Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 747982, 14 pages http://dx.doi.org/10.1155/2015/747982

Review Article Ancient Records and Modern Research on the Mechanisms of Chinese Herbal Medicines in the Treatment of Diabetes Mellitus

Hai-ming Zhang,1 Feng-xia Liang,2 and Rui Chen1

1 Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Street, Wuhan, Hubei 430022, China 2 Department of Acupuncture and Moxibustion, Hubei University of Traditional Chinese Medicine, No.1TanhualinStreet,Wuhan,Hubei430060,China

Correspondence should be addressed to Feng-xia Liang; [email protected] and Rui Chen; [email protected]

Received 15 March 2014; Accepted 25 June 2014

Academic Editor: Srinivas Nammi

Copyright © 2015 Hai-ming Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Over the past decades, Chinese herbal medicines (CHM) have been extensively and intensively studied through from both clinical and experimental perspectives and CHM have been proved to be effective in the treatment of diabetes mellitus (DM). This study, by searching ancient records and modern research papers, reviewed CHM in terms of their clinical application and principal mechanism in the treatment of DM. We summarized the use of CHM mentioned in 54 famous ancient materia medica monographs and searched papers on the hypoglycemic effect of several representative CHM. Main mechanisms and limitations of CHM and further research direction for DM were discussed. On the basis of the study, we were led to conclude that TCM, as a main form of complementary and alternative medicine (CAM), was well recorded in ancient literatures and has less adverse effects as shown by modern studies. The mechanisms of CHM treatment of DM are complex, multilink, and multitarget, so we should find main hypoglycemic mechanism through doing research on CHM monomer active constituents. Many CHM monomer constituents possess noteworthy hypoglycemic effects. Therefore, developing a novel natural product for DM and its complications is of much significance. It is strongly significant to pay close attention to CHM for treatment of DM and its complications.

1. Introduction Complementary and alternative medicine (CAM) have been extensively used in modern times. TCM, as a main form Diabetes mellitus (DM), including type 1 and type 2, has ofCAM,hasbeenprovedtobeeffectiveforthetreatment become epidemic worldwide [1–3], and its incidence has been of DM with relatively less side effects in China and beyond on rise year by year [4]. Previous reports have demonstrated [10, 11]. Some hypoglycemic drugs of plant origin have been that overweight, especially obesity at younger ages, substan- approved for clinical use by the regulatory authorities in tially increases the risk for DM [1, 5–8]. The finding is consis- China, such as Yusanxiao, Yijin,andKelening,amongothers tent with the description in the “Medical Classic of the Yellow [12]. Emperor,” the earliest monumental work on the traditional The mechanisms of Chinese herbal medicines (CHM) in Chinese medicine (TCM) dating back to the Warring States the treatment of DM have been extensively and intensively Period (about 446 B.C.−221 B.C.). DM increases the risk studied from biological, immunological, and phytochemical for micro- and macrovascular complications and premature perspectives and great advances have been made in the death and poses tremendous socioeconomic burden [2, 4, 9]. past decades. This paper reviewed records or descriptions In spite of the introduction of insulin and other hypoglycemic concerning the use of CHM for treatment of DM in ancient agents,sofar,notreatmentprotocolscanachieveacomplete Chinese literatures (before 1920 A.D.) and the modern papers cure. Moreover, the side effects of these drugs, which are on the mechanisms of CHM treating DM. We also compared substantial and inevitable, present another challenge. the CHM used in ancient and modern times, examined the 2 Evidence-Based Complementary and Alternative Medicine

Table 1: A similar comparison of the symptoms of “Xiao Ke”andDM.

Symptoms of “Xiao Ke”inZhuBingYuanHouLuna Symptoms of DM in Textbook of Internal Medicine [22] Polydipsia; dry mouth and lips; polyphagia; hunger; emptiness of the stomach; frequent urination; polyuria; Polydipsia; thirst; polyphagia; hunger; polyuria; General glucosuria; emaciation; adiposity; fatigue of limbs; marasmus; obesity; sweet taste of urine; itchy skin; symptoms mental fatigue; feverish dysphoria; itchy skin; vulva pruritus; fatigue; lightheadedness. hyperhidrosis; dizziness; sweet feeling in the mouth. Carbuncle and soreness; night blindness; internal Carbuncle and furuncle; diabetic retinopathy; oculopathy; lung tuberculosis; edema; precordial pain; pulmonary tuberculosis; diabetic cardiomyopathy; pectoral stuffiness pain; apoplexy; coma; impotence; diabetic ketoacidosis; diabetic impotence; glaucoma; foot carbuncle-abscess; unsmooth defecation; diarrhea; Complications diabetic nephropathy; atherosclerosis; cerebral anorexia; short breath; waist soreness; dizziness and ischemic stroke; diabetic foot; constipation; diarrhea; tinnitus; pachylosis; whitish and turbid urine; muscle myophagism; paralysis; oliguria; hyperhidrosis; atrophy of the lower extremities; oliguria; nightly hypohidrosis or anhidrosis; diabetic gastroparesis. sweating; coolness of extremities. aThe “Zhu Bing Yuan Hou Lun”: a book describing causes and manifestations of diseases by Yuanfang Chao, a famous TCM doctor born about AD 550and died in 630 A.D. in the Sui Dynasty. limitations of CHM for treating DM, and discussed the future ancient people believe to be able to make them achieve research trend. longevity.

