carbuncle and clears away heat from the body a popular fruit used for the treatment of diabetes and related
and tranquilizes the mind. Tanshinone IIA, an important conditions amongst the indigenous populations of Asia, South
component extracted from Salvia miltiorrhiza, can improve America, India and East Africa. Many animal and human
glucose tolerance and inhibits adipogenesis in rats fed on a high- studies have proved the potential role of Momordica charantia
fat diet, and might be beneficial in the treatment of diabetic in glycaemic control [66]. Momordica charantia reduces blood
patients with complex metabolic disorders [57]. Tanshinone glucose levels and also significantly lowers the serum insulin
IIA has protective effects on several pharmacological targets levels in KK-Ay mice after 3 weeks of oral administration [67].
in the progression of diabetic nephropathy [89]. Tanshinone The hypoglycaemic mechanisms are related to its inhibition
IIA restores impaired neural functions in the experimental of PTP1B [68], activation of AMPK [69], increase in GLUT4
diabetic rats [90] and also protects the myocardium against protein content in the plasma membrane [67] and promotion
ischaemia/reperfusion injury [91]. Danshen is used to treat of the recovery of β cells [92]. Major active compounds in
acute pancreatitis and its mechanisms of action include this herb include cucurbitane triterpenoids [93], polypeptide-
improvement of microcirculatory disturbances, elimination p [70], saponins, and so on. The butanol soluble fraction of
of oxygen free radicals, modulation of the metabolism of lipid bitter gourd placenta extract strongly suppresses LPS-induced
inflammatory mediator and blocking of calcium inflow with TNF-α production and expression of various LPS-induced
subsequent prevention of calcium overload [58]. Tanshinone inflammatory genes in RAW 264.7 cells [71]. The butanol
IIA exerts anti-inflammatory effects mediated by inhibition of fraction significantly suppresses NF-κB DNA-binding activity
iNOS gene expression and NO production, as well as inhibition and phosphorylation of p38, JNK and ERK MAPKs.
of inflammatory cytokine (IL-1β, IL-6 and TNF-α) expression Allium Sativum. Garlic (Allium sativum), which is a com-
via the endoplasmic reticulum-dependent pathway in LPS- mon cooking spice and has a long history of use as a
induced RAW 264.7 cells [59]. folk remedy, has been reported to have antidiabetic activity.
Antioxidant, anti-inflammatory and antiglycative properties
Gan Cao (Radix Glycyrrhizae). In TCM, Radix Glycyrrhizae
of garlic play an important role in preventing progres-
functions by enriching qi and invigorating the stomach and
sion of diabetes and the development of diabetes-related
spleen, moistening the lung and clearing away phlegm, clearing
complications [72]. Both garlic oil and diallyl trisulphide
away heat and toxins and relieving spasm and alleviating
improve glycaemic control in STZ-induced diabetic rats
pain. Roasted Glycyrrhizae Radix, containing glycyrrhetinic acid
through increased insulin secretion and sensitivity [73]. Sul-
(GA), improves glucose tolerance better than raw Glycyrrhizae
phur compounds isolated from garlic exert anti-inflammatory
Radix extract by enhancing insulinotropic action in partially properties. S-Allyl-l-cysteine sulphoxide can control TNF-
pancreatectomized diabetic mice [60]. Glycyrin, one of the α-mediated inflammation and mediate vascular disease [74].
main PPAR-γ ligands of licorice, significantly lowers the blood Thiacremonone, another novel sulphur compound from gar-
glucose level [61]. GA inhibits TNF-α-stimulated intercellular lic, suppresses 12-O-tetradecanoylphorbol-13-acetate-induced
adhesion molecule-1 (ICAM-1) expression, leading to a (1 μg/ear) ear edema [75]. Thiacremonone (1–10 mg/kg)
decrease in monocytes adhering to human umbilical vein administered directly onto the plantar surface of hind paw
endothelial cells [62]. This inhibition is attributed to GA also suppresses carrageenan (1.5 mg/paw) and Mycobacterium
interruption of both JNK/c-Jun and I-κB/NF-κB signalling butyricum (2 mg/paw)-induced inflammatory and arthritic
pathways, which decrease AP-1 and NF-κB-mediated ICAM-1 responses, which may be related to the inhibition of expression
expressions. The results imply that GA may manifest anti- of iNOS and COX-2.
inflammatory effects.
