Antidiabetic herbal drugs ofﬁcially approved in China

ANTIDIABETIC HERBAL DRUGS 1127

Copyright © 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 1127–1134 (2003)

Copyright © 2003 John Wiley & Sons, Ltd.

Received 11 June 2003Accepted 18 June 2003

PHYTOTHERAPY RESEARCHPhytother. Res. 17, 1127–1134 (2003)Published online 11 November 2003 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1398

REVIEW ARTICLEAntidiabetic Herbal Drugs Officially Approvedin China

Wei Jia1*, Wenyuan Gao2 and Lida Tang3

1The School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China2The College of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China3Tianjin Institute of Pharmaceutical Research, Tianjin, China

Over the centuries, Chinese herbal drugs have served as a major source of medicines for the prevention andtreatment of diseases including diabetes mellitus (known as ‘Xiao-ke’). It is estimated that more than 200species of plants exhibit hypoglycaemic properties, including many common plants, such as pumpkin, wheat,celery, wax guard, lotus root and bitter melon. To date, hundreds of herbs and traditional Chinese medicineformulas have been reported to have been used for the treatment of diabetes mellitus. This paper provides abrief review of the antidiabetic drugs of plant origin that have been approved by the Chinese health regulatoryagency for commercial use in China. It was believed, through pharmacological studies, that medicinal herbswere meticulously organized in these antidiabetic drug formulas such that polysaccharide containing herbsrestore the functions of pancreatic tissues and cause an increase in insulin output by the functional beta cells,while other ingredients enhance the microcirculation, increase the availability of insulin and facilitate themetabolism in insulin-dependent processes. Pharmacological and clinical evaluations indicated that these drugshad a mild, but significant, blood glucose lowering effect and that the long-term use of these agents may beadvantageous over chemical drugs in alleviating some of the chronic diseases and complications caused bydiabetes. Additionally, the use of these natural agents in conjunction with conventional drug treatments, suchas a chemical agent or insulin, permits the use of lower doses of the drug and/or decreased frequency ofadministration which decreases the side effects most commonly observed. Copyright © 2003 John Wiley &Sons, Ltd.

Keywords: diabetes mellitus; traditional Chinese medicine; antidiabetic drugs; herbal medicines.

* Correspondence to: Dr Wei Jia, The School of Pharmacy, Shanghai JiaoTong University, 1954 Huashan Road, Shanghai, 200030, P. R. China.E-mail: [email protected]

Achyranthes bidentata (Twotooth Achyranthes Root)Alisma orientale (Oriental Waterplantain Rhizome)Anemarrhena asphodeloides (Common AnemarrhenaRhizome)Asparagus cochinchinensis (Cochinchinese AsparagusRoot)Astragaus membranaceus (Milkvetch Root)Atractylodes macrocephala (Largehead AtractylodesRhizome)Bupleurum chinense (Chinese Thorowax Root)Cinnamomum cassia (Cassia Bark)Coptis chinensis (Coptis Root)Cornus officinalis (Asiatic Cornelian Cherry Fruit)Cucurbita moschata (Cushaw Seed)Dioscorea opposita (Common Yam Rhizome)Eriobotrya japonica (Loquat Leaf)Forsythia suspensa (Weeping Forsythia Capsule)Lonicera japonica Thunb. (Honeysuckle Flower)Morus alba (Mulberry Leaf)Ophiopogon japonicaus (Dwarf Lilyturf Tuber)Panax ginseng (Ginseng)Phragmites communis (Reed Rhizome)Pinellia ternata (Pinellia Tuber)Polygonum cuspidatum (Giant Knotweed Rhizome)Polygonum multiflorum (Fleeceflower Root)Poria cocos (Indian Bread)Pueraria lobata (Lobed Kudzuvine Root)Rehmannia glutinosa (Chinese Foxglove Root)Scrophularia ningpoensis (Figwort Root)

INTRODUCTION

Diabetes mellitus is a chronic condition in whichpatients may turn to alternative remedies that arepurported to improve glycaemic control. The diseaseis characterized by symptomatic glucose intolerance aswell as alterations in lipid and protein metabolism. Thelong-term complications of untreated or ineffectivelytreated diabetes include retinopathy, nephropathy andperipheral neuropathy. In addition, diabetic patientshave an increased risk of cardiovascular disease andstroke (Guan et al., 2000; Geng and Wang, 1997). There-fore, there is a strong need for safe and effective oralhypoglycaemic agents that provide the clinician with awider range of options for preventing, treating andmanaging diabetes.

