Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2013, Article ID 654643, 9 pages
http://dx.doi.org/10.1155/2013/654643
Review Article
Recent Advances in Astragalus membranaceus
Anti-Diabetic Research: Pharmacological Effects
of Its Phytochemical Constituents
Kojo Agyemang,1,2 Lifeng Han,1 Erwei Liu,1 Yi Zhang,1 TaoWang,1 and Xiumei Gao1
1 Tianjin State Key Laboratory of Modern Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin 300193, China
2Noguchi Memorial Institute for Medical Research, P.O. Box LG 581, Legon, Accra, Ghana
Correspondence should be addressed to Tao Wang; wangt@263.net
Received 29 August 2013; Revised 4 November 2013; Accepted 5 November 2013
Academic Editor: Tong Ho Kang
Copyright © 2013 Kojo Agyemang et al.This is an open access article distributed under theCreative CommonsAttribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The disease burden of diabetes mellitus is increasing throughout the world. The need for more potent drugs to complement the
present anti-diabetic drugs has become an imperative. Astragalus membranaceus, a key component of most Chinese herbal anti-
diabetic formulas, has been an important prospect for lead anti-diabetic compounds. It has been progressively studied for its anti-
diabetic properties. Ethnopharmacological studies have established its potential to alleviate diabetes mellitus. Recent studies have
sought to relate its chemical constituents to types 1 and 2 diabetes mellitus. Its total polysaccharides, saponins, and flavonoids
fractions and several isolated compounds have been the most studied. The total polysaccharides fraction demonstrated activity
to both types 1 and 2 diabetes mellitus. This paper discusses the anti-diabetic effects and pharmacological action of the chemical
constituents in relation to types 1 and 2 diabetes mellitus.
1. Introduction been used in many state-approved Chinese herbal formulas
for the treatment of diabetes [6, 7]. A recent publication
Diabetesmellitus (DM) has been reported as an epidemic and by Wei et al. (2011) [7] identified it as the most frequently
an increasing disease burden throughout the world [1, 2]. It is prescribed herbal medicine for diabetes treatment in China.
a chronic disease characterized by high blood glucose levels Several ethnopharmacological studies have established its
resulting fromdefects in insulin production and action. Types pharmacological significance [6, 8]. Recent studies have
1 and 2 are the most prevalent. Type 1 is characterized by progressively sought to identify the lead compounds involved
lack of insulin production caused by autoimmunedestruction in inducing its anti-diabetic effects. Its polysaccharides,
of pancreatic beta cells. Type 2 results from the ineffective saponins, and flavonoids fractions and a number of single
use of insulin due to insulin resistance and deficient glucose isolated compounds have been studied.The pharmacological
metabolism [1, 3, 4]. Research for novel anti-diabetic drugs to processes and mechanism of action of these constituents
complement those in present clinical use has intensified over have also been studied [9–11]. This paper considers it as
the years. an important anti-diabetic drug prospect. Thus, we review
Plant medicine has been important in present anti- advances in its anti-diabetic research with emphasis on the
diabetic drug research. The prospects of a number of medic- pharmacological prospects of its chemical constituents in
inal plants, herbal formulations, and natural products with relation to types 1 and 2 DM.The following database systems
anti-diabetic effects have been reported [5–7].Notable among were considered for data collection: PubMed, SpringerLink,
such isAstragalus membranaceus (AM). It is a Fabaceae flow- Wiley Online Library, Science Direct, and China National
ering plant recorded in various pharmacopoeias as a herbal Knowledge Infrastructure (CNKI)-China Academic Journal
immunomodulator and an anti-diabetic drug. Its roots have Network Publishing Database (CAJD).
2 Evidence-Based Complementary and Alternative Medicine
2. Ethnopharmacology Effects of and content analyses showed that APS I consisted of arabi-
AM on Diabetes Mellitus nose and glucose in the ratio of 1 : 3.45. ASP II consisted of
rhamnose, arabinose, and glucose in the ratio of 1 : 6.25 : 17.86
The roots of AM have a long history for the treatment of [22, 23]. Acidic polysaccharides such as AMem-P, AH-1
diabetes-related symptoms in China. In traditional Chinese and APSID3 have also been isolated [24–27]. AMem-P is a
medicine, it is used to reinforce Qi in order to induce complex acidic polysaccharide with a molecular weight of
urination, consolidate the exterior, express toxins outward, 60 kD. It consists mainly of hexuronic acid and has terminal
and make new tissues grow [7, 12]. A number of studies and 𝛼-1,5-linked-arabinofuranose, terminal and𝛽-1,3-,𝛽-1,4-
have emphasized its pharmacological relation to diabetes , 𝛽-1,6-linked, 3,6-branched-D-galactose, and 2,4-branched-
mellitus. Earlier ethnopharmacological studies analyzed var- L-rhamnose residue groups attached [24]. Other Astragalus
ious crude extracts for their anti-diabetic activities and their polysaccharides include AH-2, AE, AEF-1, and AEF-2, and
possible pharmacological processes. They were studied as astroglucans A, B, and C [27–29].
a single extract or as part of a compound formula and
were reported to have demonstrated potentials of attenuating 3.2. Saponins. The saponin content of AM consists mainly of
DM and their associated complications. They were generally triterpene saponins. Structurally, they are cycloartane triter-
observed to have lowered increasing blood glucose and pene glycosides with one-to-three sugars attached at the 3-,
lipid levels, improved insulin sensitivity, and also corrected 6-, and 25-positions. Kitagawa (1983) reported the isolation of
several pathological indicators of DM and its complications several cycloartane triterpenoids such as astragaloside I–VIII
[6, 13–16]. In a clinical study of the effect of AM on insulin [30–32] and isoastragalosides I and II [30]. AstragalosidesVII
sensitivity, AM decoction reduced fasting blood glucose and and VIII were elucidated as saponins with oleanane skeleton
homeostatic model assessment (HOMA) levels in type 2 [32]. Azukisaponin V methyl ester has been isolated and
DM patients [14]. Anti-diabetic studies onQilan Tangzhining identified as an oleanane-type triterpene saponin [33]. An
capsule, a Chinese herbal anti-diabetic formula containing astragaloside malonate has also been identified as malonylas-
AM, showed its potential to reduce blood glucose levels and tragaloside [34]. Several other astragalus saponins including
improve lipid profiles in streptotozocin-induced diabetic rats isoastragalosides III and IV, astramembrannin II, cyclogalegi-
[16]. A number of pharmacological processes for inducing noside B, cycloaraloside A, brachyoside B, cyclocanthoside E,
these anti-diabetic effects have been suggested. Some of cyclounifolioside B [27, 35, 36], and astramembranosides A
which include the suppression of macrophage- and cytokine- and B [33] have also been isolated.