2. Ancient Records on Treatment of 2.1.3. Symptoms. Thesymptomscanbecategorizedintotwo groups: general symptoms and complications. The general DM with TCM symptoms include polydipsia, polyphagia, polyuria, gluco- suria, emaciation, dry mouth, hunger, emptiness of the Our search of literatures of TCM (before 1920 A.D. or earlier) stomach, and frequent urination. And complications include failed to find the term “DM.” We found a plenty of records diabetic foot, diabetic retinopathy, lung tuberculosis, dia- or descriptions about “Xiao Ke,” which, in terms of epi- betic impotence, and diabetic nephropathy. Obviously, those demiology, symptoms, etiology, pathogenesis, and treatment, symptoms and complications are extremely similar to DM, as mimicked those of DM. And it is generally accepted that shown in Table 1. “Xiao Ke” mentioned in ancient Chinese literature is similar to DM of modern medicine [13]. On basis of this assumption, in this paper, we used DM interchangeably with “Xiao Ke” 2.1.4. Etiology and Pathogenesis. According to the theory for the convenience of discussion though they are not strictly of TCM, the symptoms are essentially caused by “Yin Xu” equivalents in a number of ways. (Yin deficiency) and “Zao Re” (dryness heat). In TCM there is a belief that Yin deficiency is the “Ben” (origin or root cause)anddrynessheatisthe“Biao” (symptoms or external 2.1. Terminology, Epidemiology, Symptoms, Etiology, and manifestations). The Ben or root causes involve the invasion Pathogenesis of “Xiao Ke” of exogenous pathogens, innate deficiency, intemperance in eating, abnormal emotional states (anger, anxiety, depression, 2.1.1. Name. In TCM, “Xiao Ke” refers to a cluster of clinical distress, panic, and fear), excessive physical strains (mental or symptoms, including polydipsia, polyphagia, polyuria, ema- physical exertion and sexual intercourse), or propensity for ciation, glucosuria, and fatigue. As aforementioned, “Xiao abusing Dan medicines [11]. Yin and Yang are two opposing Ke” is a general term for a condition that resembles DM in aspects of things. For instance, cold, moist, night, structure, terms of symptoms. DM classically was divided into three and downward mobility belong to Yin while heat, dryness, types: upper, middle, and lower “Xiao Ke.” Th e upp e r t y p e day, function, and upward mobility belong to Yang [14]. (Shang Xiao) is characterized by excessive thirst, the middle type (Zhong Xiao) by excessive hunger, and the lower type 2.2. Treatment. We searched for the term “Xiao Ke”in (Xia Xiao)byexcessiveurination[13]. By searching “Xiao Ke,” more than 1,000 TCM ebooks included in Encyclopedia of weretrievedalargenumberofrecordsconcerning“Xiao Ke” TCM (Compact Disk, ISBN: 7-900377-49-2/R⋅8), published in ancient TCM literatures. by Hunan Electronic and Audiovisual Publishing House. The database contained, among others, “Bencao Gangmu 2.1.2. Epidemiology. The earliest mention of “Xiao Ke”was (Compendium of Materia Medica)”, Puji fang, and so forth. in the “Medical Classic of the Yellow Emperor.” The book described that the “Xiao Ke”wasmostlyfoundinwealthy, 2.2.1. CHM. Wealso searched the database for Chinese crude obese individuals who liked food rich in oil or fat and in drugs for treating “Xiao Ke.” The database contained only influential officials who were on pillsDan, or“ ”asitwas 54 monographs on Chinese materia medica. Most CHM termed in the book, a mineral-based synthetic drug, which treated “Xiao Ke”by“Qing Re”(clearingheat)(Figure 1), Evidence-Based Complementary and Alternative Medicine 3

30 30 25 25 20 20 15 15 10 10 Frequency Frequency 5 5 0 0 abcdef ghi jklmnopqrs t abcdef ghi jklmnopqrs t