Many herbal extracts or derivatives have been docu-mented in traditional Chinese medicine (TCM) ashaving clinical effectiveness in treating sugar imbalancesin diabetes mellitus. Other extracts and derivativeshave been found effective in treating water retentionproblems that often accompany diabetes. Some repre-sentative medicinal herbs listed below are routinelyprescribed in TCM for the treatment of diabetes(Guan et al., 2000; Reid, 1999).

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Table 1. Drug products and their ingredients approved in China

Drug product Ingredients

Yi-jin Panax ginseng (Ginseng)Atractylodes macrocephala (Largehead Atractylodes Rhizome)Poria cocos (Indian Bread)Opuntia dillenii (Cactus)

Ke-le-nin Radix Astragalus (Milkvetch Root)Rehmannia glutinosa (Chinese Foxglove Root)

Yu-san-xiao Radix Astragalus (Milkvetch Root)Scrophularia ningpoensis (Figwort Root)Anemarrhena asphodeloides (Common Anemarrhena Rhizome)Rehmannia glutinosa (Chinese Foxglove Root)

Qi-zhi Radix Astragalus (Milkvetch Root)Rehmannia glutinosa (Chinese Foxglove Root)Hirudo nipponia (Leech)

Shen-qi Panax ginseng (Ginseng)Radix Astragalus (Milkvetch Root)Dioscorea opposita (Common Yam Rhizome)Coptis chinensis (Coptis Root)Rehmannia glutinosa (Chinese Foxglove Root)Cornus officinalis (Asiatic Cornelian Cherry Fruit)Hirudo nipponia (Leech)

Jin-qi Lonicera japonica (Honeysuckle flower)Radix Astragalus (Milkvetch Root)Coptis chinensis (Coptis Root)

Xiao-ke-an Radix Astragalus (Milkvetch Root)Pueraria lobata (Lobed Kudzuvine Root)Ophiopogon japonicus (Dwarf Lilyturf Tuber)Hirudo nipponia (Leech)

system; (2) stimulate liver functions, including synthe-sis of RNA, DNA and vital proteins; (3) regulate bloodglucose levels; (4) regulate white and red blood cellcounts; (5) relieve fatigue and increase cerebral circula-tion; and (6) antioxidant properties (Reid, 1999).

Yu-san-xiao

An Shiming et al. reported 30 cases of type II diabetestreatment with Yu-san-xiao in 1998 (An et al., 1998;Guo, 1998). Among 30 patients treated with Yu-san-xiao,(oral administration, three times a day) for 1 month,five cases were concluded with no effect. About 40%of patients (12 cases) showed significant improvementin blood glucose level. Other diabetic symptoms suchas thirst and hunger disappeared, and glucose tests inurine became negative. Blood glucose and insulin levelsof these 12 patients before and after treatment aresummarized in Table 2.

In addition to five patients with no effect and12 patients with significant improvement, there were13 patients who experienced a reasonable improve-ment after treatment, the clinical results are summarizedin Table 3.

Yi-jin

Yi-jin, upon single or multiple administration, signifi-cantly lowered blood glucose levels in alloxan induceddiabetic mice (Li et al., 2000). The efficacy was similarto that of the chemical drug, phenformin (DBI), whichwas used in the experiments as a positive control.The fact that Yi-jin was not able to alter the blood

It is estimated that more than 200 species of plantsexhibit hypoglycaemic properties, including many com-mon plants, such as pumpkin, wheat, celery, wax guard,lotus root and bitter melon (Guan et al., 2000). To date,there are hundreds of herbs and formulas reported tohave been used in traditional Chinese medicine (TCM)for the treatment of diabetes mellitus. Although eachof the above listed medicinal herbs has antidiabeticeffectiveness, Chinese herbal drugs are used preferablyin combinations, i.e. each formula comprises severalherbs or plants, to enhance the action of the main herbs,and to mitigate the toxic side effects of the principalcomponent herbs. This paper will discuss the herbalantidiabetic drug products that have been approved bythe Chinese health regulatory agency (known as StateDrug Administration, SDA) for commercial use.