induced inflammatory responses, stimulation of insulin sig-
nal transduction, and lowering of the hyperglycemic effects of 3.3. Flavonoids. Flavonoids of varying structures have been
glucagon in experimental animals. Its mechanism of action isolated from AM. They are mainly in structural groups
has been associated with several enzymes, proteins, and of flavones, isoflavones, isoflavanones, and pterocarpans.
molecularmarkers such as peroxisome-proliferator-activated Kaempferol, isorhamnetin, rhamnocitrin, kumatakenin
receptor gamma (PPAR𝛾), phosphatidylinositide-3-kinase and rhamnocitrin-3-glucoside and quercetin-3-glucoside
(PI-3-K), and Na+ K+-ATPase, among others [10, 14, 16–18]. have been isolated as flavones [27]. Formononetin, ononin,
Further studies have sought to elucidate the phytochemical calycosin, calycosin-7-O- -D-glucoside-6󸀠󸀠𝛽 -O-malonate, 3󸀠-
constituents inducing these anti-diabetic effects. methoxy-5󸀠-hydroxy-isoflavone-7-O-𝛽-D-glucoside, and
(3R)-2󸀠,3󸀠-dihydroxy-4󸀠,7-dimethoxyisoflavone have been
isolated as isoflavones [27, 37, 38]. The isoflavanones include
3. Phytochemical Constituents 2󸀠-hydroxy-3󸀠,4󸀠-dimethoxyisoflavone-7-O-𝛽-D-glucopyra-
noside, 2󸀠-hydroxy-3󸀠,4󸀠,7-trimethoxyisoflavone, 2󸀠,7-dihy-
Several classes of organic compounds, namely, Astragalus droxy-3󸀠,4󸀠,7-trimethoxyisoflavone, 3󸀠,4󸀠-dimethoxyisofla-
polysaccharides, saponins, flavonoids, isoflavonoids, sterols, vone-7-O-𝛽-D-glucoside, 8,2󸀠-dihydroxy-4󸀠,7-dimethoxyis-
amino acids, and volatile oils, have been isolated from AM. oflavone, and 2󸀠,3󸀠,7-trihydroxy-4󸀠-methoxyisoflavone
The polysaccharides, saponins, and flavonoids are the major [27]. The reported pterocarpans include 3,9,10-trimethox-
chemical constituents demonstrating biological activity to ypterocarpan, (6aR,11aR)-10-hydroxy-3,9-dimethoxyptero-
DM [19, 20]. carpan, and 9,10-dimethoxypterocarpan-7-O-𝛽-D-glucopy-
ranoside [27, 38, 39].
3.1. Polysaccharides. The polysaccharides of AM are by
extractionmethods water-soluble and -insoluble glucans and 4. Pharmacological Effects of Astragalus
heteropolysaccharides. Astragalans I, II, and III are polysac- Chemical Constituents on Diabetes Mellitus
charides extracted by hot water. Astragalan Ι was elucidated
as a neutral heteropolysaccharide containing D-glucose, D- The polysaccharides (APS), saponins (ASS), and flavonoids
galactose, and L-arabinose in the ratio of 1.75 : 1.63 : 1. It has (ASF) fractions of AM have been the most studied for
a molecular weight of 36 kD. Astragalans ΙΙ and ΙΙΙ were their anti-diabetic effects on types 1 and 2 DM. Several sin-
𝛼-(1,4)-glucans with molecular weights of 12 kD and 34 kD, gle isolated compounds including astragalin, formononetin,
respectively [21, 22]. APS I and APS II were isolated by water astragalosides I, II, and IV, and isoastragaloside I (Figure 1)
extraction and alcohol precipitation technique. Structural have also been analyzed. Their pharmacological processes
Evidence-Based Complementary and Alternative Medicine 3
OH
O
HO
OH O OHO HO
O
O
HO O
HO O OH
O HO O OO O O OH
HO
HO OH
OH OH O
O OH
Astragalin Formononetin Astragaloside II
(a) (b) (c)
OH OH
O O
OH
HO O O OH
O O
HO O HO O
OH O O O O
OH O O OH
HO OH HO OH
OH OH
Astragaloside IV Isoastragaloside I
(d) (e)
Figure 1: Phytocompounds of Astragalus membranaceus demonstrating anti-diabetic effects.
and mechanism of action on types 1 and 2 DM have been (NOD) mice. It was also reported to have lowered the
reported. proliferation of CD +4 and CD +8 T cells [41, 42, 46]. The
CD +4 and CD +8 T cells have been implicated in inflam-
matory response, apoptosis, and autoimmunity leading to
4.1. Type 1 DiabetesMellitus. Type 1 DM is caused by autoim- type 1 DM [47, 48]. APS may protect pancreatic beta cells
mune destruction of pancreatic beta cells. The polysaccha- from autoimmune destruction through the regulation of
rides fraction (APS) has been the only constituent demon- inflammatory and apoptotic responses.
strating activity to type 1 DM. It lowered the incidence rate
and postponed the onset of type 1 DM in nonobese type
1 diabetes mellitus (NOD) mice [40–42]. It also attenuated 4.1.1. Immunomodulation of Inflammatory Response. The
autoimmunal insulitis, increased the proliferation of pancre- anti-inflammatory effect of APS was studied mainly on the
+ +
atic beta cells, and decreased apoptotic beta cell mass [43– secretory cytokines of CD4 T helper cells. Naive CD4 T
45]. APS was postulated to have induced immunoprotective cells differentiate into T helper cells 1 (Th1) and 2 (Th2) for
effects in type 1 diabetic NODmodels.This potential has been inflammatory response and autoimmunity.TheTh1 expresses
widely investigated. Chen et al. (2001) and others evaluated secretory cytokines such as interferon gamma (IFN𝛾), tumor
the immunomodulatory effect of APS on CD +4 and CD +8 necrosis factor-alpha (TNF-𝛼), interleukin-2 (IL-2), and IL-
T cells. APS was observed to have decreased lymphocytic I𝛽 that induce inflammation and intracellular autoimmune
inflammation of pancreatic islets in type 1 noobese diabetic responses. The Th2 is noted for IL-4, IL-5, IL-10,and IL-13
4 Evidence-Based Complementary and Alternative Medicine
production for extracellular immunity and counteraction of to have reduced caspase-3 levels in INS-1 cells [63]. It also
Th1 inflammatory response [49, 50]. APS has demonstrated lowered in vitro nitric oxide production and apoptotic sig-
the potential to lower the expression ofTh1 cells and regulate naling via a demonstrated inhibition of IL-1𝛽 and reduction
Th1 and Th2 imbalance in in vivo diabetic models. Chen of Bax/Bcl-2 ratio. It was also shown to have inhibited the
and Yu (2004) in molecular immunomodulatory studies activation of nuclear factor-kappaB (NF-𝜅B) [63].
reported a possible correction of genetic imbalance of Th1
and Th2 genes and proteins in APS-treated type 1 DM 4.2. Type 2 Diabetes Mellitus. Type 2 of DM is caused by
NOD mice. Their studies observed about 5.47% changes insulin resistance and deficient glucosemetabolism.All of the
in gene expression, of which 17 genes were of functional major constituents of AM have been shown to differentially
relation to immunity [51]. Further studies showed that lower high blood glucose levels and body weight and improve
APS demonstrates immunomodulatory effects on Th1 and impaired glucose tolerance in type 2 diabeticmodels [64–67].