CHM CHM

Figure 1: Frequency of heat-clearing (Qing Re)drugsfor“Xiao Ke” Figure 2: Frequency of Yin-nourishing (Yang Yin) and energy- mentioned in 54 monographs on Chinese materia medica. Heat- replenishing (Yi Qi)drugsfor“Xiao Ke” mentioned in 54 mono- clearing drugs are of Liang (cold or cool) or bitter taste. a: Pueraria graphs on Chinese materia medica. Yin-nourishing and energy- lobata (Willd.) Ohwi; b: Trichosanthes kirilowii Maxim.; c: Fructus et replenishing drugsare of sweetish taste and are of cold (Liang) semen trichosanthis kirilowii;d:Lemna minor L.; e: Gypsum fibrosum; nature. a: Lycium barbarum L.; b: Tussilago farfara L.; c: Poria f: Alisma orientale (Sam.) Juz.; g: Coptis chinensis Franch.; h: cocos (Schw.) Wolf; d: Panax ginseng C. A. Mey.; e: Eleocharis Anemarrhena asphodeloides Bunge; i: Lophatherum gracile Brongn.; dulcis (Burm.f.) Trin. ex Hensch.; f: Morus alba L.; g: Adenophora j: Succus bambusae (Recens); k: Arctium lappa L.; l: Phragmites trachelioides Maxim.; h: Cannabis sativa L.; i: Ophiopogon japon- australis (Cav.) Trin. ex Steud.; m: Benincasa hispida (Thunb.) Cogn.; icus (Thunb.) Ker Gawl.; j: Armeniaca mume Siebold; k: Aspara- n: Phaseolus calcaratus Roxb.; o: Scutellaria baicalensis Georgi; p: gus cochinchinensis (Lour.) Merr.; l: Cuscuta chinensis Lam.; m: Solanum lyratum Thunb.; q: Vitex negundo var. cannabifolia (Siebold Achyranthes bidentata Blume; n: Coix lacryma-jobi L.;o:Astragalus and Zucc.) Hand.-Mazz.; r: Phellodendron chinense C. K. Schneid.; membranaceus (Fisch.) Bunge; p: Polygonatum odoratum (Mill.) s: Gardenia jasminoides J. Ellis; t: Lycium chinense Mill. Druce; q: Rhus chinensis Mill.; r: Schisandra chinensis (Turcz.) Baill.; s: Lilium lancifolium Thunb.; t: Rehmannia glutinosa Steud.

“Yang Yin”(nourishingYin), and “Yi Qi”(replenishingvital 20 energy) (Figure 2).TheLatinnamesofCHMusedinthe paper were from the website http://www.theplantlist.org/ or 15 http://www.wikipedia.org/. 10

2.2.2. Foods. Besides, the monographs also mentioned some Frequency 5 foods that help treat “Xiao Ke”inFigure 3. 0 abcdef ghi jklmnopqrs t

