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

Authors: Hai-ming Zhang; Feng-xia Liang; Rui Chen
Journal: Evidence-Based Complementary and Alternative Medicine
 (2015)

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## Abstract

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.


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## Body

## 1. Introduction

Diabetes mellitus (DM), including type 1 and type 2, has become epidemic worldwide [1–3], and its incidence has been on rise year by year [4]. Previous reports have demonstrated that overweight, especially obesity at younger ages, substantially increases the risk for DM [1, 5–8]. The finding is consistent with the description in the “Medical Classic of the Yellow Emperor,” the earliest monumental work on the traditional Chinese medicine (TCM) dating back to the Warring States Period (about 446 B.C.−221 B.C.). DM increases the risk for micro- and macrovascular complications and premature death and poses tremendous socioeconomic burden [2, 4, 9]. In spite of the introduction of insulin and other hypoglycemic agents, so far, no treatment protocols can achieve a complete cure. Moreover, the side effects of these drugs, which are substantial and inevitable, present another challenge.Complementary and alternative medicine (CAM) have been extensively used in modern times. TCM, as a main form of CAM, has been proved to be effective for the treatment of DM with relatively less side effects in China and beyond [10, 11]. Some hypoglycemic drugs of plant origin have been approved for clinical use by the regulatory authorities in China, such asYusanxiao,Yijin, andKelening, among others [12].The mechanisms of Chinese herbal medicines (CHM) in the treatment of DM have been extensively and intensively studied from biological, immunological, and phytochemical perspectives and great advances have been made in the past decades. This paper reviewed records or descriptions concerning the use of CHM for treatment of DM in ancient Chinese literatures (before 1920 A.D.) and the modern papers on the mechanisms of CHM treating DM. We also compared the CHM used in ancient and modern times, examined the limitations of CHM for treating DM, and discussed the future research trend.


## 2. Ancient Records on Treatment of DM with TCM

Our search of literatures of TCM (before 1920 A.D. or earlier) failed to find the term “DM.” We found a plenty of records or descriptions about “Xiao Ke,” which, in terms of epidemiology, symptoms, etiology, pathogenesis, and treatment, mimicked those of DM. And it is generally accepted that “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” for the convenience of discussion though they are not strictly equivalents in a number of ways.


### 2.1. Terminology, Epidemiology, Symptoms, Etiology, and Pathogenesis of “Xiao Ke”

#### 2.1.1. Name

In TCM, “Xiao Ke” refers to a cluster of clinical symptoms, including polydipsia, polyphagia, polyuria, emaciation, glucosuria, and fatigue. As aforementioned, “Xiao Ke” is a general term for a condition that resembles DM in terms of symptoms. DM classically was divided into three types: upper, middle, and lower “Xiao Ke.” The upper type (Shang Xiao) is characterized by excessive thirst, the middle type (Zhong Xiao) by excessive hunger, and the lower type (Xia Xiao) by excessive urination [13]. By searching “Xiao Ke,” we retrieved a large number of records concerning “Xiao Ke” in ancient TCM literatures.


#### 2.1.2. Epidemiology

The earliest mention of “Xiao Ke” was in the “Medical Classic of the Yellow Emperor.” The book described that the “Xiao Ke” was mostly found in wealthy, obese individuals who liked food rich in oil or fat and in influential officials who were on pills or “Dan,” as it was termed in the book, a mineral-based synthetic drug, which ancient people believe to be able to make them achieve longevity.


#### 2.1.3. Symptoms

The symptoms can be categorized into two groups: general symptoms and complications. The general symptoms include polydipsia, polyphagia, polyuria, glucosuria, emaciation, dry mouth, hunger, emptiness of the stomach, and frequent urination. And complications include diabetic foot, diabetic retinopathy, lung tuberculosis, diabetic impotence, and diabetic nephropathy. Obviously, those symptoms and complications are extremely similar to DM, as shown in Table1.Table 1
A similar comparison of the symptoms of “Xiao Ke” and DM.
Symptoms of “Xiao Ke” in Zhu Bing Yuan Hou Luna
Symptoms of DM in Textbook of Internal Medicine [22]
Generalsymptoms
Polydipsia; dry mouth and lips; polyphagia; hunger; emptiness of the stomach; frequent urination; polyuria; glucosuria; emaciation; adiposity; fatigue of limbs; mental fatigue; feverish dysphoria; itchy skin; hyperhidrosis; dizziness; sweet feeling in the mouth.
Polydipsia; thirst; polyphagia; hunger; polyuria; marasmus; obesity; sweet taste of urine; itchy skin; vulva pruritus; fatigue; lightheadedness.
Complications
Carbuncle and soreness; night blindness; internal oculopathy; lung tuberculosis; edema; precordial pain; pectoral stuffiness pain; apoplexy; coma; impotence; foot carbuncle-abscess; unsmooth defecation; diarrhea; anorexia; short breath; waist soreness; dizziness and tinnitus; pachylosis; whitish and turbid urine;  muscle atrophy of the lower extremities; oliguria; nightly sweating; coolness of extremities.
Carbuncle and furuncle; diabetic retinopathy; pulmonary tuberculosis; diabetic cardiomyopathy; diabetic ketoacidosis; diabetic impotence; glaucoma; diabetic nephropathy; atherosclerosis; cerebral ischemic stroke; diabetic foot; constipation; diarrhea; myophagism; paralysis;  oliguria; hyperhidrosis; hypohidrosis or anhidrosis; diabetic gastroparesis.
aThe “Zhu Bing Yuan Hou Lun”: a book describing causes and manifestations of diseases by Yuanfang Chao, a famous TCM doctor born about AD 550 and died in 630 A.D. in the Sui Dynasty.


#### 2.1.4. Etiology and Pathogenesis

According to the theory of TCM, the symptoms are essentially caused by “Yin Xu” (Yin deficiency) and “Zao Re” (dryness heat). In TCM there is a belief thatYin deficiency is the “Ben” (origin or root cause) and dryness heat is the “Biao” (symptoms or external manifestations). TheBen or root causes involve the invasion of exogenous pathogens, innate deficiency, intemperance in eating, abnormal emotional states (anger, anxiety, depression, distress, panic, and fear), excessive physical strains (mental or physical exertion and sexual intercourse), or propensity for abusingDan medicines [11].Yin andYang are two opposing aspects of things. For instance, cold, moist, night, structure, and downward mobility belong toYin while heat, dryness, day, function, and upward mobility belong toYang [14].