Opuntia Stricta. Opuntia stricta (cactus) has an effect on
Semen Trigonellae. Oral administration of Semen Trigonellae lowering blood glucose levels in patients with type 2 diabetes
(fenugreek) seeds soaked in hot water significantly decreased mellitus. Blood glucose and glycated haemoglobin (HbA1c)
FBG levels in patients with type 2 diabetes mellitus [63]. levels are reduced to normal values by a combined treatment of
4-Hydroxyisoleucine, an unusual amino acid isolated from insulin and Opuntia extract in STZ-induced diabetic rats [76].
fenugreek seeds, when administered orally in mice significantly When insulin is withdrawn from this combined therapy,
inhibits elevation of blood glucose and plasma insulin levels in Opuntia stricta extract alone can maintain normoglycaemic
db/db diabetic mice, which is evidenced by the enhancement state in diabetic rats. Rats receiving combination treatment of
of insulin sensitivity and glucose uptake in peripheral insulin and Opuntia extract for 7 weeks followed by Opuntia
tissues. Fenugreek also inhibits macrophage infiltration into extract alone have shown rapid return of blood glucose
adipose tissues and decreases the mRNA expression levels levels than those of non-diabetic rats after being challenged
of inflammatory genes [64]. In addition, diosgenin, a major with exogenous glucose administration. Polysaccharides may
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6. review article DIABETES, OBESITY AND METABOLISM
be responsible for this hypoglycaemic activity. The ethanol pathway [86]. A turmeric preparation depleted of essential oils
extract of Opuntia stricta manifests potent anti-inflammatory profoundly inhibits joint inflammation and periarticular joint
action [77]. In adjuvant-induced chronic inflammation model destruction in a dose-dependent manner. In vivo treatment
in mice, the active anti-inflammatory principle has been prevents local activation of NF-κB and the subsequent expres-
isolated and identified as β-sitosterol. sion of NF-κB-regulated genes that mediate joint inflammation
and destruction, including chemokines, COX-2 and receptor
Aloe Vera. Oral administration of processed Aloe vera gel activator of NF-κB ligand [87]. Further, inflammatory cell
(PAG) for 8 weeks reduces blood glucose concentrations to influx, levels of PGE2 within a joint and periarticular osteoclast
a normal level in these diet-induced obese mice [78]. In formation are inhibited by treatment with turmeric extract.
addition, PAG significantly decreases plasma insulin. The
antidiabetic effects of PAG are also confirmed by intraperitoneal
glucose tolerance testing. PAG appears to lower blood glucose Compounds Derived From TCM
concentrations by decreasing insulin resistance. Phytosterols Active components of TCM mainly contain polysaccharides,
derived from Aloe vera gel may act as active compounds in this flavonoids, terpenoids, alkaloids and so on. It is hypothesized
action [94]. However, Aloe vera used topically, administered that these common chemical components might share similar
intraperitoneally or by a combination delivery modulates mechanisms of action within different herbs. In addition to
inflammatory responses [79]. The maximal effect is observed the well-defined berberine and puerarin described above, some
with the combined delivery, indicating modulation at local as other active components from Chinese herbal medicines are
well as systemic levels. This modulation could result from the found to have significant or moderate hypoglycaemic effects as
potential of Aloe vera to attenuate peroxidative damage by a well as anti-inflammatory action (figure 1).
decrease in the levels of TNF-α, IL-1 and IL-6, and an increase
in the level of superoxide dismutase. Quercetin. Quercetin, a bioflavonoid widely used in TCM,
is a food component that may ameliorate diabetic symp-
Rou Gui (Cortex Cinnamomi). In TCM, Cortex Cinnamomi toms. Diets containing 0.1 or 0.5% quercetin lowered the
functions by supplementing fire and strengthening yang, STZ-induced increase in blood glucose levels and enhanced
expelling cold and alleviating pain and warming channels plasma insulin levels [95]. Dietary quercetin may improve
to promote blood circulation. Intake of 2 g of cinnamon hepatic and pancreatic functions by facilitating cell prolif-
for 12 weeks significantly reduces the HbA1c among patients eration through inhibition of Cdkn1a expression. Quercetin
with poorly controlled type 2 diabetes [80]. Cinnamon oil promotes glucose- and glibenclamide-induced insulin secre-
(CO), when administered for 35 days, significantly decreases tion and protects β cells against oxidative damage through the
FBG levels in an animal model of type 2 diabetes (KK- ERK1/2 pathway [96]. Quercetin enhances glucose metabolism
Ay mice) [81]. Meanwhile, glucose tolerance is improved, through activation of both silent mating type information reg-
and the immunoreactive capacity of pancreatic islets β cells ulation 2 homolog 1 (SIRT1) and AMPK in HepG2 cells [97].