3. Mechanisms by Which CHM Work on DM Food and Its Complications Figure 3: Frequency of meat, grains, fishes, and other food that help We searched the databases of PubMed, Web of Science, treat “Xiao Ke” mentioned in 54 monographs on Chinese materia MEDLINE, and CNKI and found that less research attention medica. a: chicken; b: millet; c: barley; d: bamboo shoot; e: cony was paid to Chinese herbal compounds while most studies meat; f: Benincasa hispida; g: watershield leaf; h: mud eel; i: radish; focusedonasingleherbalmedicine. j:foxtailmilletseed;k:snail;l:cow’smilk;m:goosemeat;n:Charr; The mechanisms of CHM in the treatment of DM have o: long surf clam; p: wheat; q: mung bean; r: Gallus black-bone silky been extensively and intensively studied from biological, fowl;s:hairychestnutseed;t:giantgecko. immunological, and phytochemical perspectives (Tables 2, 3, and 4). become drugs for the treatment of DM by further exploring 4. Results their hypoglycemic effects. We also found that some foods were used for treatment of DM in ancient times, and their We found more than 40 CHM with hypoglycemic effect hypoglycemic effects have been confirmed nowadays [15, 16]. in ancient works and reviewed the mechanism of CHM The mechanisms by which CHM treat diabetes include lowering blood sugar. We were led to conclude that a number the following: (1) CHM increase insulin sensitivity and of CHM, including Panax ginseng C. A. Mey., Astragalus ameliorate insulin resistance; (2) CHM promote insulin membranaceus (Fisch.) Bunge, and Lonicera japonica Thunb., secretion and elevate serum insulin levels; (3) CHM inhibit were used in ancient times and also nowadays. In addition, 𝛼-glucosidase activity; (4) CHM protect islet 𝛽 cells and pro- some CHM used for treating DM in ancient works have not mote their regeneration; (5) CHM increase hepatic glycogen been studied for hypoglycemic effect in modern times, such content and suppress gluconeogenesis; (6) CHM inhibit the as Lemna minor L., Gardenia jasminoides J. Ellis, Eleocharis secretion of glucagon; (7) CHM promote the glucose uptake dulcis (Burm.f.) Trin. ex Hensch., and Achyranthes bidentata by adipose and muscular tissues (Figure 4). Mechanisms of Blume (Figures 1 and 2). These CHM may have potential to CHM treating diabetic complications include the following: 4 Evidence-Based Complementary and Alternative Medicine ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 31 41 33 32 35 23 25 39 27 38 24 29 30 36 26 34 42 37 28 40 [ [ [ g/mL 𝜇 ND 200 < ). YES, Yi Qi IIAI NO [ IIAI ND [ IIAI ND [ IIAI ND [ IIAI ND IIAIIIAI ND ND [ [ PIEI ND [ PIEI ND [ PIEI ND [ PIPR ND [ PIPR ND [ BLIR ND [ BLIR ND [ BLIR ND [ IHSG COSR ND [ RAAR ND [ Mechanisms Toxic effect References PIEI, PIPR, PRGU ND [ IIAI, IHSG, PRGU ND ) and benefiting vital energy ( mol g/mL 𝜇 𝜇 range 0.01 50 mg/Kg 700 mg/Kg 700 mg/Kg 200 mg/Kg 0.5, 5 Yang Yin 1, 5, 10 mg/Kg 75, 300 mg/Kg ( Effective doses/doses Yin Human umbilical vein endothelial cells Sprague-Dawley (SD) rats C2C12 cells 0.05–0.2 mg/mL SD rats 1, 5 mg/Kg Models BABL/c mice 100, 200 mg/Kg Goto-Kakizaki rats, Wistar rats 3T3-L1 adipocytes, Min6 cells, human embryo kidney 293 cells, C57BL/KsJ-db/db mice, C57BL/6J mice Wistar ratsKun Ming miceSD rats 4.5 g/Kg 4 mg/Kg 200 mg/Kg KKAy mice, C57BL/6J mice KKAy mice, C57BL/6J mice Ob/ob miceC57BL/6J mice 300 mg/Kg 100, 400 mg/Kg SD rats islet 0.1–1 mg/mL KK/HIJ mice 300 mg/Kg WistarratsWistar ratsSD rats 50,100mg/Kg 1 mg/Kg 20 mg/Kg BALB/c mice, SD rats 200, 400 mg/Kg Wistarrats 100,200mg/Kg In vivo In vitro In vitro In vivo In vivo/ in vitro In vivo In vitro In vivo In vivo In vivo In vivo In vivo In vivo In vivo In vitro In vivo In vivo In vivo In vivo In vivo In vivo In