### 2.2. Treatment

We searched for the term “Xiao Ke” in more than 1,000 TCM ebooks included in Encyclopedia of TCM (Compact Disk, ISBN: 7-900377-49-2/R·8), published by Hunan Electronic and Audiovisual Publishing House. The database contained, among others, “Bencao Gangmu(Compendium of Materia Medica)”,Puji fang,and so forth.


#### 2.2.1. CHM

We also searched the database for Chinese crude drugs for treating “Xiao Ke.” The database contained only 54 monographs on Chinese materia medica. Most CHM treated “Xiao Ke” by “Qing Re” (clearing heat) (Figure 1), “Yang Yin” (nourishingYin), and “Yi Qi” (replenishing vital energy) (Figure 2). The Latin names of CHM used in the paper were from the website http://www.theplantlist.org/ or http://www.wikipedia.org/.Figure 1
Frequency of heat-clearing (Qing Re) drugs for “Xiao Ke” mentioned in 54 monographs on Chinese materia medica. Heat-clearing drugs are ofLiang (cold or cool) or bitter taste. a:Pueraria lobata(Willd.) Ohwi; b:Trichosanthes kirilowiiMaxim.; c:Fructus et semen trichosanthis kirilowii; d:Lemna minorL.; e:Gypsum fibrosum; f:Alisma orientale(Sam.) Juz.; g:Coptis chinensisFranch.; h:Anemarrhena asphodeloidesBunge; i:Lophatherum gracileBrongn.; j:Succus bambusae(Recens); k:Arctium lappa L.; l:Phragmites australis(Cav.) Trin. ex Steud.; m:Benincasa hispida(Thunb.) Cogn.; n:Phaseolus calcaratusRoxb.; o:Scutellaria baicalensisGeorgi; p:Solanum lyratumThunb.; q:Vitex negundovar.cannabifolia(Siebold and Zucc.) Hand.-Mazz.; r:Phellodendron chinenseC. K. Schneid.; s:Gardenia jasminoidesJ. Ellis; t:Lycium chinenseMill.Figure 2
Frequency ofYin-nourishing (Yang Yin) and energy-replenishing (Yi Qi) drugs for “Xiao Ke” mentioned in 54 monographs on Chinese materia medica.Yin-nourishing and energy-replenishing drugsare of sweetish taste and are of cold (Liang) nature. a:Lycium barbarumL.; b:Tussilago farfaraL.; c:Poria cocos(Schw.) Wolf; d:Panax ginsengC. A. Mey.; e:Eleocharis dulcis(Burm.f.) Trin. ex Hensch.; f:Morus albaL.; g:Adenophora trachelioidesMaxim.; h:Cannabis sativaL.; i:Ophiopogon japonicus(Thunb.) Ker Gawl.; j:Armeniaca mumeSiebold; k:Asparagus cochinchinensis(Lour.) Merr.; l:Cuscuta chinensisLam.; m:Achyranthes bidentataBlume; n:Coix lacryma-jobiL.; o:Astragalus membranaceus(Fisch.) Bunge; p:Polygonatum odoratum(Mill.) Druce; q:Rhus chinensisMill.; r:Schisandra chinensis(Turcz.) Baill.; s:Lilium lancifoliumThunb.; t:Rehmannia glutinosaSteud.


#### 2.2.2. Foods

Besides, the monographs also mentioned some foods that help treat “Xiao Ke” in Figure 3.Figure 3
Frequency of meat, grains, fishes, and other food that help treat “Xiao Ke” mentioned in 54 monographs on Chinese materia medica. a: chicken; b: millet; c: barley; d: bamboo shoot; e: cony meat; f:Benincasa hispida; g: watershield leaf; h: mud eel; i: radish; j: foxtail millet seed; k: snail; l: cow’s milk; m: goose meat; n: Charr; o: long surf clam; p: wheat; q: mung bean; r: Gallus black-bone silky fowl; s: hairy chestnut seed; t: giant gecko.


## 2.1. Terminology, Epidemiology, Symptoms, Etiology, and Pathogenesis of “Xiao Ke”

### 2.1.1. Name

In TCM, “Xiao Ke” refers to a cluster of clinical symptoms, including polydipsia, polyphagia, polyuria, emaciation, glucosuria, and fatigue. As aforementioned, “Xiao Ke” is a general term for a condition that resembles DM in terms of symptoms. DM classically was divided into three types: upper, middle, and lower “Xiao Ke.” The upper type (Shang Xiao) is characterized by excessive thirst, the middle type (Zhong Xiao) by excessive hunger, and the lower type (Xia Xiao) by excessive urination [13]. By searching “Xiao Ke,” we retrieved a large number of records concerning “Xiao Ke” in ancient TCM literatures.


### 2.1.2. Epidemiology

The earliest mention of “Xiao Ke” was in the “Medical Classic of the Yellow Emperor.” The book described that the “Xiao Ke” was mostly found in wealthy, obese individuals who liked food rich in oil or fat and in influential officials who were on pills or “Dan,” as it was termed in the book, a mineral-based synthetic drug, which ancient people believe to be able to make them achieve longevity.