is enhanced. Indeed, it is evident that Cortex cinnamomi Quercetin affects inflammation by modulating several intra-
extract prevents STZ- and cytokine-induced β-cell damage cellular signalling kinases, phosphatases, enzymes and mem-
by inhibition of NF-κB [82]. Further, cinnamon extracts brane proteins that are often crucial for a specific cellular
increase GLUT1 mRNA and decrease the expression of further function [98]. Quercetin attenuates lethal systemic inflamma-
genes encoding insulin signalling pathway proteins [83]. The tion caused by endotoxaemia [99]. In macrophage cultures,
main component of CO is cinnamaldehyde. Twig essential quercetin limits the activation of MAPK and NF-κB.
oil and its major constituents such as trans-cinnamaldehyde,
caryophyllene oxide, l-borneol, l-bornyl acetate, eugenol, β- Ferulic Acid. Ferulic acid (FA), a phenolic compound, is a
caryophyllene, E-nerolidol and cinnamyl acetate significantly strong membrane antioxidant and is reported to have positive
inhibit NO and PGE2 production in LPS-activated RAW 264.7 effects on human health. FA at 0.01 and 0.1% of t basal diet
cells [84]. significantly suppresses blood glucose levels in STZ-induced
diabetic mice [100]. In KK-Ay mice, 0.05% FA suppresses
Jiang Huang (Rhizoma Curcumae Longae). In TCM, Rhi- blood glucose levels effectively. FA also stimulates insulin
zoma Curcumae Longae is traditionally used to promote secretion from pancreatic β cells [101], protects against cellular
circulation of blood and qi, dredge the meridian passage to redox disruption and several oxidative stress-related diseases,
alleviate pain. The ethanol extract of turmeric significantly including inflammation in animal studies [102], suppresses
inhibits increase in blood glucose levels in type 2 diabetic NF-κB activation and modulates the expression of NF-
KK-Ay mice [85]. In an in vitro evaluation, the extract stim- κB-induced, proinflammatory COX-2, iNOS, vascular cell
ulated human adipocyte differentiation in a dose-dependent adhesion molecule-1 (VCAM-1) and ICAM-1 [102]. Further,
manner and showed human PPAR-γ ligand-binding activ- FA prevents the induction of ICAM-1 and VCAM-1 expression
ity. The main constituents of the extract are identified as in a concentration-dependent manner after being stimulated
curcumin, demethoxycurcumin, bisdemethoxycurcumin and by radiation [103]. The inhibitory effect of FA on adhesion
ar-turmerone, and it also has PPAR-γ ligand-binding activity. molecule expression is mediated by blockade of JNK.
Curcumin increased GLUT4 expression and glucose uptake
into skeletal muscle, isolated from Wistar rats, through the Astragaloside IV. Astragaloside IV, a new cycloartane-type
phospholipase C (PLC)–phosphoinositide 3 kinase (PI3K) triterpene glycoside extract of Radix Astragalus membranaceus
294 Xie and Du Volume 13 No. 4 April 2011

7. DIABETES, OBESITY AND METABOLISM review article
Figure 1. Antihyperglycaemic and anti-inflammatory compounds from traditional Chinese medicines (TCM) (structures were sourced from
http://www.pubchem.ncbi.nlm.nih.gov/).
Bunge, at doses of 25 and 50 mg/kg, significantly decreases AS-IV improved TNF-α-induced insulin resistance in 3T3-L1
blood glucose, TG and insulin levels, and inhibits mRNA and adipocytes [105]. AS-IV has been reported to have anti-
protein expression as well as enzymatic activity of glycogen inflammatory effects in vivo [106]. AS-IV inhibits cytokine-
phosphorylase (GP) and glucose-6-phosphatase (G-6-Pase) in and LPS-stimulated expression of adhesion molecules in, and
diabetic mice, induced by a high-fat diet and STZ [104]. The leucocyte adhesion to, endothelial cells. AS-IV’s inhibition
hypoglycaemic effect of this compound may be explained, in of the NF-κB pathway might be one underlying mechanism
part, by its inhibition of hepatic GP and G-6-Pase activities. contributing to its anti-inflammatory potential in vivo.
Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01336.x 295

8. review article DIABETES, OBESITY AND METABOLISM
Curcumin. Curcumin, an antioxidant compound, lowers Glycyrrhizin. Glycyrrhizin treatment significantly lowers blood
blood glucose levels and ameliorates the long-term com- insulin level in diabetic KK-Ay mice [124]. The mice fed
plications of diabetes in animal models of diabetes [107]. on a glycyrrhizin diet also have improved tolerance to oral
Curcumin increases the phosphorylation of AMPK and its glucose loading 9 weeks after the beginning of test feeding.
downstream target acetyl-CoA carboxylase (ACC) in cells with Glycyrrhizin inhibits the LPS/d-galactosamine-induced hepatic
400 times the potency of metformin. Curcumin suppresses injury through prevention of inflammatory responses and IL-18
hepatic gluconeogenesis. Curcumin inhibits proinflammatory production [125]. Further, it appears that glycyrrhizin prevents
cytokine concentrations in the serum and pancreas of STZ- IL-18-mediated inflammation in hepatic injury.
treated animals [108]. Curcumin, in combination with aspirin
or rofecoxib, causes a further decrease in serum TNF-α lev- Emodin. Emodin, a natural product and active ingredient of
els that could possibly be mediated by inhibition of the various Chinese herbs, significantly decreases blood glucose
COX enzyme [109]. Curcumin attenuates the development levels in high-fat diet-fed- and low-dose STZ-induced diabetic
of allergic airway inflammation and hyper-responsivity, pos- mice [126]. The glucose tolerance and insulin sensitivity
sibly through inhibition of NF-κB activation in the asthmatic in the emodin-treated group were significantly improved
lung tissue [110]. compared with the controls. The activation of PPAR-γ and
the modulation of metabolism-related genes likely mediate the
Epigallocatechin Gallate. Epigallocatechin gallate (EGCG) is antidiabetic effects of emodin. Further, emodin is considered
one of the main compounds derived from green tea. EGCG can a potent and selective inhibitor of 11β-hydroxysteroid
prevent abnormal changes in blood glucose and lipid profile and dehydrogenase type 1 [127]. Emodin can inhibit the activation
attenuate hepatic lipid peroxidation in STZ-induced diabetic of NF-κB and the expression of ICAM-1 induced by LPS
rats [111]. EGCGs have protective effect on the insulinoma-1 in corneas, protect against acute corneal injury and improve
(INS-1) beta cells against oxidative stress both through antiox- symptoms in rats [128].
idant effect and antiapoptotic signalling [112]. EGCG inhibits
Baicalin. Baicalin, a flavonoid known for its radical scavenging
ERK and activates AMPK [113]. Pretreatment with EGCG sup-
activity, significantly decreases plasma glucose levels in a dose-
presses the secretion of monocyte chemoattractant protein-1
dependent manner in nicotinamide–STZ-induced diabetic
and the activation of AP-1 in porcine aortic endothelial cells
rat [129]. Administration of baicalin results in a significant
stimulated by TNF-α [114]. EGCG attenuates LPS-induced
increase in hepatic glycogen content and glycolysis, and a
lung injury by inhibition of the macrophage inflammatory
reduction in serum TNF-α level. Baicalin significantly alleviated
protein-2 and TNF-α production, as well as ERK1/2 and JNK
the morphological injury to the pancreas caused by STZ.
activation in macrophages stimulated by LPS [115].
Baicalin inhibits macrophage activation and protects mice from
Resveratrol. Resveratrol, a polyphenolic SIRT1 activator, macrophage-mediated endotoxic shock. It also suppresses the
showed a significant antihyperglycaemic effect in type 2 diabetic increased generation of NO and expression of iNOS induced
ob/ob mice [116]. The STZ–nicotinamide-induced diabetic by LPS or interferon-γ without directly affecting iNOS activity
rats, when orally treated with resveratrol, exhibit significant in RAW264.7 cells and peritoneal macrophages [130].