vivo In vivo Astragaloside IV Calycosin Polysaccharide Aqueous extract Polysaccharose Dehydrotumulosic acid, dehydrotrametenolic acid, pachymic acid, triterpenes Crude polysaccharide, water extract Decocted water Extracts or monomers Malonyl ginsenosides Ginsenoside Rh2 Polysaccharide Polysaccharide Ginsenoside Ginsenoside Re Polysaccharide Polysaccharide Polysaccharide Crude extract solid-state fermented mycelium Schisandraceae Lignan Liliaceae Leguminosae Clavicipitaceae Table 2: Main mechanisms of CHM treating DM and its complications by nourishing L. Dioscoreaceae Wall. Araliaceae Panax notoginoside (Turcz.) Lour. Liliaceae C. A. Mey. Araliaceae (Schw.) Wolf Polyporaceae Latin nameLiriope spicata Ophiopogon japonicus (Thunb.) KerGawl. Family Astragalus membranaceus (Fisch.) Bunge Panax ginseng Panax pseudoginseng Poria cocos Dioscorea oppositifolia Schisandra chinensis Ophiocordyceps sinensis (Berk.) G. H. Sung, J. M.Hywel-Jones, Sung, and Spatafora Baill. Evidence-Based Complementary and Alternative Medicine 5 ] ] ] ] ] ] ] ] ] ] ] ] 51 52 39 39 43 45 47 50 49 48 46 44 [ [ [ -glucosidase activity; PIPR: CHM protect 𝛼 PIEI ND [ IHSG ND [ INGA ND COSR ND RAARRAAR ND ND [ [ glucagon; PRGU: CHM promote the glucose uptake PIPR, PIEI ND [ Mechanisms Toxic effect References PIPR, COSR NO COSR, BLIR NO [ COSR, INGA NO [ PIEI, PIPR, IHSG YES, cytotoxicity [ INSG, IHSG, PIEI ND [ r inhibiting nitric oxide synthesis; RAAR: CHM regulate the GA: CHM inhibit L 𝜇 mol 𝜇 g/ 𝜇 g/mL g/mL g/mL g/mL 𝜇 𝜇 𝜇 𝜇 range 1000 mg/Kg 0–25 125, 250, 500, 0–200 5, 125, 250 50, 100, 200 mg/Kg Effective doses/doses cell 𝛽 -Glucosidase 1.2–2.1 Wistarratislets 25–100 𝛼 Mouse splenocytes, Jurkat cell, MCF-7 cells THP-1 cells 100, 300, 500 Models Kun Ming miceKun Ming mice 1.8 g/Kg 4.5 g/Kg BALB/c mice,Albino Swiss mice 200, 500 mg/Kg 50, 100, 200 mg/Kg BRIN-BD11 cells, H4IIE cells Kun Ming mice, SD rats Wistar rats 20 mg/Kg Rat pancreatic Wistar rats 0.1 mg/Kg SD rats 500 mg/Kg derived cell line, INS-1 NIH mice, SD rats Table 2: Continued. In vitro In vitro In vitro In vitro In vivo/ in vitro In vivo In vivo In vivo In vivo In vivo In vivo In vitro In vivo In vivo In vivo In vitro Catalpol Flavonoid, saponin Catalpol Extracts or monomers Methanol extract Total flavonoids Atractylenolide, amino acid Saccharides, amino acid Proanthocyanidins Cornaceae Liliaceae Compositae Campanulaceae PunicaceaePunicaceae Water extract Polyporaceae Polysaccharide Polysaccharides Scrophulariaceae L. Araliaceae Ginsenoside Siebold cells and promote their regeneration; IHSG: CHM increase hepatic glycogen content and suppress gluconeogenesis; INSG: CHM inhibit the secretion of 𝛽 and Zucc Latin nameCornus Officinalis Polygonatum odoratum Family (Mill.) Druce Atractylodes macrocephala Koidz. Codonopsis pilosula (Franch.) Nannf. Panax quinquefolius Rehmannia glutinosa Steud. Dendrobium moniliforme (L.) Sw. Dendrobium chrysotoxum Lindl. Ganoderma lucidum (Leyss. ex Fr.) Karst IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; IN islet by adipose and muscular tissues.activity COSR: of CHM aldose control reductase; oxidative BLIR: stress CHM response, block such inflammatory as response. NO scavenging means oxygennot radicals, toxic. preventing lipid ND means peroxidation, o data no available. meansYES toxic. 