Th2 cytokines. It was reported to have downregulated the The postulated pharmacological processes include various
expression levels of Th1 cytokines such as IL-12, TNF-𝛼, glucose transportation and insulin signaling pathways that
and IFN𝛾 and enhanced Th2 cytokines such as IL-4, IL- lead to insulin sensitivity and restoration of the proliferative
5, IL-6, and IL-10 [42, 45, 52]. APS also demonstrated a ability of the pancreatic beta cells.
significant lowering effect on Th1/Th2 ratio [44, 53], an
important apoptotic index that measures relatively lowered
levels of Th1 per Th2 cytokines as an indication for reduced 4.2.1. Promotion of Intracellular Glucose Transportation. The
intracellular autoimmunity and inflammatory response [54]. polysaccharides fraction has exhibited potentials of reducing
The effect of APS on other inflammatory markers such as hyperglycemia through the induction of glucose transloca-
peroxisome-proliferator-activated receptor gamma (PPAR- tion enzymes and proteins. It has been studied as a promoter
), superoxide dismutase (SOD), and nitric oxide (NO) of increased glucose transporter protein-4 (GLUT4) levels.𝛾
has also been studied. APS significantly enhanced the gene In a molecular expression study of the effect of APS on
expression of PPAR- in a time- and dose-dependentmanner GLUT4, APS increased the expression and translocation of𝛾
[53] and promoted SOD anti-oxidation in type 1 DMmodels GLUT4 in skeletal muscle and adipose tissues [64, 68]. The
[42, 55]. It also lowered the expression of inducible nitric GLUT4 is an insulin-regulated intracellular transporter noted
oxide synthase (iNOS) [42, 55]. PPAR-𝛾, NO, iNOS, and for the mediation of glucose translocation into muscle and
SOD among a variety of functions also play various roles fat cells. Liu et al. (2010) analyzed the effect of APS on
in the stimulation and regulation of inflammatory response the GLUT4/protein kinase B (PKB) glucose transportation
[56]. pathway in the skeletal muscles of insulin-resistant KKAy
The effect of astragalin, a flavonoid isolate of AM, mice. APS was reported to have partially restored lowered
on apoptotic cytokines has also been studied. It showed activation levels of PKB and GLUT4 translocation [64].
an inhibitory effect on the production levels of TNF-𝛼,
IL-1, and IL-6 [57]. It was reported to have repressed the 4.2.2. Regulation of Glucose and Lipid Metabolism. Increased
expression of these Th1 cells via NF-𝜅B inhibition. It has levels of circulating glucose, free fatty acids, and accumu-
also been shown as exhibiting inhibitory effects on proin- lation lipids in nonadipose tissues have been implicated in
flammatory mediators similar to quercetin. It was shown to the development of insulin resistance and type 2 DM [69].
have attenuated the production of nitric oxide (NO) and APS, ASS, and ASF have all shown differential regulatory
repressed the expression and production levels of iNOS and effects on several glucose- and lipid-metabolizing enzymes,
cyclooxygenase-2 (COX-2) in J774A.1 mice macrophages proteins, and receptors. The polysaccharides fraction has
[57, 58]. been the most widely studied. It has been shown to have
enhanced the phosphorylation and activation of hepatic
glycogen synthase and regulated the expression and acti-
4.1.2. Promotion of Antiapoptotic Response. APS has exhib- vation of adenosine monophosphate-alpha (AMP-𝛼) and
ited the potential to regulate a number of apoptosis-related acetyl-CoA carboxylase to alleviate glucose accumulation
proteins and enzymes. It demonstrated significant inhibitory in in vitro skeletal muscle cells and KKAy mice models
effect on caspase-3 enzyme [45, 59] while enhancing the [65]. It also exhibited an upregulatory effect on the levels
expression of B-cell lymphoma-2 (Bcl-2) [55] in type 1 DM of adiponectin [70] and its receptor, adipo-R1 [71], in type
models. Caspase-3 is noted for apoptosis execution, whereas 2 DM rats. It promoted the expression and activation of
Bcl-2 has apoptosis regulatory effects. APS was also positively adenosine monophosphate protein kinase (AMPK) and its
correlated to increased galectin-1 levels in the muscles of alpha-subunit, AMPK-alpha [65, 71, 72]. Adiponectin and
type 1 DM mice. Its correlation with galectin-1 was further AMPK are important activating factors for glucose and lipid
shown to have a negative regulatory effect onCD8+ T cells, an metabolism in the liver, muscles, and adipocytes. Increased
apoptosis-enhancing T cell [60]. APS has also been reported levels of their activity have been associated with reduced risk
to have lowered the expression of Fas [42, 61, 62]. Fas is a for type 2 DM [73, 74]. Other studies have demonstrated
member of the TNF family of receptors that expresses on cells APS as regulating glucose and lipid metabolism through
to trigger their apoptosis. the promotion of peroxisome proliferator-activated receptor-
Formononetin, an O-methylated isoflavone, has been (PPAR-) alpha activity and inhibition of the autonomic
reported as inhibiting the activity of caspase-3. It was shown neurotransmitter neuropeptide-Y (NPY). The PPARs are
Evidence-Based Complementary and Alternative Medicine 5
a family of ligand-dependent transcription factors that con- decrease in the expression of PERK and inhibition of ATF-
trol energy homeostasis through the regulation of carbo- 6 activity [82]. It also reduced the levels of the transcription
hydrate and lipid metabolism. PPAR-alpha potentiates fatty repressor protein XBP1 and GSK3𝛽 in KKAy mice [83].
acid catabolism and reduces circulating lipids [75]. APS The inhibitory effect of APS on ATF-6 was further studied
enhanced the gene and protein expression of PPAR-𝛼 and in relation to protein tyrosine phosphatase-1-B (PTP1B), a
improved the lipoprotein profiles of streptozotocin-induced negative regulator of insulin-receptor signal transduction.
diabetic hamsters [76]. Neuropeptide-Y is an autonomic ATF-6 inhibition was positively correlated with lowered
neurotransmitter that induces increased food intake leading expression and activation levels of PTP1B in experimental
to obesity and type 2 DM. Chen et al. (2011) reported lowered animals [67, 84, 85]. APS may have indirectly promoted
levels of increased blood glucose and body weight in relation insulin signaling via ER stress alleviation. Other insulin
to neuropeptide-Y in streptozotocin-induced diabetic rats. signaling studies have reported the upregulatory effect of
APS was reported to have reduced the mRNA expression APS on insulin receptors. APS was shown to have increased
levels of neuropeptide-Y and its receptor neuropeptide- the levels of insulin receptor substrate-1 (IRS-1) and its beta
Y2 protein [77]. The effect of APS on aldose reductase, transmembrane receptor (IR-𝛽) subunit in muscle cells [84].