Thus far, there are seven antidiabetic drug productsof plant origin that have been approved for clinical usein China (Shang, 2000). Table 1 lists all these approvedproducts and the composition of the formulas.

POLYSACCHARIDE CONTAINING DRUGSWHICH HELP PROTECT PANCREATIC ISLETSAND BETA CELLS

Many Chinese herbs contain polysaccharides, whichare found to lower the blood sugar. Therapeutic herbaldrugs listed in Table 1 with polysaccharide compositionsas the main ingredients are: Yu-san-xiao, Yi-jin andShen-qi. These drugs contain panaxans, anemarans, dio-scorans, astragalus and poria cocos polysaccharides, etc.These polysaccharide containing herbs are found to havethe following medical virtues: (1) stimulate immune



glucose level in normal mice (Table 7) suggested thatthis herbal drug could not stimulate the pancreaticislets and beta cells to produce more insulin. Thehypoglycaemic effect might be due to its capacity torestore activity of pancreatic beta cells. Additionally,this herbal drug significantly reduced the concentrationof cholesterol, triglyceride and lactic acid in serum, sug-gesting that this agent is also useful for the com-plications of diabetes.

Li Xiangzhong et al. reported that Yi-jin was evalu-ated in 328 type II diabetic patients in a multicentreclinical trial in Northeast China, and 85.8% of thepatients treated with Yi-jin showed a clinical improve-ment (Li et al., 2000).

The acute toxicity of Yi-jin appeared to be very low,the maximum tolerance level being 384 g/kg, which wasabout 320 times the recommended human dosage. No

Table 2. Blood glucose and insulin levels of 12 patients treated with Yu-san-xiao

Blood glucose (mmol/L) Insulin (mU/L)

n = 12 FBG PBG (at 2 h) Before meal After meal (at 2 h)

Before treatment 9.7 ± 2.28 15.28 ± 3.16 8.6 ± 4.8 35.6 ± 13.99At 2-weeks during treatment 8.6 ± 3.16 12.13 ± 3.57 7.86 ± 4.57 40.17 ± 8.85At 4-weeks during treatment 6.58 ± 3.38 9.0 ± 1.24 14.0 ± 11.1 41.56 ± 12.59

significant long-term toxicity was observed with oraladministration of Yi-jin at 30, 15, 7.5 g/kg in 120 ratsfor 6 months, no significant changes were observed inthe body weight, blood, liver, kidney and other organs.Part of the pharmacological studies in various animalmodels is summarized in Tables 4–8.

Shen-qi

Yang Yingwu and Wang Chun reported the hypo-glycaemic efficacy of Shen-qi in a clinical study con-ducted at Ruzhou Hospital, in which 150 diabeticpatients were included (Yang and Wang, 2000). In thegroup with 150 patients treated with Shen-qi, bloodglucose levels were tested before a meal, and at 2 hafter the meal. Glucose levels in urine, cholesterol

Table 5. The effect of Yi-jin on blood glucose level in alloxan induced diabetic mice by multiple oral administration once a day, withphenformin (DBI) as positive control

Blood glucose (x ± s) (mg/dL)

DoseAfter

Group (g/kg) No. Before 1 wk 2 wk 4 wk

Control Water 17 365.4 ± 66.5 396.3 ± 71.9 422.1 ± 105.6 422.1 ± 100.8Yi-jin 30 16 375.8 ± 70.5 293.8 ± 103.0b 280.5 ± 139.4c 260.2 ± 138.8c

Yi-jin 20 16 371.1 ± 61.0 379.7 ± 66.0 404.7 ± 93.5 340.6 ± 76.6a

Yi-jin 10 15 370.0 ± 56.7 392.5 ± 106.3 410.0 ± 74.0 360.0 ± 101.2a

DBI 0.075 18 376.4 ± 79.8 347.2 ± 88.0a 308.3 ± 128.0b 263.2 ± 121.1c

a p < 0.05, b p < 0.01, c p < 0.001 compared with the control group.