6 Evidence-Based Complementary and Alternative Medicine ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 61 55 57 39 59 63 65 62 56 67 54 60 66 64 53 58 [ [ PIEI, PRGU ND PRGU, INGA ND ). Qing Re g/mL PIEI NO [ 𝜇 mol IHSG NO [ mol PIPR, COSR ND [ g/mL 𝜇 𝜇 𝜇 2g/Kg IIAI ND [ 2.3 g/Kg INGA, RAAR ND [ 100 60 mg/Kg IIAI ND [ 40 mg/Kg COSR ND [ 1–20 150 mg/Kg IHSG, PIPR ND [ 150 mg/Kg COSR ND [ 150 mg/Kg IIAI ND [ 0.01 5, 10 mg/Kg 0.01–1 mg/mL, 150, 300 mg/Kg PIPR, IHSG, PRGU ND [ 100, 200 mg/Kg IIAI ND [ 200, 400 mg/Kg 200, 400 mg/Kg IHSG ND [ 0.01–0.125 Powder 5% in rat food BLIR ND [ Effective doses/doses range Mechanisms Toxic effect References cells 𝛽 Albino rats Human HepG2 cells, HUVECs Wistar rats Intestinal brush border membrane vesicles, rat hepatoma cell line H4IIE, humanskinfibroblastscell line Hs68, mouse adipocytes 3T3-L1 ICR mice C57BL/6J mice 3T3-L1 adipocytes, C2C12 cells MIN6 Models Newborn Wistar rats Wistar rats Db/db mice Wistar rats Albino Wistar rats Albino Wistar rats SD rats C57BL/6J mice Kun Ming mice Wistar rats islets In vivo In vitro In vivo In vitro In vitro In vivo In vivo In vitro In vivo/ in vitro In vivo In vivo In vivo In vitro In vivo In vivo In vivo In vivo In vivo In vivo Table 3: Main mechanisms of CHM treating DM and its complications by clearing heat ( Fenugreek seeds powder Trigonelline Paeonoside, apiopaeonoside, 6- methoxypaeoniflori- genone Polysaccharide-2b Saponins, momordicine II, kuguaglycoside Aqueous extract Ethanolic extract 1-Deoxynojirimycin, polysaccharide Puerarin Hydroalcoholic extract Geniposide Extracts or monomers Paeonol Saponin fraction, lipid fraction Puerarin Daidzein Protein extract Moraceae Leguminosae Rubiaceae Family Paeoniaceae Cucurbitaceae Leguminosae J. L. L. (Willd.) L. Ellis Latin name Paeonia x suffruticosa Andrews Morus alba Momordica charantia Pueraria lobata Ohwi Trigonella foenum-graecum Gardenia jasminoides Evidence-Based Complementary and Alternative Medicine 7 ] ] ] ] ] ] ] ] ] ] ] ] 75 74 72 39 39 77 68 71 73 76 70 69 [ [ [ [ [ [ IIAI ND PIEI ND IIAI ND INGA ND PRGU ND PIEI, INGA ND g/mL mol/L COSR ND [ 𝜇 g/mL 𝜇 g/mL 𝜇 mol/L 𝜇 𝜇 1.8 g/Kg INGA ND [ 2.3 g/Kg RAAR ND [ 5 5mg/Kg 3 80 mg/Kg 108 mg/Kg 100 mg/Kg 380 mg/Kg 200 mg/Kg BLIR ND [ 0.41 0.032 mg/mL 25, 50 mg/Kg 12.5, 25 0.1–100 369, 501 mg/Kg PIPR, COSR ND [ 100, 200 mg/Kg PIPR, COSR ND [ 2.5, 10, 40 mg/L 400, 800 mg/Kg 125, 500, 250 mg/Kg, Effective doses/doses range Mechanisms Toxic effect References db mice /Lepr ob db /Lep ob B6. V- Lep Homozygous C57BL/Ks db/db mice mice, Rat insulinoma cell line, INS-1 cells SD rats ventricular myocytes Models Wistar rats, Beagle dogs Kun Ming mice Kun Ming mice 3T3-L1 adipocytes Wistar rats L6 rat skeletal muscle cells Wister rats Caco-2 cells Wistar rats 3T3-L1 cells, L6 cells C57BLKS/J-Lepr Wistar rats SD rats ICR mice HIT-T15 cell line Table 3: Continued. In vivo In vivo In vivo In vivo In vitro In vitro In vitro In vivo/ in vitro In vivo In vivo In vitro In vivo In vitro In vitro In vivo In vivo In vivo In vivo In vitro Crude ethanol extract Timosaponin, anemaran Chlorogenic acid, ginnol Extracts or monomers Cinchonain-Ib Total saponins Berberine chloride form Flavonoids, triterpenoids Berberine Berberine Ethyl acetate fraction Berberine Araceae Liliaceae Caprifoliaceae Family Rosaceae Ranunculaceae Rosaceae L. Emodin Bunge Thunb. Franch. L. Bunge Latin name Rheum palmatum Acorus calamus Eriobotrya japonica (Thunb.) Lindl. Anemarrhena asphodeloides Lonicera japonica Coptis chinensis Potentilla discolor 8 Evidence-Based Complementary and Alternative Medicine ] ] ] ] 78 79 81 80 [ [ -glucosidase activity; PIPR: CHM protect 𝛼 INGA ND IHSG, PRGU ND glucagon; PRGU: CHM promote the glucose uptake r inhibiting nitric oxide synthesis; RAAR: CHM regulate the GA: CHM inhibit g/mL g/mL 𝜇 𝜇 0.1–3 0.5–32 60, 120 mg/Kg COSR, BLIR ND [ 200, 25 mg/Kg 100–500 mg/Kg 0.3%, 0.9%, 2.7% gum IIAI, IHSG ND [ Effective doses/doses range Mechanisms Toxic effect References mice ob /Lep ob -glucosidase Table 3: Continued. Models SD rats Zucker diabetic fatty rats, Zucker lean rats C57BL/6J mice, B6. V-Lep 𝛼 L6 myotubes Wistar