a glucose-metabolizing enzyme target implicated in high- IRS-1 s key role in insulin signal transduction. Lowered levels
glucose-induced diabetes complications [78], has also been of IRS-1 have been associated with increased susceptibility to
studied. APS had no significant inhibitory effect on aldose type 2 DM [86, 87]. APS has also demonstrated regulatory
reductase [79]. effects on resistin, an insulin-resistance protein [88, 89]. It
The saponins (ASS) and flavonoids (ASF) fractions exhib- decreased the mRNA and protein expression levels of resistin
ited their antagonizing effects on ascending blood glucose in type 2 DMWistar rats.
levels in type 2 DM rats through a common adiponectin
and AMPK-metabolizing pathway. They increase the genetic
and cellular expression of AMPK, adiponectin, and adipo-R1 5. Pharmacological Prospects and
levels in the liver and skeletal muscle of diabetic rats [70, 71]. Concluding Remarks
The expression levels of AMPK and adipo-R1 induced by the
saponinswere reported to bemore pronounced in the skeletal The anti-diabetic potential of Astragalus membranaceus has
muscles than in the liver, whereas the flavonoids showed an been progressively studied in the recent past. Its crude
increased effect in the liver than in the skeletal muscle [71]. extracts have been reported in several ethnopharmacological
Several Astragalus saponins isolates have been studied. studies as potential prospect for further anti-diabetic studies.
Astragaloside II and isoastragaloside I exhibited regulatory Recent studies have analyzed its phytochemical constituents
effects on adiponectin and AMPK action. They significantly in elucidating its pharmacological significance to types 1 and
increased adiponectin levels and promoted the activation of 2 DM. Its polysaccharides, saponins, and flavonoids fractions
AMPK in type 2 DM mice. Their induction of increased and several isolated compounds have been studied. They
adiponectin levels was reported to be independent of PPAR , all exhibited differential potentials of correcting the charac-𝛾
an adiponectin agonist [75, 80]. The Astragalus saponins teristic defects of inadequate insulin production, secretion,
astragalosides I and IV have demonstrated inhibitory effect and action on target cells. The total polysaccharides fraction
on aldose reductase. They downregulated its activation levels demonstrates significant activity to type 1 DM. It protects
to ameliorate accumulation of advanced glycation endprod- pancreatic beta cells from intracellular (autoimmune) cell
ucts in both erythrocytes and nerve cells of diabetic rats [81]. death via the immunomodulation of several inflammatoryand apoptotic cytokines, enzymes, and proteins. It demon-
The comparative effects of formononetin and caly- strated the potential tomodulate T helper cells 1 and 2, reduce
cosin isoflavonoids on the peroxisome-proliferator-activated inflammatory response, and promote antioxidant activities
receptors activation system have also been studied. For- towards antiapoptotic protection of pancreatic beta cells.
mononetin was reported to be more potent activator of Astragalin and formononetin also demonstrated regulatory
PPAR𝛾-induced differentiation of 3T3-L1 preadipocyte than effects on various inflammatory and apoptotic indicators.
calycosin [18]. PPAR𝛾 plays crucial role in the differentiation The polysaccharides, saponins, and flavonoids fractions
and maturity of fat cells [75]. all exhibited significant activities to type 2 DM. They gen-
erally induce their hypoglycemic effects through various
4.2.3. Alleviation of ER Stress and Induction of Insulin Signal insulin sensitizing pathways. They all demonstrated regu-
Transduction. Stress responses in the endoplasmic reticulum latory effects on AMPK and adiponectin and its receptor
(ER) have been associated with increased 𝛽-cell apoptosis adipo-R1. Astragaloside II and isoastragaloside I isolates were
rates, reduced beta cell mass, lowered insulin production, and also associated with this effect. The polysaccharides fraction
increased insulin resistance in type 2 DM patients. APS has has been most extensively studied in relation to type 2 DM.
been reported as a negative regulator of key ER stress indica- It promotes insulin sensitization through various coordi-
tors such as phosphorylated protein kinase-like endoplasmic nated pathways towards intracellular glucose transportation,
reticulum kinase (PERK), activating transcription factor-6 insulin signal transduction, and protection of pancreatic
(ATF-6), glycogen synthase kinase 3 beta (GSK3𝛽), and XhoI beta cells from apoptotic death. It promoted the PKB/Akt
site-binding protein 1 (XBP1) in type 2 diabetes models. It and -PPAR-𝛼 and -𝛾 systems, activated insulin recep-
relieved ER stress in type 2 DM SD rats through a significant tors, and regulated ER stress-related proteins and enzymes.
6 Evidence-Based Complementary and Alternative Medicine
The PKB/Akt system differentially coordinates PKB to glyco- mechanisms,” Zhongguo Zhongyao Zazhi, vol. 28, no. 2, pp. 108–
gen synthase kinase 3 (GSK3), GLUT4, apoptotic caspases, 113, 2003.
IR, and IRS-1, among others, to induce glucose transportation [7] D. X. Wei, N. Z. Yu, and O. Z. Ya, “Traditional Chinese
and cell proliferation. The phosphorylation and activation medicines in treatment of patients with type 2 diabetes melli-
of PKB lead to increased IRS-1 and GLUT4 activity for tus,” Evidence-Based Complementary and Alternative Medicine,
glucose translocation and insulin signaling. Its activation also vol. 2011, Article ID 726723, 13 pages, 2011.
results in the inactivation of GSK3 and caspase proteases to [8] W. L. Li, H. C. Zheng, J. Bukuru, and N. De Kimpe, “Natural
inhibit apoptosis [90, 91]. Stress-induced apoptosis in the medicines used in the traditional Chinese medical system for
endoplasmic reticulum of pancreatic and liver cells has also therapy of diabetesmellitus,” Journal of Ethnopharmacology, vol.
been related to reduced insulin production and increased 92, no. 1, pp. 1–21, 2004.
insulin resistance [92, 93]. APS notably exhibited a negatively [9] S. F. Zang, L. Ning, H. X. Ni, Q. L. Zhang, and Z. J. Chen,
regulatory effect on PERK, ATF-6, and XBP1 ER stress “The effect of Astragalus on PPAR-𝛾 mRNA expression in
indicators. The PPAR are a family of ligand-dependent tran- macrophage with Type2 Diabetic Mellitus,” Chinese Archives of
scription factors that control energy homeostasis through the Traditional Chinese Medicine, vol. 29, no. 8, p. 1853, 2006.