Table 4. The effect of Yi-jin on blood glucose level in alloxan induced diabetic mice by single oral administration

Dose MiceBlood glucose (x ± s) (mg/dL)

Group (g/kg) no. Before After 2 h Change (%)

Control (water) – 15 358.46 ± 14.98 330.19 ± 85.68 −6.44Yi-jin 30 14 363.17 ± 77.46 245.55 ± 108.16a −33.49

a p < 0.01 compared with control.

Table 3. Blood glucose and insulin levels of 13 patients treated with Yu-san-xiao

Blood glucose (mmol/L) Insulin (mU/L)

n = 13 FBG PBG (at 2 h) Before meal After meal (at 2 h)

Before treatment 9.7 ± 1.86 15.19 ± 2.55 15.23 ± 9.4 27.5 ± 14.83At 2-weeks during treatment 7.1 ± 2.0 14.14 ± 1.0 data not available data not availableAt 4-weeks during treatment 7.4 ± 1.19 10.6 ± 0.92 17.28 ± 7.22 39.32 ± 20.25

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and triglyceride were also analysed quantitatively. Theclinical results are summarized in Table 9.

Despite the results indicating a significant dose-dependent blood sugar lowering activity, the hypogly-caemic mechanisms and pharmacology of these herbalextracts remains unknown. It was generally believed,however, by a number of investigators that the poly-saccharides in the herbal drugs may protect pancreaticislets and beta cells, help the regeneration of betacells, and therefore, increase the insulin secretionfrom pancreas (Wang et al., 2000; Zhang and Li, 2000;Hong, 2001). Typical polysaccharides in medicinalherbs that have been reported to have bloodsugarlowering activities are listed below (Wang et al., 2000).

Aconitan A, B, C, and D (from Aconitum carmichiDebeaux.)Abelmosan A, B, and C (from Abelmoschus manihot)Anemarans A, B, C, and D (from Anemarrhenaasphodeloides Bunge.)

Astragalus mongholicus polysaccharide GAtractan A, B, and C (from Atractylodes macrocephalaKoidz)Auricularia auricula polysaccharideCordyceps sinensis polysaccharidesDioscoran C and DEleutheran F and G (from Eleutherococus senticocus)Ephedran C (from Ephedra distachya)Ganoderan A and B (from Ganoderma lucidum)Hericium erinacaus polysaccharideLaminarinLithosperman A, B, and C (from Lithospermumerythrorhizon)Lycium barbarum polysaccharide D and XMoran A (from Morus alba)Ophipogon japonicus polysaccharidePanaxan A–U (from Panax ginseng C. A. Meyer))PestalotiopsisPorphyrayezoensis Ueda polysaccharidePoria cocos polysaccharide

Table 6. The blood glucose level vs time of alloxan diabetic mice treated with Yi-jin

Blood glucose (x ± s) mg/dL

DoseAfter

Group (g/kg) No. Before 1 h 2 h 8 h

Control Water 15 403.1 ± 72.5 411.0 ± 71.9 419.0 ± 71.1 241.8 ± 94.3Yi-jin 30 15 398.1 ± 80.5 365.2 ± 49.5a 325.09 ± 60.45b 184.4 ± 104.3b

a p < 0.05, b p < 0.001 compared with the control group.