rats In vivo In vivo/ in vitro In vivo In vitro In vivo In vitro In vivo Artemisia sphaerocephala Krasch. gum Extracts or monomers Oxymatrine Methanolic extract Arctigenin Compositae Family Leguminosae Punicaceae Compositae Aiton L. Krasch. L. cells and promote their regeneration; IHSG: CHM increase hepatic glycogen content and suppress gluconeogenesis; INSG: CHM inhibit the secretion of 𝛽 Latin name Artemisia sphaerocephala Sophora flavescens Punica granatum Arctium lappa IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; IN islet by adipose and muscular tissues.activity COSR: of CHM aldose control reductase; oxidative BLIR: stress CHM response, block such inflammatory as response. NO scavenging means oxygennot radicals, toxic. preventing lipid ND means peroxidation, o data no available. meansYES toxic. Evidence-Based Complementary and Alternative Medicine 9 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 93 39 82 39 39 92 88 89 86 84 90 91 83 85 87 [ [ [ [ g/mL 𝜇 NO 200 < -glucosidase activity; PIPR: CHM protect 𝛼 PIEI ND PIEI ND PIPR ND [ IHSG ND [ INGA ND COSR ND [ COSR ND [ COSR ND [ COSRCOSR ND ND [ [ COSR ND [ PRGU NO [ PRGU, IIAI ND [ Mechanisms Toxic effect References PIPR, COSR glucagon; PRGU: CHM promote the glucose uptake PIPR, COSR, IHSG ND [ r inhibiting nitric oxide synthesis; RAAR: CHM regulate the GA: CHM inhibit (activating blood circulation and easing congestion). g/mL g/mL g/mL 𝜇 𝜇 𝜇 g/mL 𝜇 1.87 g/Kg 10 300 mg/Kg 300 mg/Kg 50–150 Long term study, Huo Xue Hua Yu Short term study, 100, 200, )or Yang (tonifying C57BL/KsJ-db/db mice Caco-2 cells 0.03–4 mg/mL Models Effective doses/doses range HMEC-1 cells, human microvascular endothelial cells HIT-T15 cells, human pancreatic islets 3T3-L1 adipocytesICR mice, 0.02–0.5 mg/mL Kun Ming miceKun Ming mice 10,Kun 30 Ming mg/Kg mice 1.4 g/Kg ICR mice 700 mg/Kg 1.4Db/db g/Kg mice 1.2 g/Kg 500 mg/Kg SD rats 80 mg/Kg RIN-m5F cells 10–100 Wistar rats 200 mg/Kg L6 rat myoblastBALB/c miceWistar rats 5–40 SD rats 0.0125 mg/mL, 0.75, 1.5 g/100 mL, Wen Yang / In vitro In vivo in vitro In vitro In vivo In vivo In vivo In vivo In vivo In vivo In vivo In vitro In vitro In vivo In vivo In vitro In vivo In vivo In vivo In vitro Water extract Polysaccharide Extracts or monomers Aqueous ethanolic extract Methanolic extract Cinnamaldehyde, benzyl benzoate Cinnamaldehyde, cinnamyl acetate, cassioside Lignans Ethanol extract Phenolic gingerol Hot water extract L-Ephedrine, alkaloid Aqueous extract Chloroform extract Icariin Hydrophilic extract Family Zingiberaceae Umbelliferae Lauraceae Lauraceae Eucommiaceae Arecaceae Zingiberaceae Araliaceae Ephedraceae Caricaceae Combretaceae Berberidaceae Lamiaceae Stapf L. Maxim. (Rupr. and Table 4: Main mechanisms of CHM treating DM and its complications by cells and promote their regeneration; IHSG: CHM increase hepatic glycogen content and suppress gluconeogenesis; INSG: CHM inhibit the secretion of 𝛽 Maxim.) Harms Latin name Amomum xanthioides Wall. ex BakerAngelica hirsutiflora Tang S. Liu,andT.I.Chuang C. Y. Chao, Ramulus cinnamomi Cinnamomum cassia (Nees and T. Nees) J. Presl Eucommia ulmoides Oliv. Daemonorops draco (Willd.) Blume Zingiber officinale Roscoe Acanthopanax senticosus Ephedra sinica Carica papaya Terminalia chebulaRetz. Epimedium brevicornum Salvia miltiorrhiza Bunge IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; IN islet by adipose and muscular tissues.activity COSR: of CHM aldose control reductase; oxidative BLIR: stress CHM response, block such inflammatory as response. NO scavenging means oxygennot radicals, toxic. preventing lipid ND means peroxidation, o data no available. meansYES toxic. 10 Evidence-Based Complementary and Alternative Medicine