regulation of carbohydrate and lipid metabolism [94]. They [10] X. C. Liang, L. Y. Cui, S. S. Guo et al., “Clinical study
are also involved in the regulation of inflammatory responses of Jinmaitong composita on diabetic peripheral neuropathy,”
[56, 75]. PPAR-alpha [75] and PPAR-gamma [94] have been Chinese Journal of IntegrativeMedicine, vol. 7, no. 2, pp. 103–106,2001.
associated with the regulation of DM. APS demonstrated
activity to both of them to alleviate high blood glucose levels. [11] D. Seely, E. Mills, and B. Rachlis, “Patients with diabetesusing alternative medicine,” in Contemporary Endocrinology
The demonstrated regulatory effects of APS on these systems (Evidence-Based Endocrinology), vol. 4, pp. 323–342, 2006.
suggest its importance and prospects for further research and [12] C. Keji, “Understanding and treatment of diabetes mellitus
development for diabetes therapy. by traditional Chinese medicine,” American Journal of Chinese
Further studies on more single-compound isolates are Medicine, vol. 9, no. 1, pp. 93–94, 1981.
important to understand the overall mechanisms and pro- [13] Z. Sang, L. Zhou, X. Fan, and R. J. McCrimmon, “Radixz
cesses of anti-diabetic effects as well as their structure-activity astragali (Huangqi) as a treatment for defective hypoglycemia
relationships. counterregulation in diabetes,” American Journal of Chinese
Medicine, vol. 38, no. 6, pp. 1027–1038, 2010.
Conflict of Interests [14] S. F. Zang, L. Ning, H. X. Ni, Q. L. Zhang, and Z. J. Chen,
“The effect of Astragalus on PPAR-𝛾 mRNA expression in
The authors have no conflict of interests in this paper. macrophage with type2 diabetic mellitus,” Chinese Archives of
Traditional Chinese Medicine, vol. 29, no. 8, pp. 1853–1855, 2011.
[15] M. Chao, D. Zou, Y. Zhang et al., “Improving insulin resistance
Acknowledgments with traditional Chinese medicine in type 2 diabetic patients,”
This paper was supported by the Program for New Cen- Endocrine, vol. 36, no. 2, pp. 268–274, 2009.
tury Excellent Talents in University (NCET-10-0958, and [16] D. Q. Zhang, J. J. Zhang, J. X. Wang et al., “Effects of Qilan
1069), the Important Drug Development Fund, Ministry of Tangzhining capsule on glucose and lipid metabolism in rats
Science and Technology of China (nos. 2011ZX09307-002- with diabetes mellitus and hyperlipemia,” Zhongguo ZhongyaoZazhi, vol. 30, no. 10, pp. 773–777, 2005.
01 and 2012ZX09304007), and the National Natural Science
Foundation of China (81173524). [17] Q. J. Qin, J. Y. Niu, Z. X. Wang, W. J. Xu, Z. D. Qiao, and Y. Gu,“Astragalus membranaceus Inhibits Inflammation via Phospho-
P38 Mitogen-Activated Protein Kinase (MAPK) and Nuclear
References Factor (NF)-𝜅B Pathways in Advanced Glycation End Product-
Stimulated Macrophages,” International Journal of Molecular
[1] S. Wild, G. Roglic, A. Green, R. Sicree, and H. King, “Global Sciences, vol. 13, no. 7, pp. 8379–8387, 2012.
prevalence of diabetes: estimates for the year 2000 and projec- [18] P. Shen, M. H. Liu, T. Y. Ng, Y. H. Chan, and E. L. Yong, “Differ-
tions for 2030,”Diabetes Care, vol. 27, no. 5, pp. 1047–1053, 2004. ential effects of isoflavones, fromAstragalus membranaceus and
[2] D. Einhorn, “Advances in diabetes for the millennium: insulin Pueraria Thomsonii, on the activation of PPAR𝛼, PPAR𝛾, and
treatment and glucose monitoring CME,” MedGenMed Med- adipocyte differentiation in vitro,” Journal of Nutrition, vol. 136,
scape General Medicine, vol. 6, supplement 3, p. 8, 2004. no. 4, pp. 899–905, 2006.
[3] M. Rendell, “Advances in diabetes for the millennium: drug [19] WHO, Radix Astragali, vol. 1, WHO Monographs on Selected
therapy of type 2 diabetes,” Medscape General Medicine, vol. 6, Medicinal Plants, Geneva, Switzerland, 1999.
supplement 3, p. 9, 2004. [20] Thorne Research Incoporated, “Astragulus membranaceus
[4] P. Lambert and P. J. Bingley, “What is type 1 diabetes?”Medicine, monograph alternative medicine review,”Thorne Research Inco-
vol. 30, no. 1, pp. 1–5, 2002. porated, vol. 8, no. 1, pp. 72–77, 2003.
[5] B. M. Berman, J. P. Swyers, and J. Kaczmarczyk, “Complemen- [21] X. Liu, M. Wang, H. Wu, X. Zhao, and H. Li, “Isolation of
tary and alternative medicine: herbal therapies for diabetes,” astragalan and its immunological activities,” Tianran Chanwu
Journal of the Association for Academic Minority Physicians, vol. Yanjiu Yu Kaifa, vol. 6, pp. 23–31, 1994.
10, no. 1, pp. 10–14, 1999. [22] S. D. Fang, Y. Chen, C. Q. Ye, S. K. Zhai, and M. L. Shen,
[6] W. Jia, W. Gao, and P. Xiao, “Antidiabetic drugs of plant origin “Studies of the active principles of Astragalus Mongholicus
used in China: compositions, pharmacology, and hypoglycemic Bunge I. isolation, characterization and biological effect of its
Evidence-Based Complementary and Alternative Medicine 7
polysaccharides,” Chinese Journal of Organic Chemistry, vol. 1, [37] E. J. Lee, M. H. Yean, H. S. Jung, J. S. Kim, and S. S. Kang,
pp. 26–31, 1982. “Phytochemical studies on Astragalus root (2)-flavonoids and a
[23] Y. Y. Zou, X.Q.Gu, andQ.Chen, “Investigation of the polyphase lignan,”Natural Product Sciences, vol. 14, no. 2, pp. 131–137, 2008.
liposomal bipolysaccharides-Part 1. Selection and analysis of [38] L. J. Zhang, H. K. Liu, P. C. Hsiao et al., “New isoflavonoid gly-
the effective ingredients in the two polysaccharides,” Journal of cosides and related constituents from astragali radix (Astragalus
Shenyang Pharmaceutical University, vol. 4, no. 3, pp. 170–174, membranaceus) and their inhibitory activity on nitric oxide
1987. production,” Journal of Agricultural and Food Chemistry, vol. 59,
[24] M. Tomoda, N. Shimizu, N. Ohara, R. Gonda, S. Ishii, and H. no. 4, pp. 1131–1137, 2011.