### 2.1.3. Symptoms

The symptoms can be categorized into two groups: general symptoms and complications. The general symptoms include polydipsia, polyphagia, polyuria, glucosuria, emaciation, dry mouth, hunger, emptiness of the stomach, and frequent urination. And complications include diabetic foot, diabetic retinopathy, lung tuberculosis, diabetic impotence, and diabetic nephropathy. Obviously, those symptoms and complications are extremely similar to DM, as shown in Table1.Table 1
A similar comparison of the symptoms of “Xiao Ke” and DM.
Symptoms of “Xiao Ke” in Zhu Bing Yuan Hou Luna
Symptoms of DM in Textbook of Internal Medicine [22]
Generalsymptoms
Polydipsia; dry mouth and lips; polyphagia; hunger; emptiness of the stomach; frequent urination; polyuria; glucosuria; emaciation; adiposity; fatigue of limbs; mental fatigue; feverish dysphoria; itchy skin; hyperhidrosis; dizziness; sweet feeling in the mouth.
Polydipsia; thirst; polyphagia; hunger; polyuria; marasmus; obesity; sweet taste of urine; itchy skin; vulva pruritus; fatigue; lightheadedness.
Complications
Carbuncle and soreness; night blindness; internal oculopathy; lung tuberculosis; edema; precordial pain; pectoral stuffiness pain; apoplexy; coma; impotence; foot carbuncle-abscess; unsmooth defecation; diarrhea; anorexia; short breath; waist soreness; dizziness and tinnitus; pachylosis; whitish and turbid urine;  muscle atrophy of the lower extremities; oliguria; nightly sweating; coolness of extremities.
Carbuncle and furuncle; diabetic retinopathy; pulmonary tuberculosis; diabetic cardiomyopathy; diabetic ketoacidosis; diabetic impotence; glaucoma; diabetic nephropathy; atherosclerosis; cerebral ischemic stroke; diabetic foot; constipation; diarrhea; myophagism; paralysis;  oliguria; hyperhidrosis; hypohidrosis or anhidrosis; diabetic gastroparesis.
aThe “Zhu Bing Yuan Hou Lun”: a book describing causes and manifestations of diseases by Yuanfang Chao, a famous TCM doctor born about AD 550 and died in 630 A.D. in the Sui Dynasty.


### 2.1.4. Etiology and Pathogenesis

According to the theory of TCM, the symptoms are essentially caused by “Yin Xu” (Yin deficiency) and “Zao Re” (dryness heat). In TCM there is a belief thatYin deficiency is the “Ben” (origin or root cause) and dryness heat is the “Biao” (symptoms or external manifestations). TheBen or root causes involve the invasion of exogenous pathogens, innate deficiency, intemperance in eating, abnormal emotional states (anger, anxiety, depression, distress, panic, and fear), excessive physical strains (mental or physical exertion and sexual intercourse), or propensity for abusingDan medicines [11].Yin andYang are two opposing aspects of things. For instance, cold, moist, night, structure, and downward mobility belong toYin while heat, dryness, day, function, and upward mobility belong toYang [14].


## 2.1.1. Name

In TCM, “Xiao Ke” refers to a cluster of clinical symptoms, including polydipsia, polyphagia, polyuria, emaciation, glucosuria, and fatigue. As aforementioned, “Xiao Ke” is a general term for a condition that resembles DM in terms of symptoms. DM classically was divided into three types: upper, middle, and lower “Xiao Ke.” The upper type (Shang Xiao) is characterized by excessive thirst, the middle type (Zhong Xiao) by excessive hunger, and the lower type (Xia Xiao) by excessive urination [13]. By searching “Xiao Ke,” we retrieved a large number of records concerning “Xiao Ke” in ancient TCM literatures.


## 2.1.2. Epidemiology

The earliest mention of “Xiao Ke” was in the “Medical Classic of the Yellow Emperor.” The book described that the “Xiao Ke” was mostly found in wealthy, obese individuals who liked food rich in oil or fat and in influential officials who were on pills or “Dan,” as it was termed in the book, a mineral-based synthetic drug, which ancient people believe to be able to make them achieve longevity.


## 2.1.3. Symptoms

The symptoms can be categorized into two groups: general symptoms and complications. The general symptoms include polydipsia, polyphagia, polyuria, glucosuria, emaciation, dry mouth, hunger, emptiness of the stomach, and frequent urination. And complications include diabetic foot, diabetic retinopathy, lung tuberculosis, diabetic impotence, and diabetic nephropathy. Obviously, those symptoms and complications are extremely similar to DM, as shown in Table1.Table 1
A similar comparison of the symptoms of “Xiao Ke” and DM.
Symptoms of “Xiao Ke” in Zhu Bing Yuan Hou Luna
Symptoms of DM in Textbook of Internal Medicine [22]
Generalsymptoms
Polydipsia; dry mouth and lips; polyphagia; hunger; emptiness of the stomach; frequent urination; polyuria; glucosuria; emaciation; adiposity; fatigue of limbs; mental fatigue; feverish dysphoria; itchy skin; hyperhidrosis; dizziness; sweet feeling in the mouth.
Polydipsia; thirst; polyphagia; hunger; polyuria; marasmus; obesity; sweet taste of urine; itchy skin; vulva pruritus; fatigue; lightheadedness.
Complications
Carbuncle and soreness; night blindness; internal oculopathy; lung tuberculosis; edema; precordial pain; pectoral stuffiness pain; apoplexy; coma; impotence; foot carbuncle-abscess; unsmooth defecation; diarrhea; anorexia; short breath; waist soreness; dizziness and tinnitus; pachylosis; whitish and turbid urine;  muscle atrophy of the lower extremities; oliguria; nightly sweating; coolness of extremities.
Carbuncle and furuncle; diabetic retinopathy; pulmonary tuberculosis; diabetic cardiomyopathy; diabetic ketoacidosis; diabetic impotence; glaucoma; diabetic nephropathy; atherosclerosis; cerebral ischemic stroke; diabetic foot; constipation; diarrhea; myophagism; paralysis;  oliguria; hyperhidrosis; hypohidrosis or anhidrosis; diabetic gastroparesis.
aThe “Zhu Bing Yuan Hou Lun”: a book describing causes and manifestations of diseases by Yuanfang Chao, a famous TCM doctor born about AD 550 and died in 630 A.D. in the Sui Dynasty.


## 2.1.4. Etiology and Pathogenesis

According to the theory of TCM, the symptoms are essentially caused by “Yin Xu” (Yin deficiency) and “Zao Re” (dryness heat). In TCM there is a belief thatYin deficiency is the “Ben” (origin or root cause) and dryness heat is the “Biao” (symptoms or external manifestations). TheBen or root causes involve the invasion of exogenous pathogens, innate deficiency, intemperance in eating, abnormal emotional states (anger, anxiety, depression, distress, panic, and fear), excessive physical strains (mental or physical exertion and sexual intercourse), or propensity for abusingDan medicines [11].Yin andYang are two opposing aspects of things. For instance, cold, moist, night, structure, and downward mobility belong toYin while heat, dryness, day, function, and upward mobility belong toYang [14].


## 2.2. Treatment

We searched for the term “Xiao Ke” in more than 1,000 TCM ebooks included in Encyclopedia of TCM (Compact Disk, ISBN: 7-900377-49-2/R·8), published by Hunan Electronic and Audiovisual Publishing House. The database contained, among others, “Bencao Gangmu(Compendium of Materia Medica)”,Puji fang,and so forth.