Table 7. The effect of Yi-jin on blood glucose level in normal mice by single oral administration

Dose MiceBlood glucose (x ± s) mg/dL

Group (g/kg) no. Before After 2 h Change (%)

Control (water) – 8 104.9 ± 21.4 83.8 ± 27.6 −18.5Yi-jin 30 10 115.7 ± 25.4 92.8 ± 14.6 −18.6

Table 8. The improvement of lactic acid, cholesterol, triglyceride and beta-lipoprotein levels in alloxan diabetic rats after 1 monthtreatment with Yi-jin

DoseLactic acid Cholesterol (mmol/L) Triglyceride (mmol/L) β-lipoprotein (mmol/L)

Group (g/kg) No. Before After Before After Before After Before After

Control Water 9 47.75 ± 23.88 53.62 ± 21.18 2.25 ± 0.32 2.07 ± 0.31 0.92 ± 0.38 0.65 ± 0.26 3.02 ± 1.83 1.82 ± 0.63Yi-jin 20 9 52.20 ± 21.60 44.40 ± 20.28 2.28 ± 0.36 1.77 ± 0.29 0.92 ± 0.40 0.39 ± 0.22 2.47 ± 1.14 1.83 ± 0.87Yi-jin 10 9 48.55 ± 24.36 44.83 ± 12.91 2.14 ± 0.30 1.76 ± 0.29 0.85 ± 0.43 0.42 ± 0.29 1.94 ± 0.84 1.37 ± 0.45Yi-jin 5 9 44.92 ± 20.37 36.14 ± 9.66 2.22 ± 0.30 1.89 ± 0.25 0.81 ± 0.37 0.56 ± 0.24 2.56 ± 1.59 1.67 ± 0.67

Table 9. Changes of FBG, PBG and glucose in urine, total cholesterol and triglyceride after treatment with Shen-qi

Glucose in TotalFBG PBG urine cholesterol Triglyceride

n = 150 (mmol/L) (mmol/L) (g/24 h) (mmol/L) (mmol/L)

Before treatment 12.44 ± 3.34 15.53 ± 4.06 29.40 ± 10.30 7.49 ± 1.42 2.96 ± 0.95After treatment 8.98 ± 3.38a 11.50 ± 4.26a 15.10 ± 9.80a 5.84 ± 1.06a 1.53 ± 0.86a

a p < 0.01 compared with before treatment group.



Rhodiola sachalinensis polysaccharideTremella fuciformis polysaccharideTrichosan A, B, C, D and E (from Trichosanthesririlowii Maxim.)

DRUG COMPOSITIONS THAT IMPROVE THEMICROCIRCULATION

Many herbs and natural products have been found toregulate carbohydrate and fat metabolism and to im-prove the blood circulation and immunity, and there-fore, have the effect of lowering the blood glucose levelof diabetic patients. The following are typical naturalproducts that can improve the microcirculation (Long,1998): Achyranthes bidentata, Astragalus membranaceus,Atractylodes macrocephala, Carthamus tinctosius, Co-donopsis pilosula, Dioscorea opposita, Hirudo nipponia,Ligusticum, Opuntia dillenii, Panax ginseng, Rehmanniaglutinosa and Salvia miltiorrhiza.

These agents have been studied most extensively bymodern medical science, which not only validated mostof the traditional therapeutic claims but also discoveredmany important pharmacological effects (Xiao, 2002).For instance, Astragalus and Dioscorea have been underintensive medical research in China and in many coun-tries of the world as tonic restoratives for immune de-ficiency. Astragalus is present in most of the productslisted in Table 1. Astragalus root is found to strengthennonspecific immunity, significantly enhance the func-tion of T-lymphocytes, and to promote humoral im-munity. It can dilate peripheral, coronary, cerebral andintestinal vessels, and improve microcirculation. Theseherbs help to restore impaired immune functions, stimu-late secretions of vital immune factors, and to enhanceoverall immune response throughout the system.

Several drug products listed in Table 1, the composi-tions of which contain the above extracts, were devel-oped and approved for both type I and II diabetes.These drugs are Ke-le-nin, Qi-zhi and Xiao-ke-an. BothKe-le-nin and Xiao-ke-an contain an extract from

Hirudo nipponia (leech), a non-herbal ingredient. Themain ingredient of leech extract is hirudin, which canreadily inhibit the action of thrombin on fibrinogen,and hence has an anticoagulant effect. Both Ke-le-ninand Qi-zhi contain an extract from Rehmannia glutinosa,which is the root of the perennial herb, produced mainlyin Hunan, Hebei, Inner Mongolia and Northeast China.Dried Rehmannia root has been widely used for defi-ciency of body fluid, thirst, diabetes and constipation.Its decoction is believed to possess the effects ofprotecting the liver and preventing the decrease ofhepatic glycogen. The pharmacological studies of thesethree drugs are discussed as follows.