Otsuki, “A reticuloendothelial system-activating glycan from [39] L. Z. Lin, X. G. He, M. Lindenmaier et al., “Liquid
the roots of Astragalus membranaceus,” Phytochemistry, vol. 31, chromatography-electrospray ionization mass spectrometry
no. 1, pp. 63–66, 1991. study of the flavonoids of the roots of Astragalus mongholicus
[25] L. X.Mu, L. Zhu, A. H. Zhao,M.M. Zhou, andW. Jia, “Study on and A. membranaceus,” Journal of Chromatography A, vol. 876,
extraction and purification of polysaccharides from Astragalus no. 1-2, pp. 87–95, 2000.
membranaceus,” Zhong Yao Cai, vol. 32, no. 11, pp. 1741–1745, [40] X. Y. Wu, W. Chen, and M. H. Yu, “Effect of astragalus
2009. polysaccharides on expression of IL-4 and IFN-𝛾 in non-obese
[26] S. C. Wang, J. J. Shan, Z. T. Wang, and Z. B. Hu, “Isolation and diabetic mice,” Chinese Journal of Rehabilitation Theory and
structural analysis of an acidic polysaccharide from Astragalus Practice, vol. 14, no. 2, pp. 147–149, 2008.
membranaceus (Fisch.) Bunge,” Journal of Integrative Plant [41] W. Chen, F. Liu, M. Yu, Q. Zhu, and X. Zhu, “Astragalus
Biology, vol. 48, no. 11, pp. 1379–1384, 2006. polysaccharide prevent type 1 diabetes in nonobese diabetic
[27] L. Jing, Z. Z. Zhen, and C. H. Biao, “Review of Astragali radix,” mice,” Fudan University Journal of Medical Sciences, vol. 28, no.
Chinese Herbal Medicines, vol. 3, no. 2, pp. 90–105, 2011. 1, pp. 57–60, 2001.
[28] K. Kajimura, Y. Takagi, N. Ueba et al., “Protective effect of [42] W. Chen, Y.-M. Li, and M.-H. Yu, “Astragalus polysaccharides:
Astragali Radix by intraperitoneal injection against Japanese an effective treatment for diabetes prevention in NOD mice,”
encephalitis virus infection inmice,” Biological and Pharmaceu- Experimental and Clinical Endocrinology and Diabetes, vol. 116,
tical Bulletin, vol. 19, no. 6, pp. 855–859, 1996. no. 8, pp. 468–474, 2008.
[29] E. Bombardelli and R. Pozzi, “Polysaccharides with [43] W. Chen, Y. P. Xia, M. H. Yu, and X. M. Shi, “Astragalus
immunomodulating properties from Astragalus membranaceus polysaccharides effect on pancreatic histopathology,” China
and pharmaceutical compositions containing them,” 1994, Journal of Modern Medicine, vol. 17, no. 2, pp. 146–148, 2007.
http://brevets-patents.ic.gc.ca/opic-cipocpd/eng/patent/20359- [44] R. J. Li, S. D. Qiu, H. X. Chen, H. Tian, and H. X. Wang, “The
48/summary.html. immunotherapeutic effects of Astragalus polysaccharide in type
[30] I. Kitagawa, H. K.Wang, andM. Saito, “Saponin and Sapogenol. 1 diabetic mice,” Biological and Pharmaceutical Bulletin, vol. 30,
XXXV. Chemical constituents of Astragali Radix, the root no. 3, pp. 470–476, 2007.
of Astragalus membranaceus Bunge. (2). Astragalosides I, II, [45] R. J. Li, S. D. Qiu, H. X. Chen, H. Tian, and G. Liu, “Effect
and IV, acetylastragaloside I and isoastragalosides I and II,”
Chemical and Pharmaceutical Bulletin of Astragalus polysaccharide on pancreatic cell mass in type 1, vol. 31, no. 2, pp. 698– diabetic mice,” Zhongguo Zhongyao Zazhi, vol. 32, no. 20, pp.
708, 1983. 2169–2173, 2007.
[31] I. Kitagawa, H. K. Wang, M. Saito, andM. Yoshikawa, “Saponin
and Sapogenol. XXXVI. Chemical constituents of Astragali [46] W. Chen, Y. M. Li, M. H. Yu, and X. M. Shi, “Immunoloreg-
Radix, the root of Astragalus membranaceus Bunge. (3). Astra- ulation effects of Astragalus Polysaccharides on T helper lym-
galosides III, V, and VI,” Chemical and Pharmaceutical Bulletin, phocyte subgroups in nonobese diabetic Mice,” China Journal
vol. 31, no. 2, pp. 709–715, 1983. of Modern Medicine, vol. 17, no. 1, pp. 28–35, 2007.
[32] I. Kitagawa, H. K. Wang, and M. Yoshikawa, “Saponin and [47] F. S. Wong, L. K. Siew, G. Scott et al., “Activation of insulin-
Sapogenol. XXXVII. Chemical constituents of Astragali Radix, reactive cd8 t-cells for development of autoimmune diabetes,”
the root of Astragalus membranaceus Bunge. (4) Astragalosides Diabetes, vol. 58, no. 5, pp. 1156–1164, 2009.
VII andVIII,”Chemical and Pharmaceutical Bulletin, vol. 31, no. [48] J. T. Harty, A. R. Tvinnereim, and D. W. White, “Cd8+ T cell
2, pp. 716–722, 1983. effector mechanisms in resistance to infection,” Annual Review
[33] J. S. Kim, M. Yean, E. Lee et al., “Two new cycloartane saponins of Immunology, vol. 18, pp. 275–308, 2000.
from the roots of Astragalus membranaceus,” Chemical and [49] C. Dong and R. A. Flavell, “Cell fate decision: T-helper 1 and
Pharmaceutical Bulletin, vol. 56, no. 1, pp. 105–108, 2008. subsets in immune responses,” Arthritis Research, vol. 2, no. 3,
[34] C. Chu, H. Cai, M. Ren et al., “Characterization of novel pp. 179–188, 2000.
astragalosidemalonates fromRadixAstragali byHPLCwithESI [50] I. J. Crane and J. V. Forrester, “Th1 and Th2 lymphocytes in
quadrupole TOFMS,” Journal of Separation Science, vol. 33, no. autoimmune disease,” Critical Reviews in Immunology, vol. 25,
4-5, pp. 570–581, 2010. no. 2, pp. 75–102, 2005.