### 2.2.1. CHM

We also searched the database for Chinese crude drugs for treating “Xiao Ke.” The database contained only 54 monographs on Chinese materia medica. Most CHM treated “Xiao Ke” by “Qing Re” (clearing heat) (Figure 1), “Yang Yin” (nourishingYin), and “Yi Qi” (replenishing vital energy) (Figure 2). The Latin names of CHM used in the paper were from the website http://www.theplantlist.org/ or http://www.wikipedia.org/.Figure 1
Frequency of heat-clearing (Qing Re) drugs for “Xiao Ke” mentioned in 54 monographs on Chinese materia medica. Heat-clearing drugs are ofLiang (cold or cool) or bitter taste. a:Pueraria lobata(Willd.) Ohwi; b:Trichosanthes kirilowiiMaxim.; c:Fructus et semen trichosanthis kirilowii; d:Lemna minorL.; e:Gypsum fibrosum; f:Alisma orientale(Sam.) Juz.; g:Coptis chinensisFranch.; h:Anemarrhena asphodeloidesBunge; i:Lophatherum gracileBrongn.; j:Succus bambusae(Recens); k:Arctium lappa L.; l:Phragmites australis(Cav.) Trin. ex Steud.; m:Benincasa hispida(Thunb.) Cogn.; n:Phaseolus calcaratusRoxb.; o:Scutellaria baicalensisGeorgi; p:Solanum lyratumThunb.; q:Vitex negundovar.cannabifolia(Siebold and Zucc.) Hand.-Mazz.; r:Phellodendron chinenseC. K. Schneid.; s:Gardenia jasminoidesJ. Ellis; t:Lycium chinenseMill.Figure 2
Frequency ofYin-nourishing (Yang Yin) and energy-replenishing (Yi Qi) drugs for “Xiao Ke” mentioned in 54 monographs on Chinese materia medica.Yin-nourishing and energy-replenishing drugsare of sweetish taste and are of cold (Liang) nature. a:Lycium barbarumL.; b:Tussilago farfaraL.; c:Poria cocos(Schw.) Wolf; d:Panax ginsengC. A. Mey.; e:Eleocharis dulcis(Burm.f.) Trin. ex Hensch.; f:Morus albaL.; g:Adenophora trachelioidesMaxim.; h:Cannabis sativaL.; i:Ophiopogon japonicus(Thunb.) Ker Gawl.; j:Armeniaca mumeSiebold; k:Asparagus cochinchinensis(Lour.) Merr.; l:Cuscuta chinensisLam.; m:Achyranthes bidentataBlume; n:Coix lacryma-jobiL.; o:Astragalus membranaceus(Fisch.) Bunge; p:Polygonatum odoratum(Mill.) Druce; q:Rhus chinensisMill.; r:Schisandra chinensis(Turcz.) Baill.; s:Lilium lancifoliumThunb.; t:Rehmannia glutinosaSteud.


### 2.2.2. Foods

Besides, the monographs also mentioned some foods that help treat “Xiao Ke” in Figure 3.Figure 3
Frequency of meat, grains, fishes, and other food that help treat “Xiao Ke” mentioned in 54 monographs on Chinese materia medica. a: chicken; b: millet; c: barley; d: bamboo shoot; e: cony meat; f:Benincasa hispida; g: watershield leaf; h: mud eel; i: radish; j: foxtail millet seed; k: snail; l: cow’s milk; m: goose meat; n: Charr; o: long surf clam; p: wheat; q: mung bean; r: Gallus black-bone silky fowl; s: hairy chestnut seed; t: giant gecko.


## 2.2.1. CHM

We also searched the database for Chinese crude drugs for treating “Xiao Ke.” The database contained only 54 monographs on Chinese materia medica. Most CHM treated “Xiao Ke” by “Qing Re” (clearing heat) (Figure 1), “Yang Yin” (nourishingYin), and “Yi Qi” (replenishing vital energy) (Figure 2). The Latin names of CHM used in the paper were from the website http://www.theplantlist.org/ or http://www.wikipedia.org/.Figure 1
Frequency of heat-clearing (Qing Re) drugs for “Xiao Ke” mentioned in 54 monographs on Chinese materia medica. Heat-clearing drugs are ofLiang (cold or cool) or bitter taste. a:Pueraria lobata(Willd.) Ohwi; b:Trichosanthes kirilowiiMaxim.; c:Fructus et semen trichosanthis kirilowii; d:Lemna minorL.; e:Gypsum fibrosum; f:Alisma orientale(Sam.) Juz.; g:Coptis chinensisFranch.; h:Anemarrhena asphodeloidesBunge; i:Lophatherum gracileBrongn.; j:Succus bambusae(Recens); k:Arctium lappa L.; l:Phragmites australis(Cav.) Trin. ex Steud.; m:Benincasa hispida(Thunb.) Cogn.; n:Phaseolus calcaratusRoxb.; o:Scutellaria baicalensisGeorgi; p:Solanum lyratumThunb.; q:Vitex negundovar.cannabifolia(Siebold and Zucc.) Hand.-Mazz.; r:Phellodendron chinenseC. K. Schneid.; s:Gardenia jasminoidesJ. Ellis; t:Lycium chinenseMill.Figure 2
Frequency ofYin-nourishing (Yang Yin) and energy-replenishing (Yi Qi) drugs for “Xiao Ke” mentioned in 54 monographs on Chinese materia medica.Yin-nourishing and energy-replenishing drugsare of sweetish taste and are of cold (Liang) nature. a:Lycium barbarumL.; b:Tussilago farfaraL.; c:Poria cocos(Schw.) Wolf; d:Panax ginsengC. A. Mey.; e:Eleocharis dulcis(Burm.f.) Trin. ex Hensch.; f:Morus albaL.; g:Adenophora trachelioidesMaxim.; h:Cannabis sativaL.; i:Ophiopogon japonicus(Thunb.) Ker Gawl.; j:Armeniaca mumeSiebold; k:Asparagus cochinchinensis(Lour.) Merr.; l:Cuscuta chinensisLam.; m:Achyranthes bidentataBlume; n:Coix lacryma-jobiL.; o:Astragalus membranaceus(Fisch.) Bunge; p:Polygonatum odoratum(Mill.) Druce; q:Rhus chinensisMill.; r:Schisandra chinensis(Turcz.) Baill.; s:Lilium lancifoliumThunb.; t:Rehmannia glutinosaSteud.