Ke-le-nin

Liu Yunling et al. reported that the clinical evaluationof Ke-le-nin with 30 type II diabetic patients showed asignificant hypoglycaemic effect (Liu and Li, 1996). Oraladministration of Ke-le-nin, four capsules, three timesa day, for 90 days lowered the blood glucose level (FBS)from 10.35 mmol/L to 7.54 mmol/L. Other analyses aresummarized in Table 10.

Qi-zhi

Xing Haiyan of Henan TCM College conducted phar-macological studies on several herbal drugs in alloxaninduced diabetic rats (Xing, 2000). Qi-zhi was found tolower the blood glucose levels in diabetic animals in a30 day trial. The chemical drug, phenformin (DBI), wasused as a positive control. The experimental results arepartially included in Table 11.

Xiao-ke-an

Xiao-ke-an contains extracts from two types ofmedicinal herbs, Astragalus mongholicus and Ophio-pogon japonicus Ker-Gawl, which mainly contain

Table 11. Hypoglycaemic effect of Qi-zhi on alloxan induced rats

FBG mmol/L FBG mmol/L FBG mmol/L FBG mmol/LGroup n at time 0 at 10 days at 20 days at 30 days

Normal 10 7.58 ± 1.07 7.14 ± 1.10 7.21 ± 1.19 7.02 ± 1.11Diabetic 10 20.62 ± 6.54 21.80 ± 6.19 23.87 ± 10.00 19.17 ± 9.41DBI 10 21.14 ± 4.47 9.70 ± 7.07 24.17 ± 10.75 16.72 ± 13.33Qi-zhi 10 20.92 ± 6.23 12.45 ± 7.52 15.96 ± 6.49 12.84 ± 4.14

Table 10. Comparison of various parameters before and after treatment with Ke-le-nin

Before treatment After treatment p value

FBG (mmol/L) 10.85 ± 3.11 17.54 ± 4.01 <0.05PBG (mmol/L) at 2 h 14.88 ± 3.28 10.36 ± 3.94 <0.01HBA1 (%) 9.96 ± 0.74 7.32 ± 0.87 <0.01Insulin (mU/L) 14.51 ± 6.47 13.98 ± 6.49 >0.05C peptide (nmol/L) 0.78 ± 0.22 0.77 ± 0.24 >0.05Triglyceride (mmol/L) 1.22 ± 0.81 1.20 ± 0.92 >0.05Cholesterol (mmol/L) 4.98 ± 1.27 4.87 ± 1.32 >0.05

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polysaccharides, and Pueraria lobata and Hirudo nipponia,which contain ingredients that can improve the micro-circulation (Ji, 2001). Pueraria lobata include puerain,the pharmacology of which has been extensively studied.Puerain can readily promote the blood circulation,and has been used to treat heart problems includingmyocardial ischaemia and infarction. Puerain alsoshowed a significant hypoglycaemic effect in alloxaninduced diabetic mice.

Yang Xiaofeng et al. investigated the pharmacologi-cal effect of Xiao-ke-an in animal models and reportedthat this agent was able to lower the blood glucoselevel in normal mice as well as streptozocin induceddiabetic mice (Yang et al., 1999). The study withnormal animals was conducted using four groups, a totalof 48 mice, for a 14 day test. The agent, Xiao-ke-an,was orally administered, and a chemical drug, glyburide,was used as control. Blood samples were collectedon the last day and analysed for blood sugar values.A 14 day study with a drug induced diabetic animalmodel was also conducted using 50 mice (22–24 g),and a chemical drug, phenformin, as control. Experi-mental data are given in Tables 12 and 13.