[35] Z. Q. He and J. A. Findlay, “Constituents of Astragalus mem- [51] W. Chen andM.H. Yu, “Effects of Astragalus polysaccharide on
branaceus,” Journal of Natural Products, vol. 54, no. 3, pp. 810– gene expression profiles in islets of NOD mice with microar-
815, 1991. ray technique Chinese,” Chinese Journal of Endocrinology and
[36] Q. Xu, X. Q. Ma, and X. M. Liang, “Determination of astraga- Metabolism, vol. 20, no. 6, pp. 545–548, 2004.
losides in the roots of Astragalus spp. using liquid chromatog- [52] W. Chen, Y. M. Li, and M. H. Yu, “Astragalus polysaccharides
raphy tandem atmospheric pressure chemical ionization mass influence ultrastructure of islets and Th1/Th2 cvtokine gene
spectrometry,” Phytochemical Analysis, vol. 18, no. 5, pp. 419– expression of pancrease in NOD mice,” Chinese Journal of
427, 2007. Endocrinology andMetabolism, vol. 23, no. 3, pp. 269–271, 2007.
8 Evidence-Based Complementary and Alternative Medicine
[53] R. J. Li, S. D. Qiu, H. X. Chen, and L. R. Wang, “Immunomod- [68] H. F. Liu, Y. H. Ren, Z. X. Han et al., “Effect of astragalus poly
ulatory effects of Astragalus polysaccharide in diabetic mice,” saccharides on insulin resistance and gene expression ofGLUT4
Zhong Xi Yi Jie He Xue Bao, vol. 6, no. 2, pp. 166–170, 2008. in type 2 diabetes mellitus rats,” Chinese Journal of Gerontology,
[54] S. T. Azar, H. Tamim, H. N. Beyhum, M. Zouhair Habbal, vol. 31, no. 20, pp. 3988–3989, 2011.
and W. Y. Almawi, “Type I (insulin-dependent) diabetes is [69] D. E. Kelley and B. H. Goodpaster, “Skeletal muscle triglyceride:
a Th1- and Th2-mediated autoimmune disease,” Clinical and an aspect of regional adiposity and insulin resistance,” Diabetes
Diagnostic Laboratory Immunology, vol. 6, no. 3, pp. 306–310, Care, vol. 24, no. 5, pp. 933–941, 2001.
1999. [70] N. Li, Y. Fan, X. M. Jia, Z. Ma, and S. R. Lin, “Effect of astragali
[55] W. Chen, M. H. Yu, and Y. M. Li, “Effects of astragalus radix active ingredients on serum insulin and adiponectin
polysaccharides on ultrastructure and oxidation/ apoptosis in diabetes rats,” Chinese Journal of Experimental Traditional
related cytokines’ gene expression of non-obese diabetic mice’s Medical Formulae, vol. 17, no. 5, pp. 144–146, 2011.
islets,” Fudan University Journal of Medical Sciences, vol. 34, no. [71] N. Li, Y. Fan, X.M. Jia, S. R. Lin, and Z.Ma, “Effect of Astragalus
2, pp. 269–272, 2007. active ingredients on AdipoR1 and AMPKmRNA expression in
[56] A. J. Guri, S. K. Mohapatra, W. T. Horne II, R. Hontecillas, diabetic rats,”China Journal of Traditional ChineseMedicine and
and J. Bassaganya-Riera, “The Role of T cell PPAR 𝛾 in Pharmacy, vol. 26, no. 5, pp. 1176–1181, 2011.
mice with experimental inflammatory bowel disease,” BMC [72] D. H. Wu, F. J. Wang, J. Deng et al., “Effect of APS on the
Gastroenterology, vol. 10, no. 10, p. 60, 2010. expression of phosphyorylation of AMPK in liver tissue of type
[57] L. W. Soromou, N. Chen, L. Jiang et al., “Astragalin attenuates 2 diabetic rat,” Chinese Journal of Microcirculation, vol. 19, no. 3,
lipopolysaccharide-induced inflammatory responses by down- pp. 1–3, 2009.
regulating NF-𝜅B signaling pathway,” Biochemical and Biophys- [73] J. Spranger, A. Kroke, M. Möhlig et al., “Adiponectin and
ical Research Communications, vol. 419, no. 2, pp. 256–261, 2012. protection against type 2 diabetes mellitus,”The Lancet, vol. 361,
[58] M. S. Kim and S. H. Kim, “Inhibitory effect of astragalin on no. 9353, pp. 226–228, 2003.
expression of lipopolysaccharideinduced inflammatory medi- [74] R. D. Lele, “Pro-insulin, C peptide, glucagon, adiponectin,
ators through NF-𝜅B in macrophages,” Archives of Pharmacal TNF𝛼, AMPK: neglected players in type 2 diabetes mellitus,”
Research, vol. 34, no. 12, pp. 2101–2107, 2011. Journal of Association of Physicians of India, vol. 58, no. 30, pp.
[59] S. M. Mao, C. D. Li, L. Wang, J. Wang, G. Dai, and B. 35–40, 2010.
Kang, “Effect and mechanism of astragalus polysaccharides on [75] E. H. Koh, M. Kim, J. Park et al., “Peroxisome proliferator-
apoptosis of the islet beta cell in diabetes mellitus rats,” Chinese activated receptor (PPAR)-𝛼 activation prevents diabetes in
Pharmacological Bulletin, vol. 25, no. 9, pp. 1227–1229, 2009. OLETF rats: comparisonwith PPAR-𝛾 activation,”Diabetes, vol.
[60] X. J. Zhou, Y. C. Xu, G. M. Yang, and F. Li, “Increased galectin-1 52, no. 9, pp. 2331–2337, 2003.
expression inmuscle of Astragalus polysaccharide-treated Type [76] C. Wei, X. Yanping, Z. Xuelan et al., “The critical role of
1 diabetic mice,” Journal of Natural Medicines, vol. 65, no. 3-4, Astragalus polysaccharides for the improvement of PPRA𝛼-
pp. 500–507, 2011. mediated lipotoxicity in diabetic cardiomyopathy,” PLOS One,
[61] C. D. Li, J. J. Li, L. Wang et al., “Inhibitory effect of astragalus vol. 7, no. 10, Article ID e45541, pp. 1–10, 2012.
polysaccharides on apoptosis of pancreatic beta-cells mediated [77] Y. S. Chen, H. Q. Liu, W. Qin, and X. M. Luo, “Effect of
by Fas in diabetes mellitus rats,” Zhong Yao Cai, vol. 34, no. 10, Astragalus polysaccharides on neuropeptide Y and its receptor
pp. 1579–1582, 2011. Y expression in streptozotocin-induced diabetic rats,” Journal
2
[62] S.M.Mao, C. D. Li, L.Wang et al., “Effects of astragalus polysac- of Liaoning University of Traditional Chinese Medicine, vol. 13,
charides on the ultrastructure and Fas expression of pancreatic no. 1, pp. 48–49, 2011.
beta-cells in diabetes mellitus rats,” Chinese Pharmacological [78] S. Narayanan, “Aldose reductase and its inhibition in the control
Bulletin, vol. 26, no. 6, pp. 791–793, 2010. of diabetic complications,” Annals of Clinical and Laboratory
[63] Y. Wang, Y. Zhu, L. Gao et al., “Formononetin attenuates IL- Science, vol. 23, no. 2, pp. 148–158, 1993.