## 2.2.2. Foods

Besides, the monographs also mentioned some foods that help treat “Xiao Ke” in Figure 3.Figure 3
Frequency of meat, grains, fishes, and other food that help treat “Xiao Ke” mentioned in 54 monographs on Chinese materia medica. a: chicken; b: millet; c: barley; d: bamboo shoot; e: cony meat; f:Benincasa hispida; g: watershield leaf; h: mud eel; i: radish; j: foxtail millet seed; k: snail; l: cow’s milk; m: goose meat; n: Charr; o: long surf clam; p: wheat; q: mung bean; r: Gallus black-bone silky fowl; s: hairy chestnut seed; t: giant gecko.


## 3. Mechanisms by Which CHM Work on DM and Its Complications

We searched the databases of PubMed, Web of Science, MEDLINE, and CNKI and found that less research attention was paid to Chinese herbal compounds while most studies focused on a single herbal medicine.The mechanisms of CHM in the treatment of DM have been extensively and intensively studied from biological, immunological, and phytochemical perspectives (Tables2, 3, and 4).Table 2
Main mechanisms of CHM treating DM and its complications by nourishingYin (Yang Yin) and benefiting vital energy (Yi Qi).
Latin name
Family
Extracts ormonomers
In vivo/ in vitro
Models
Effective doses/doses range
Mechanisms
Toxic effect
References
Liriope spicata Lour.
Liliaceae
Crude polysaccharide, water extract
In vivo
BABL/c mice
100, 200 mg/Kg
IIAI
NO
[23]
Ophiopogon japonicus(Thunb.) Ker Gawl.
Liliaceae
Polysaccharide
In vivo
KKAy mice, C57BL/6J mice
75, 300 mg/Kg
IIAI
ND
[24]
Polysaccharide
In vivo
Ob/ob mice
300 mg/Kg
IIAI
ND
[25]
Astragalus membranaceus(Fisch.) Bunge
Leguminosae
Polysaccharide
In vivo
KKAy mice, C57BL/6J mice
700 mg/Kg
IIAI
ND
[26]
Polysaccharide
In vivo
C57BL/6J mice
100, 400 mg/Kg
PIPR
ND
[27]
Polysaccharide
In vivo
Sprague-Dawley (SD) rats
700 mg/Kg
IHSG
ND
[28]
In vitro
C2C12 cells
0.05–0.2 mg/mL
YES, <200µg/mL
Astragaloside IV
In vivo
SD rats
1, 5 mg/Kg
BLIR
ND
[29]
Calycosin
In vitro
Human umbilical vein endothelial cells
0.01µmol
BLIR
ND
[30]
Panax ginsengC. A. Mey.
Araliaceae
Malonyl ginsenosides
In vivo
Wistar rats
50, 100 mg/Kg
IIAI
ND
[31]
Ginsenoside Rh2
In vivo
Wistar rats
1 mg/Kg
PIEI
ND
[32]
Ginsenoside
In vitro
SD rats islet
0.1–1 mg/mL
PIEI
ND
[33]
Aqueous extract
In vivo
Goto-Kakizaki rats, Wistar rats
200 mg/Kg
PIEI, PIPR, PRGU
ND
[34]
Ginsenoside Re
In vivo
SD rats
20 mg/Kg
BLIR
ND
[35]
Panax pseudoginsengWall.
Araliaceae
Panax notoginoside
In vivo
Wistar rats
100, 200 mg/Kg
COSR
ND
[36]
Poria cocos(Schw.) Wolf
Polyporaceae
Crude extract
In vivo
C57BL/KsJ-db/db mice, C57BL/6J mice
50 mg/Kg
IIAI
ND
[37]
Dehydrotumulosic acid, dehydrotrametenolic acid, pachymic acid, triterpenes
1, 5, 10 mg/Kg
Dioscorea oppositifoliaL.
Dioscoreaceae
Decocted water
In vivo
Wistar rats
4 mg/Kg
IIAI
ND
[38]
Polysaccharose
In vivo
Kun Ming mice
4.5 g/Kg
RAAR
ND
[39]
Schisandra chinensis(Turcz.) Baill.
Schisandraceae
Lignan
In vivo
SD rats
200 mg/Kg
IIAI, IHSG, PRGU
ND
[40]
In vitro
3T3-L1 adipocytes,Min6 cells, human embryo kidney 293 cells,
0.5, 5µg/mL
Ophiocordyceps sinensis(Berk.) G. H. Sung, J. M. Sung, Hywel-Jones, and Spatafora
Clavicipitaceae
Polysaccharide
In vivo
BALB/c mice, SD rats
200, 400 mg/Kg
PIEI
ND
[41]
solid-state fermented mycelium
In vivo
KK/HIJ mice
300 mg/Kg
PIPR
ND
[42]
Cornus OfficinalisSiebold and Zucc
Cornaceae
Methanol extract
In vitro
BRIN-BD11 cells, H4IIE cells
0–25µg/mL
PIEI, PIPR, IHSG
YES, cytotoxicity
[43]
Proanthocyanidins
In vivo
Wistar rats
20 mg/Kg
INGA
ND
[44]
In vitro
α-Glucosidase
1.2–2.1µg/mL
Polygonatum odoratum (Mill.) Druce
Liliaceae
Total flavonoids
In vivo
Kun Ming mice, SD rats
50, 100, 200 mg/Kg
PIEI
ND
[45]
Flavonoid, saponin
In vivo
SD rats
500 mg/Kg
COSR, INGA
NO
[46]
Atractylodes macrocephalaKoidz.
Compositae
Atractylenolide, amino acid
In vivo
Kun Ming mice
1.8 g/Kg
RAAR
ND
[39]
Codonopsis pilosula (Franch.) Nannf.
Campanulaceae
Saccharides, amino acid
In vivo
Kun Ming mice
4.5 g/Kg
RAAR
ND
[39]
Panax quinquefoliusL.
Araliaceae
Ginsenoside
In vitro
Rat pancreaticβ cell derived cell line, INS-1
5, 125, 250µg/µL
PIPR, PIEI
ND
[47]
Rehmannia glutinosa Steud.
Scrophulariaceae
Catalpol
In vivo
Wistar rats
0.1 mg/Kg
IHSG
ND
[48]
Catalpol
In vitro
THP-1 cells
100, 300, 500µmol
COSR, BLIR
NO
[49]
Dendrobium moniliforme (L.) Sw.
Punicaceae
Water extract
In vivo
NIH mice, SD rats
125, 250, 500, 1000 mg/Kg
INSG, IHSG, PIEI
ND
[50]
Dendrobium chrysotoxumLindl.
Punicaceae
Polysaccharide
In vivo
BALB/c mice,
200, 500 mg/Kg
COSR
ND
[51]
In vitro
Mouse splenocytes, Jurkat cell, MCF-7 cells
0–200µg/mL
Ganoderma lucidum (Leyss. ex Fr.) Karst
Polyporaceae
Polysaccharides
In vivo
Albino Swiss mice
50, 100, 200 mg/Kg
PIPR, COSR
NO
[52]
In vitro
Wistar rat islets
25–100µg/mL
IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; INGA: CHM inhibitα-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. COSR: CHM control oxidative stress response, such as scavenging oxygen radicals, preventing lipid peroxidation, or inhibiting nitric oxide synthesis; RAAR: CHM regulate the activity of aldose reductase; BLIR: CHM block inflammatory response. NO means not toxic. ND means no data available. YES means toxic.Table 3
Main mechanisms of CHM treating DM and its complications by clearing heat (Qing Re).
Latin name
Family
Extracts or monomers
In vivo/ in vitro
Models
Effective doses/doses range
Mechanisms
Toxic effect
References
Paeonia x suffruticosaAndrews
Paeoniaceae
Paeonol
In vivo
Newborn Wistar rats
200, 400 mg/Kg
PRGU, INGA
ND
[53]
In vitro
Intestinal brush border membrane vesicles, rat hepatoma cell line H4IIE, human skin fibroblasts cell line Hs68, mouse adipocytes 3T3-L1
0.01–1 mg/mL,
Polysaccharide-2b
In vivo
Wistar rats
60 mg/Kg
IIAI
ND
[54]
Paeonoside, apiopaeonoside, 6-methoxypaeoniflori-genone
In vitro
Human HepG2 cells, HUVECs
1–20µmol
IHSG
NO
[55]
Morus albaL.
Moraceae
1-Deoxynojirimycin, polysaccharide
In vivo
ICR mice
150 mg/Kg
IHSG, PIPR
ND
[56]
Momordica charantiaL.
Cucurbitaceae