DRUG PRODUCTS THAT CAN REDUCEINSULIN RESISTANCE

Many type II diabetic patients have normal levels ofinsulin in the blood. The diabetes is not caused by thedestruction of beta cells in the pancreas but by othermechanisms, such as insulin resistance, related to down-regulation of insulin receptors, defects in insulin secre-tion from the pancreatic beta cells and other changesto the glucose transporter system. Jin-qi was reportedto have the pharmacological effect of restoring sensi-tivity to insulin and therefore, reducing insulin resist-ance (Cui, 2000). Jin-qi’s composition comprises extractsfrom honeysuckle flower, milkvetch root and coptis root.Honeysuckle flower is a vinelike shrub that grows to aheight of 6–9 m, with slender, prickly branches and

flowers that bloom white then turn yellow, hence theChinese name meaning ‘gold and silver flower’. Theflower, stem and leaves contain inositol, saponin andtannin. Honeysuckle flower is routinely used for detoxica-tion and thirst. Coptis root is a perennial herb withlong trifoliated leaves, small yellowish white flowersand a reddish brown root covered with fine rootlets.This plant is cultivated throughout China and also inparts of northern India. The root is yellowish orangeon the inside, the inner pith being deeper in colour,and contains berberine, alkaloids coptisine, palmatine,jatrorrhizine and magnoflorine, etc. Among theseingredients, berberine is the most popular and well-characterized compound with demonstrated antidiabeticeffects (Xiao, 2002).

Pharmacological studies with Jin-qi were performedusing genetically diabetic KK mice (female, 20–22 g)and hydrocortisone (HC) induced diabetic mice (Shenet al., 1997). Both groups were insulin-resistant andduring the experiment, were given Jin-qi daily, and wereinjected with insulin at 23 and 9 days, respectively.Table 14 and Figs 1 and 2 summarize the experimentalresults, showing that Jin-qi was able to reduce the insulinresistance in the two animal models. The blood glucoselevels in the Jin-qi group were higher than those in thenormal control groups, upon i.p. injection of insulin, butsignificantly lower than those in diabetic groups whichwere insulin-resistant. The serum insulin concentrationin Jin-qi treated KK mice was 12.1 ± 5.5 mU/L, com-pared with 21.4 ± 14.9 mU/L in the KK mice control.

A single-blinded, randomized, multicentre clinicalinvestigation of Jin-qi was conducted in 1993 atfour major hospitals in Beijing, in which a total of442 patients with type II diabetes participated. Theclinical dosage was 7–10 pills (0.42 g/pill) of Jin-qi, perdose, and three doses per day (Cui, 2000). A differentantidiabetic herbal drug was used, at eight pills perdose, and three doses per day, as a control. Combineddrug treatment using Jin-qi and chemical hypogly-caemic agents was also used to evaluate the synergisticeffect of chemical – herbal therapeutic drugs. Theclinical results are shown in Table 15.

Table 12. Blood glucose lowering effect on normal mice treated with Xiao-ke-an

Group Dosage (g/kg) No. mice/group Blood glucose (mmol/L)

Blank – 12 8.21 ± 0.70Glyburide 0.05 12 6.47 ± 1.38a

Xiao-ke-an high dose 10 12 4.69 ± 1.47a

Xiao-ke-an low dose 5 12 6.00 ± 1.59a

a p < 0.01 compared with control blank.

Table 13. Blood glucose lowering effect on streptozocin induced diabetic model mice

Group Dosage (g/kg) No. mice/group Blood sugar (mmol/L)

Blank – 10 8.18 ± 1.90Diabetic model – 10 29.88 ± 7.09Phenformin 0.05 10 15.31 ± 5.90a

Xiao-ke-an high dose 10 10 19.56 ± 4.34a

Xiao-ke-an low dose 5 10 21.09 ± 6.53a

a p < 0.01, compared with diabetic model.