1𝛽-induced apoptosis and NF-𝜅B activation in INS-1 cells,” [79] H. Z. Yang, M. M. Zhou, A. H. Zhao, S. N. Xing, Z. Q.
Molecules, vol. 17, no. 9, pp. 10052–10064, 2012. Fan, and W. Jia, “Study on effects of baicalin, berberine and
[64] M. Liu, K. Wu, X. Mao, Y. Wu, and J. Ouyang, “Astragalus Astragalus polysaccharides and their combinative effects on
polysaccharide improves insulin sensitivity in KKAy mice: aldose reductase in vitro,”ZhongYaoCai, vol. 32, no. 8, pp. 1259–
regulation of PKB/GLUT4 signaling in skeletal muscle,” Journal 1261, 2009.
of Ethnopharmacology, vol. 127, no. 1, pp. 32–37, 2010. [80] A. Xu, H. Wang, R. L. C. Hoo et al., “Selective elevation of
[65] F. Zou, X.Q.Mao,N.Wang, J. Liu, and J. P.Ou-Yang, “Astragalus adiponectin production by the natural compounds derived
polysaccharides alleviates glucose toxicity and restores glucose from a medicinal herb alleviates insulin resistance and glucose
homeostasis in diabetic states via activation of AMPK,” Acta intolerance in obese mice,” Endocrinology, vol. 150, no. 2, pp.
Pharmacologica Sinica, vol. 30, no. 12, pp. 1607–1615, 2009. 625–633, 2009.
[66] W. P. Liao and Y. G. Shi, “Effect of astragalus polysaccharides [81] J. Yu, Y. Zhang, S. Sun et al., “Inhibitory effects of astragaloside
and soy isoflavones on glucose metabolism in diabetic rats,” IV on diabetic peripheral neuropathy in rats,”Canadian Journal
Acta Academiae Medicinae Militaris Tertiae, vol. 29, no. 5, pp. of Physiology and Pharmacology, vol. 84, no. 6, pp. 579–587,
416–418, 2007. 2006.
[67] N. Wang, D. Zhang, X. Mao, F. Zou, H. Jin, and J. Ouyang, [82] N. Wang, X. Q. Mao, S. Wang, C. Zhang, F. Zou, and J. P.
“Astragalus polysaccharides decreased the expression of PTP1B Ouyang, “Effects of APS on reducing ER stress and increasing
through relieving ER stress induced activation of ATF6 in a rat insulin sensitivity in a rat model of type 2 diabetes,” Journal of
model of type 2 diabetes,”Molecular andCellular Endocrinology, Public Health and Preventive Medicine, vol. 18, no. 4, pp. 13–16,
vol. 307, no. 1-2, pp. 89–98, 2009. 2007.
Evidence-Based Complementary and Alternative Medicine 9
[83] X. Q. Mao, Y. Wu, K. Wu et al., “Astragalus polysaccharide
reduces hepatic endoplasmic reticulum stress and restores
glucose homeostasis in a diabetic KKAy mouse model,” Acta
Pharmacologica Sinica, vol. 28, no. 12, pp. 1947–1956, 2007.
[84] Y. Wu, J. P. Ou-Yang, K. Wu, Y. Wang, Y. Zhou, and C. Wen,
“Hypoglycemic effect of Astragalus polysaccharide and its effect
on PTP1B,” Acta Pharmacologica Sinica, vol. 26, no. 3, pp. 345–
352, 2005.
[85] X. Mao, F. Yu, N. Wang et al., “Hypoglycemic effect of
polysaccharide enriched extract ofAstragalus membranaceus in
diet induced insulin resistant C57BL/6J mice and its potential
mechanism,” Phytomedicine, vol. 16, no. 5, pp. 416–425, 2009.
[86] P. Kovacs, R. L. Hanson, Y. Lee et al., “The role of insulin
receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima
Indians,” Diabetes, vol. 52, no. 12, pp. 3005–3009, 2003.
[87] E. Zeggini, J. Parkinson, S. Halford et al., “Association studies
of insulin receptor substrate 1 gene (IRS1) variants in type 2
diabetes samples enriched for family history and early age of
onset,” Diabetes, vol. 53, no. 12, pp. 3319–3322, 2004.
[88] H. F. Liu, Y. Zhang, Z.Hu et al., “Effect ofAstragalus polysaccha-
rides on gene expression of resistin in type 2 diabetes mellitus
rats,” Journal of Mudanjiang Medical University, vol. 32, no. 4,
pp. 9–10, 2011.
[89] H. F. Liu,H. J. Chen, G. Y.Wang, Z. X.Han, and J. Zhang, “Effect
of astragalus polysaccharides on insulin resistance and protein
pxpression of resistin in type 2 diabetes mellitus rats,” Food and
Nutrition in China, vol. 18, no. 1, pp. 69–71, 2012.
[90] M. A. Lawlor and D. R. Alessi, “PKB/Akt: a key mediator of cell
proliferation, survival and insulin responses?” Journal of Cell
Science, vol. 114, no. 16, pp. 2903–2910, 2001.
[91] H. K. R. Karlsson, J. R. Zierath, S. Kane, A. Krook, G. E.
Lienhard, and H. Wallberg-Henriksson, “Insulin-stimulated
phosphorylation of the Akt substrate AS160 is impaired in
skeletal muscle of type 2 diabetic subjects,”Diabetes, vol. 54, no.
6, pp. 1692–1697, 2005.
[92] U. Özcan, Q. Cao, E. Yilmaz et al., “Endoplasmic reticulum
stress links obesity, insulin action, and type 2 diabetes,” Science,
vol. 306, no. 5695, pp. 457–461, 2004.
[93] Z. Fu, E. R. Gilbert, and D. M. Liu, “Regulation of insulin
synthesis and secretion and pancreatic beta-cell dysfunction in
diabetes,”Current Diabetes Reviews, vol. 9, no. 1, pp. 25–53, 2013.
[94] M. J. Reginato and M. A. Lazar, “Mechanisms by which thiazo-
lidinediones enhance insulin action,” Trends in Endocrinology
and Metabolism, vol. 10, no. 1, pp. 9–13, 1999.
MEDIATORS
of
INFLAMMATION
The Scientific Gastroenterology Journal of
World Journal Research and Practice Diabetes Research Disease Markers
Hindawi Publishing Corporation
Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
Journal of International Journal of
Immunology Research Endocrinology
Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
Submit your manuscripts at
http://www.hindawi.com
BioMed 
PPAR Research Research International
Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
Journal of
Obesity
Evidence-Based 
Journal of Stem Cells Complementary and Journal of
Ophthalmology International Alternative Medicine Oncology
Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014
Parkinson’s 
Disease
 Computational and  
Mathematical Methods Behavioural AIDS Oxidative Medicine and 
in Medicine Neurology Research and Treatment Cellular Longevity
Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014