𝛽 cells 𝛼 cells PIPR

PIEI Polygonatum odoratum Panax ginseng C. A. Mey. Pancreas (Mill.) Druce

Glucagon Insulin

Dendrobium moniliforme INSG IIAI Schisandra chinensis (L.) Sw. (Turcz.) Baill.

Blood glucose PRGU

Liver Muscle and IHSG adipose tissue

INGA

Astragalus membranaceus Paeonia x suffruticosa More (Fisch.) Bunge Andrews CHM

Coptis chinensis Franch. Small intestine

Figure 4: Main mechanisms of CHM working on DM. IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; INGA: CHM inhibit 𝛼-glucosidase activity; PIPR: CHM protect islet 𝛽 cells and promote their regeneration; IHSG: CHM increase hepatic glycogen content and suppress gluconeogenesis; INSG: CHM inhibit the secretion of glucagon; PRGU: CHM promote the glucose uptake by adipose and muscular tissues. In the figure, seven CHM examples were given. CHM may involve a variety of hypoglycemic mechanisms, and only the main mechanism is mentioned in this figure. Dotted line means the possible ways in which CHM exert hypoglycemic effects. Solid lines show potential hypoglycemic mechanisms.

(1) CHM control oxidative stress response, such as scavenging In addition, many modern clinical researches tended oxygen radicals, preventing lipid peroxidation, or inhibiting to focus on curative effects rather than underlying mecha- nitric oxide synthesis; (2) CHM regulate the activity of nisms. Although molecular biological, immunological, and aldose reductase; (3) CHM block inflammatory response. phytochemical techniques have been widely applied to study Furthermore, CHM hypoglycemic effects are mainly based the mechanism of CHM treating DM, the nature of many on IIAI, PIEI, INGA, PIPR, PRGU, and IHSG and fewer components or extracts was still not very clear. CHM are based on INSG. 5.2. Advantages of CHM in the Treatment of DM. Although CHM have many limitations, as aforementioned, the hypo- 5. Discussion glycemic effects of some CHM were well documented, and 5.1. Limitations of Ancient Records and Modern Studies. First, some can effectively ameliorate certain clinical symptoms of someCHMcanalleviatesomesymptomsofDMsuchas DM, such as polydipsia, polyuria, and polyphagia. A number polydipsia, polyuria, and polyphagia. However, this does not of studies have shown that CHM or their extracts used in necessarily mean that they are able to lower blood sugar. combination with western medicines work even better for the These drugs include Phragmites australis (Cav.) Trin. ex treatment of DM [19, 20]. For example, Trigonella foenum- Steud., Alisma orientale (Sam.) Juz., and Gypsum fibrosum. graecum L. Saponin given together with sulphonylureas could Second, toxicological studies on CHM were rarely conducted effectively control the serum glucose, with few side effects, in or no information was available on the toxicity of CHM. DM patients whose serum glucose was not well controlled by Fourth, many modern clinical and experimental studies on oral administration of sulphonylureas [21]. CHM were methodologically defective, which reduces their reliability and validity. Chen et al. and Li et al.’s results also 5.3. Recommendations for Further Study of CHM for the Treat- stated this limitation [17, 18]. ment of DM. CHM are increasingly used for the treatment Evidence-Based Complementary and Alternative Medicine 11 of DM primarily because of increased awareness, on the [4]S.Wild,G.Roglic,A.Green,R.Sicree,andH.King,“Global part of patients and doctors, of their advantages, such as prevalence of diabetes: estimates for the year 2000 and projec- effectiveness, natural origin, and safety. However, in order tions for 2030,” Diabetes Care,vol.27,no.5,pp.1047–1053,2004. to further extend their scope of application, the limitations [5]K.M.V.Narayan,J.P.Boyle,T.J.Thompson,E.W.Gregg,and of CHM should be avoided. More evidence-based clinical D. F. Williamson, “Effect of BMI on lifetime risk for diabetes in trials should be performed to substantiate the efficacy of the U.S.,” Diabetes Care, vol. 30, no. 6, pp. 1562–1566, 2007. CTM prescriptions and crude CHM for the treatment of [6] P.Zimmet,K.G.M.M.Alberti,andJ.Shaw,“Globalandsocietal DM. To confirm the effect of CHM on DM, larger-scale, implications of the diabetes epidemic,” Nature,vol.414,no. multicentered, randomized, and controlled clinical trials 6865, pp. 782–787, 2001. areneededandstatisticalmethodsshouldbeusedinall [7] K. M. Flegal, M. D. Carroll, C. L. Ogden, and L. R. Curtin, clinical trials. Besides, the mechanisms of CHM and pre- “Prevalence and trends in obesity among US adults, 1999–2008,” the Journal of the American Medical Association,vol.303,no.3, scriptions should be examined at the molecular and cellular pp.235–241,2010. levelsbyfullytakingadvantageofthelatesttechniques, [8] P.Hossain, B. Kawar, and M. El Nahas, “Obesity and diabetes in such as biochemical, biological, molecular biological, and the developing world—a growing challenge,” The New England immunological methods. Since adverse side effects associated Journal of Medicine,vol.356,no.3,pp.213–215,2007. with use of CHM, such as hepatotoxicity, nephrotoxicity [9]T.K.Schramm,G.H.Gislason,L.Køberetal.,“Diabetes and genotoxicity, were reported frequently, it is urgent to patients requiring glucose-lowering therapy and nondiabetics conduct toxicological studies on CHM. In order to achieve with a prior myocardial infarction carry the same cardiovascu- higher accuracy and better reproducibility, all studies on lar risk: a population study of 3.3 million people,” Circulation, CHM should be conducted by following well-established and vol.117,no.15,pp.1945–1954,2008. standardized procedures. [10] T.-T. Zhang and J.-G. 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