Table 14. Experimental method using genetically diabetic KK mice or hydrocortisone induced diabetic mice

Group Mice No. Duration Insulin injection (i.p.) at 0.5 U/kg

Control (normal) SWR/J 10 22 d or 9 d Measure glucose level at 0, 30, 120 minModel mice KK or HC 10 22 d or 9 d As aboveJin-qi group KK or HC 10 22 d or 9 d As above

pharmacological studies in China. Due to the differentpharmacological roles of those hydro-alcohol extracts,the hypoglycaemic mechanism of drug products contain-ing a mixture of those extracts becomes complicated.The authors speculated that polysaccharide-containingagents restored the functions of pancreatic tissues andcaused an increase in insulin output by the functionalbeta cells. Others attributed the hypoglycaemic effectof many products to their ability to inhibit the intestinalabsorption of glucose, to the increased availability ofinsulin, or to the facilitation of metabolites in insulin-dependent processes. However, none of the investiga-tors was able to provide conclusive evidence to ascertainthe actual hypoglycaemic mechanism(s) of a singleherbal drug developed in China.

This paper reviews the compositions, pharmacologi-cal and clinical effects of seven antidiabetic herbal drugscommercially available in China. Combination formu-las, i.e. mixtures of certain herbal extracts, were used inall the drug products, and each product possessedsignificant dose-dependent blood glucose loweringactivity in various animal models as well as in humans.These alterations will further lead to a decrease inatherosclerosis. The difference between a single-herbformula and a multi-herb combination formula is notmerely the addition of more herbs, but also the interac-tion between the components of mixtures of herbs. Asystem of synergistic interactions among herbal drugsis formed in a combination formula which is believedto take a multi-targeted therapeutic approach in thetreatment.

The treatment of diabetic patients with naturallyderived agents has the advantage that it does not causethe significant side effects as do chemical agents suchas sulfonylurea. One of the side effects with sulfonylureais that it causes a decreased amount of insulin produc-tion by putting too great a strain on the insulin produc-ing beta cells. Treatment with herbal drugs has an effectof protecting beta cells and smoothing out fluctuations

Table 15. Clinical blood glucose lowering effect with Jin-qi

PatientAvg. blood glucose (mg/dL)

Group no. Before After Change (%)

Jin-qi 120 Before meal 195.5 147.4 −24.5After meal 292.2 219.1 −25.0

Controla 35 Before meal 184.9 173.9 −6.0After meal 268.6 233.2 −13.2

Combined 216 Before meal 206.0 168.6 −18.2(Jin-qi + chemical drugsb) After meal 291.7 251.4 −13.8Control ∆ 71 Before meal 198.7 172.6 −13.1

After meal 275.1 258.4 −9.8

a A herbal antidiabetic drug (the name of which was not given in the report) was used in two control groups.b Names of chemical drugs used in this group were not available in the report.

Figure 1. The effect of Jin-qi on the insulin-tolerance level of KKmice. �, normal control group; �, KK model mice; �, KK micetreated with Jin-qi.

Figure 2. The effect of Jin-qi on the insulin-tolerance level ofHC diabetic mice. �, normal control group; �, HC model mice;�, HC model mice treated with Jin-qi.

DISCUSSION

There are several review articles (Liu and Lu, 2000; Li,2000; Jiang and Li, 2001) published in various Chinesejournals discussing traditional antidiabetic agents and

1134 W. JIA ET AL.


in glucose levels. Some agents, such as Jin-qi, can reducethe insulin resistance and, hence, improve the apparentinsulin activity. Improved insulin activity leads to de-creased circulating insulin, which leads to lower bloodglucose and glycosylated haemoglobin levels as well astotal cholesterol, LDL-cholesterol and triglyceridelevels, and increased HDL-cholesterol levels. Addition-ally, the use of these natural agents in conjunction withconventional drug treatments such as a chemical agentor insulin permits the use of lower doses of the drug

and/or decreased frequency of administration whichdecreases the side effects most commonly observed. Itwas also widely observed during the clinical studies inChina that the mixtures of herbal extracts could lowerthe cholesterol and triglyceride levels, in addition tothe blood glucose level. This suggests that the long-term use of herbal drugs may be advantageous overchemical drugs in alleviating some chronic diseases andcomplications caused by diabetes, while adverse effectsof these herbal extracts are minimal.

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Antidiabetic herbal drugs ofﬁcially approved in China

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