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

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.


Introduction
Diabetes mellitus (DM), including type 1 and type 2, has become epidemic worldwide [1][2][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][6][7][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 as Yusanxiao, Yijin, and Kelening, 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 2 Evidence-Based Complementary and Alternative Medicine

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.  [13]. By searching "Xiao Ke, " we retrieved a large number of records concerning "Xiao Ke" in ancient TCM literatures.

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.

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 Table 1.

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 that Yin deficiency is the "Ben" (origin or root cause) and dryness heat is the "Biao" (symptoms or external manifestations). The Ben 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 abusing Dan medicines [11]. Yin and Yang are two opposing aspects of things. For instance, cold, moist, night, structure, and downward mobility belong to Yin while heat, dryness, day, function, and upward mobility belong to Yang [14].

Foods.
Besides, the monographs also mentioned some foods that help treat "Xiao Ke" in

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 (Tables 2, 3, and 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, including Panax ginseng C. A. Mey., Astragalus membranaceus (Fisch.) Bunge, and Lonicera japonica Thunb., 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 as Lemna minor L., Gardenia jasminoides J. Ellis, Eleocharis dulcis (Burm.f.) Trin. ex Hensch., and Achyranthes bidentata Blume (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 inhibit -glucosidase activity; (4) CHM protect islet 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:     Punica granatum L.

Punicaceae Methanolic extract
In vivo Zucker diabetic fatty rats, Zucker lean rats   (1) CHM control oxidative stress response, such as scavenging oxygen radicals, preventing lipid peroxidation, or inhibiting nitric oxide synthesis; (2)  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.

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 foenumgraecum L. 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].

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.

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.