Saponin fraction, lipid fraction
In vivo
Db/db mice
150 mg/Kg
IIAI
ND
[57]
Protein extract
In vivo
Wistar rats
5, 10 mg/Kg
PIEI, PRGU
ND
[58]
In vitro
3T3-L1 adipocytes, C2C12 cells
0.01µg/mL
Saponins, momordicine II, kuguaglycoside
In vitro
MIN6β cells
0.01–0.125µg/mL
PIEI
NO
[59]
Ethanolic extract
In vivo
Albino Wistar rats
150, 300 mg/Kg
PIPR, IHSG, PRGU
ND
[60]
Aqueous extract
In vivo
Albino Wistar rats
150 mg/Kg
COSR
ND
[61]
Pueraria lobata(Willd.) Ohwi
Leguminosae
Puerarin
In vivo
SD rats
100, 200 mg/Kg
IIAI
ND
[62]
Daidzein
In vivo
Kun Ming mice
2.3 g/Kg
INGA, RAAR
ND
[39]
Puerarin
In vitro
Wistar rats islets
100µmol
PIPR, COSR
ND
[63]
Trigonella foenum-graecumL.
Leguminosae
Hydroalcoholic extract
In vivo
C57BL/6J mice
2 g/Kg
IIAI
ND
[64]
Trigonelline
In vivo
Wistar rats
40 mg/Kg
COSR
ND
[65]
Fenugreek seeds powder
In vivo
Albino rats
Powder 5% in rat food
BLIR
ND
[66]
Gardenia jasminoidesJ. Ellis
Rubiaceae
Geniposide
In vivo
C57BL/6J mice
200, 400 mg/Kg
IHSG
ND
[67]
Rheum palmatum L.
Emodin
In vivo
B6. V- Lepob/Lepob mice
25, 50 mg/Kg
PRGU
ND
[68]
In vitro
3T3-L1 adipocytes
3µmol/L
Acorus calamusL.
Araceae
Crude ethanol extract
In vivo
Homozygous C57BL/Ks db/db mice
100 mg/Kg
IIAI
ND
[69]
In vitro
L6 rat skeletal muscle cells
12.5, 25µg/mL
Ethyl acetate fraction
In vivo
ICR mice
400, 800 mg/Kg
PIEI, INGA
ND
[70]
In vitro
HIT-T15 cell line
0.41µg/mL
Eriobotrya japonica(Thunb.) Lindl.
Rosaceae
Cinchonain-Ib
In vivo
Wister rats
108 mg/Kg
PIEI
ND
[71]
In vitro
Rat insulinoma cell line, INS-1 cells
0.032 mg/mL
Anemarrhena asphodeloides Bunge
Liliaceae
Timosaponin, anemaran
In vivo
Kun Ming mice
1.8 g/Kg
INGA
ND
[39]
Total saponins
In vivo
SD rats
200 mg/Kg
BLIR
ND
[72]
Lonicera japonicaThunb.
Caprifoliaceae
Chlorogenic acid, ginnol
In vivo
Kun Ming mice
2.3 g/Kg
RAAR
ND
[39]
Coptis chinensisFranch.
Ranunculaceae
Berberine chloride form
In vivo
Wistar rats,
125, 500, 250 mg/Kg,
INGA
ND
[73]
Beagle dogs
80 mg/Kg
In vitro
Caco-2 cells
2.5, 10, 40 mg/L
Berberine
In vitro
SD rats ventricular myocytes
0.1–100µmol/L
COSR
ND
[74]
Berberine
In vivo
Wistar rats
100, 200 mg/Kg
PIPR, COSR
ND
[75]
Berberine
In vivo
C57BLKS/J-Leprdb/Leprdb mice,
5 mg/Kg
IIAI
ND
[76]
Wistar rats
380 mg/Kg
In vitro
3T3-L1 cells, L6 cells
5µg/mL
Potentilla discolorBunge
Rosaceae
Flavonoids, triterpenoids
In vivo
Wistar rats
369, 501 mg/Kg
PIPR, COSR
ND
[77]
Artemisia sphaerocephalaKrasch.
Compositae
Artemisia sphaerocephala Krasch. gum
In vivo
SD rats
0.3%, 0.9%, 2.7% gum
IIAI, IHSG
ND
[78]
Sophora flavescensAiton
Leguminosae
Oxymatrine
In vivo
Wistar rats
60, 120 mg/Kg
COSR, BLIR
ND
[79]
Punica granatumL.
Punicaceae
Methanolic extract
In vivo
Zucker diabetic fatty rats, Zucker lean rats
100–500 mg/Kg
INGA
ND
[80]
In vitro
α-glucosidase
0.5–32µg/mL
Arctium lappaL.
Compositae
Arctigenin
In vivo
C57BL/6J mice, B6. V-Lepob/Lepob mice
200, 25 mg/Kg
IHSG, PRGU
ND
[81]
In vitro
L6 myotubes
0.1–3µg/mL
IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; INGA: CHM inhibitα-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. COSR: CHM control oxidative stress response, such as scavenging oxygen radicals, preventing lipid peroxidation, or inhibiting nitric oxide synthesis; RAAR: CHM regulate the activity of aldose reductase; BLIR: CHM block inflammatory response. NO means not toxic. ND means no data available. YES means toxic.Table 4
Main mechanisms of CHM treating DM and its complications byWen Yang (tonifying Yang) or Huo Xue Hua Yu (activating blood circulation and easing congestion).
Latin name
Family
Extracts or monomers
In vivo/ in vitro
Models
Effective doses/doses range
Mechanisms
Toxic effect
References
Amomum xanthioidesWall. ex Baker
Zingiberaceae
Aqueous ethanolic extract
In vitro
3T3-L1 adipocytes
0.02–0.5 mg/mL
PRGU, IIAI
ND
[82]
Angelica hirsutifloraTang S. Liu, C. Y. Chao, and T. I. Chuang
Umbelliferae
Methanolic extract
In vivo
ICR mice,
10, 30 mg/Kg
PIEI
ND
[83]
In vitro
HIT-T15 cells, human pancreatic islets
50–150µg/mL
Ramulus cinnamomi
Lauraceae
Cinnamaldehyde, benzyl benzoate
In vivo
Kun Ming mice
1.4 g/Kg
COSR
ND
[39]
Cinnamomum cassia(Nees and T. Nees) J. Presl
Lauraceae
Cinnamaldehyde, cinnamyl acetate, cassioside
In vivo
Kun Ming mice
700 mg/Kg
COSR
ND
[39]
Eucommia ulmoidesOliv.
Eucommiaceae
Lignans
In vivo
Kun Ming mice
1.4 g/Kg
COSR
ND
[39]
Water extract
In vivo
C57BL/KsJ-db/db mice
1.87 g/Kg
IHSG
ND
[84]
Daemonorops draco(Willd.) Blume
Arecaceae
Ethanol extract
In vivo
ICR mice
1.2 g/Kg
PIPR, COSR
NO
[85]
In vitro
RIN-m5F cells
10–100µg/mL
<200µg/mL
Zingiber officinaleRoscoe
Zingiberaceae
Phenolic gingerol
In vitro
L6 rat myoblast
5–40µg/mL
PRGU
NO
[86]
Acanthopanax senticosus(Rupr. and Maxim.) Harms
Araliaceae
Hot water extract
In vivo
Db/db mice
500 mg/Kg
INGA
ND
[87]
In vitro
Caco-2 cells
0.03–4 mg/mL
Polysaccharide
In vivo
Wistar rats
200 mg/Kg
COSR
ND
[88]
Ephedra sinicaStapf
Ephedraceae
L-Ephedrine, alkaloid
In vivo
BALB/c mice
0.0125 mg/mL,
PIPR
ND
[89]
Carica papayaL.
Caricaceae
Aqueous extract
In vivo
Wistar rats
0.75, 1.5 g/100 mL,
PIPR, COSR, IHSG
ND
[90]
Terminalia chebulaRetz.
Combretaceae
Chloroform extract
In vivo
SD rats
Short term study, 100, 200, 300 mg/Kg
PIEI
ND
[91]
Long term study, 300 mg/Kg
Epimedium brevicornumMaxim.
Berberidaceae
Icariin
In vivo
SD rats
80 mg/Kg
COSR
ND
[92]
Salvia miltiorrhizaBunge
Lamiaceae
Hydrophilic extract
In vitro
HMEC-1 cells, human microvascular endothelial cells
10µg/mL
COSR
ND
[93]
IIAI: CHM increase insulin sensitivity and ameliorate insulin resistance; PIEI: CHM promote insulin secretion and elevate serum insulin levels; INGA: CHM inhibitα-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. COSR: CHM control oxidative stress response, such as scavenging oxygen radicals, preventing lipid peroxidation, or inhibiting nitric oxide synthesis; RAAR: CHM regulate the activity of aldose reductase; BLIR: CHM block inflammatory response. NO means not toxic. ND means no data available. YES means toxic.