decrease in the levels of blood glucose and glycosylated
haemoglobin [117]. Its antidiabetic properties may be mediated
TCM With Anti-inflammatory Effects Only
by enhanced insulin secretion and antioxidant competence in
pancreatic β cells of diabetic rats [118]. Further, resveratrol However, many of the classic or potent anti-inflammatory
activates APMK and increases energy metabolism. Resveratrol components in herbs, for example daphnetin [131], sinome-
significantly inhibits airway inflammation in respiratory nine [132], tripterysium glucosides [133], decanoylacetalde-
disease [119]. Resveratrol treatment decreases the expression of hyde [134], oxymatrine [135], phthalide lactones [136] and
p65 and I-κB−α and ameliorates elevation in levels of TNF-α, tetramethylpyrazine [137] have no reported hypoglycaemic
IL-6 and COX-2 in treated rats [120]. activities. Frequently used anti-inflammatory drugs are clas-
sified as: non-steroidal anti-inflammatory and steroidal
Tetrandrine. Tetrandrine, an active plant alkaloid derived anti-inflammatory drugs. Non-steroidal anti-inflammatory
from Stephaniae tetrandrae, significantly decreases the plasma drugs include salicylates, acetaminophen, phenylbutazone,
glucose levels in a dose-dependent manner in STZ-induced indomethacin, ibuprofen, colchicines, and so on. With the
diabetic rats [121]. Tetrandrine prevents the spontaneous exception of salicylates [138,139], these drugs have no antidi-
development of diabetes mellitus in biobreeding (BB) abetic effects. Of note, most patients requiring non-steroidal
rats [122]. Tetrandrine has the ability to enhance glucose anti-inflammatory drugs for pain control show a high inci-
utilization in peripheral tissue and protect islet β cells from dence of gastrointestinal and cardiovascular risk factors [140].
injury induced by alloxan. Tetrandrine, remarkably, suppresses Steroidal anti-inflammatory drugs increase blood glucose lev-
the LPS induction of NO release and PGE2 generation [123]. els, for example dexamethasone [141]. Therefore, it may be
It also significantly attenuates LPS-induced transcription of inappropriate to use potent anti-inflammatory drugs to pre-
proinflammatory cytokines (TNF-α, IL-4 and IL-8) in a dose- vent the development of diabetes. In turn, these results indicate
dependent manner. Further, tetrandrine significantly blocks that diabetes is a low-grade inflammatory disease. Only those
the LPS induction of iNOS and COX-2 expression, which may drugs with slight or mild anti-inflammatory activities may be
account for its anti-inflammatory mechanisms. able to prevent the development of diabetes.
296 Xie and Du Volume 13 No. 4 April 2011

9. DIABETES, OBESITY AND METABOLISM review article
Discussion and Perspectives chronic low-grade inflammation or preinflammatory state.
Inflammatory cytokines, for example TNF-α, IL-1β, IL6,
This review, firstly, indicates that most of TCM with hypo-
NO, and so on, are released from macrophages and or
glycaemic activities usually have separate anti-inflammatory
other tissues during a state of inflammation (figure 2). These
effects, although their anti-inflammatory effects are weak
factors can activate the IκB kinase (IKK)/JNK pathway,
as compared with the classic anti-inflammatory drugs. In
which results in the inhibition of insulin-receptor substrate
addition to routinely used hypoglycaemic Western/allopathic
(IRS)/phosphatidylinositide 3-kinase (PI3K) pathway and
drugs, there are several Chinese hypoglycaemic herbs that
brings about insulin resistance. The action of the IKK/JNK
have anti-inflammatory properties; this implies that we
pathway also inhibits the production of pancreatic and
need to reunderstand the mechanism of action of these
duodenal homeobox-1 (PDX-1)/MafA in pancreatic tissues and
hypoglycaemic drugs, apart from the routine hypoglycaemic
results in decreased insulin secretion. Therefore, inflammation
mechanisms. In actuality, the aetiology of diabetes is still
may promote the development of diabetes. Active components
far from fully proven. Indeed, diabetes is associated with a
among traditional Chinese herbs with hypoglycaemic activities
mainly comprise polysaccharides, terpenoids, flavonoids, and
so on. Generally, these components have anti-inflammatory
effects by their inhibition of TNF-α, IL-1β, IL-6, NO, and so
on, release. The slight or moderate anti-inflammatory effects of
TCM may be responsible for their hypoglycaemic mechanisms.
This may contribute new evidences indicating that slight or
moderate regulatory modulation by TCM on inflammation
may be an effective tactic to prevent the development of
diabetes. This review has provided different perspectives that
reveal that diabetes may be an inflammatory disease and diverse
TCM may share a common antidiabetic mechanism: anti-
inflammatory action. Further research focusing on TCM in
diabetes is required to validate these inflammation-regulating
targets of TCM that may inhibit the development of diabetes.
Acknowledgement
This study was supported by the National Natural Science
Foundation of China (81072680), Natural Science Foundation
of Guangdong Province (2010), Tertiary College Science
Foundation of Nanshan, Shenzhen (2008028) and the Science
Seed Foundation (2008) of the Graduate School at Shenzhen,
Tsinghua University, China.
Conflict of Interest
W. X. helped in data collection, analysis and paper writing. L. D.
helped in design, data analysis and discussion. The authors have
nothing to disclose.
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