## 4. Results

We found more than 40 CHM with hypoglycemic effect in ancient works and reviewed the mechanism of CHM lowering blood sugar. We were led to conclude that a number of CHM, includingPanax ginsengC. A. Mey.,Astragalus membranaceus(Fisch.) Bunge, andLonicera japonicaThunb., were used in ancient times and also nowadays. In addition, some CHM used for treating DM in ancient works have not been studied for hypoglycemic effect in modern times, such asLemna minorL.,Gardenia jasminoidesJ. Ellis,Eleocharis dulcis(Burm.f.) Trin. ex Hensch., andAchyranthes bidentataBlume (Figures 1 and 2). These CHM may have potential to become drugs for the treatment of DM by further exploring their hypoglycemic effects. We also found that some foods were used for treatment of DM in ancient times, and their hypoglycemic effects have been confirmed nowadays [15, 16].The mechanisms by which CHM treat diabetes include the following: (1) CHM increase insulin sensitivity and ameliorate insulin resistance; (2) CHM promote insulin secretion and elevate serum insulin levels; (3) CHM inhibitα-glucosidase activity; (4) CHM protect islet β cells and promote their regeneration; (5) CHM increase hepatic glycogen content and suppress gluconeogenesis; (6) CHM inhibit the secretion of glucagon; (7) CHM promote the glucose uptake by adipose and muscular tissues (Figure 4). Mechanisms of CHM treating diabetic complications include the following: (1) CHM control oxidative stress response, such as scavenging oxygen radicals, preventing lipid peroxidation, or inhibiting nitric oxide synthesis; (2) CHM regulate the activity of aldose reductase; (3) CHM block inflammatory response. Furthermore, CHM hypoglycemic effects are mainly based on IIAI, PIEI, INGA, PIPR, PRGU, and IHSG and fewer CHM are based on INSG.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 inhibitα-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.


## 5. Discussion

### 5.1. Limitations of Ancient Records and Modern Studies

First, some CHM can alleviate some symptoms of DM such as polydipsia, polyuria, and polyphagia. However, this does not necessarily mean that they are able to lower blood sugar. These drugs includePhragmites australis(Cav.) Trin. ex Steud.,Alisma orientale(Sam.) Juz., and Gypsum fibrosum. Second, toxicological studies on CHM were rarely conducted or no information was available on the toxicity of CHM. Fourth, many modern clinical and experimental studies on CHM were methodologically defective, which reduces their reliability and validity. Chen et al. and Li et al.’s results also stated this limitation [17, 18].In addition, many modern clinical researches tended to focus on curative effects rather than underlying mechanisms. Although molecular biological, immunological, and phytochemical techniques have been widely applied to study the mechanism of CHM treating DM, the nature of many components or extracts was still not very clear.


### 5.2. Advantages of CHM in the Treatment of DM

Although CHM have many limitations, as aforementioned, the hypoglycemic effects of some CHM were well documented, and some can effectively ameliorate certain clinical symptoms of DM, such as polydipsia, polyuria, and polyphagia. A number of studies have shown that CHM or their extracts used in combination with western medicines work even better for the treatment of DM [19, 20]. For example,Trigonella foenum-graecumL. Saponin given together with sulphonylureas could effectively control the serum glucose, with few side effects, in DM patients whose serum glucose was not well controlled by oral administration of sulphonylureas [21].


### 5.3. Recommendations for Further Study of CHM for the Treatment of DM

CHM are increasingly used for the treatment of DM primarily because of increased awareness, on the part of patients and doctors, of their advantages, such as effectiveness, natural origin, and safety. However, in order to further extend their scope of application, the limitations of CHM should be avoided. More evidence-based clinical trials should be performed to substantiate the efficacy of CTM prescriptions and crude CHM for the treatment of DM. To confirm the effect of CHM on DM, larger-scale, multicentered, randomized, and controlled clinical trials are needed and statistical methods should be used in all clinical trials. Besides, the mechanisms of CHM and prescriptions should be examined at the molecular and cellular levels by fully taking advantage of the latest techniques, such as biochemical, biological, molecular biological, and immunological methods. Since adverse side effects associated with use of CHM, such as hepatotoxicity, nephrotoxicity and genotoxicity, were reported frequently, it is urgent to conduct toxicological studies on CHM. In order to achieve higher accuracy and better reproducibility, all studies on CHM should be conducted by following well-established and standardized procedures.


## 5.1. Limitations of Ancient Records and Modern Studies

First, some CHM can alleviate some symptoms of DM such as polydipsia, polyuria, and polyphagia. However, this does not necessarily mean that they are able to lower blood sugar. These drugs includePhragmites australis(Cav.) Trin. ex Steud.,Alisma orientale(Sam.) Juz., and Gypsum fibrosum. Second, toxicological studies on CHM were rarely conducted or no information was available on the toxicity of CHM. Fourth, many modern clinical and experimental studies on CHM were methodologically defective, which reduces their reliability and validity. Chen et al. and Li et al.’s results also stated this limitation [17, 18].In addition, many modern clinical researches tended to focus on curative effects rather than underlying mechanisms. Although molecular biological, immunological, and phytochemical techniques have been widely applied to study the mechanism of CHM treating DM, the nature of many components or extracts was still not very clear.


## 5.2. Advantages of CHM in the Treatment of DM

Although CHM have many limitations, as aforementioned, the hypoglycemic effects of some CHM were well documented, and some can effectively ameliorate certain clinical symptoms of DM, such as polydipsia, polyuria, and polyphagia. A number of studies have shown that CHM or their extracts used in combination with western medicines work even better for the treatment of DM [19, 20]. For example,Trigonella foenum-graecumL. Saponin given together with sulphonylureas could effectively control the serum glucose, with few side effects, in DM patients whose serum glucose was not well controlled by oral administration of sulphonylureas [21].


## 5.3. Recommendations for Further Study of CHM for the Treatment of DM

CHM are increasingly used for the treatment of DM primarily because of increased awareness, on the part of patients and doctors, of their advantages, such as effectiveness, natural origin, and safety. However, in order to further extend their scope of application, the limitations of CHM should be avoided. More evidence-based clinical trials should be performed to substantiate the efficacy of CTM prescriptions and crude CHM for the treatment of DM. To confirm the effect of CHM on DM, larger-scale, multicentered, randomized, and controlled clinical trials are needed and statistical methods should be used in all clinical trials. Besides, the mechanisms of CHM and prescriptions should be examined at the molecular and cellular levels by fully taking advantage of the latest techniques, such as biochemical, biological, molecular biological, and immunological methods. Since adverse side effects associated with use of CHM, such as hepatotoxicity, nephrotoxicity and genotoxicity, were reported frequently, it is urgent to conduct toxicological studies on CHM. In order to achieve higher accuracy and better reproducibility, all studies on CHM should be conducted by following well-established and standardized procedures.


## 6. Conclusion

CHM used to and still play an important role in the treatment of DM in China and great progresses have been made over the last decades. A great many CHM monomer components possess antidiabetes actions. Therefore, it is of great significance to develop novel CHM for the treatment of DM and its complications. The underlying mechanism by which CHM treat DM are complicated and multifactorial and involve multiple organs; studying the effect of active monomer components of CHM might be a good starting point. It is strongly significant to pay close attention to CHM for treatment of DM and its complications.



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*Source: 747982-2015-03-01.xml*