mapping the knowledge of international chinese medicines treatment on type 2 diabetes a biblimetrical study

Accepted Manuscript Mapping the knowledge of international Chinese medicines treatment on type diabetes: a biblimetrical study Jiahui Hu, Kangle Shi, Qinggang Meng PII: S2095-7548(16)30208-3 DOI: 10.1016/j.jtcms.2016.12.002 Reference: JTCMS 91 To appear in: Journal of Traditional Chinese Medical Sciences Received Date: 28 December 2016 Accepted Date: 28 December 2016 Please cite this article as: Hu J, Shi K, Meng Q, Mapping the knowledge of international Chinese medicines treatment on type diabetes: a biblimetrical study, Journal of Traditional Chinese Medical Sciences (2017), doi: 10.1016/j.jtcms.2016.12.002 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Mapping the knowledge of international Chinese medicines treatment on type diabetes: a biblimetrical study Jiahui Hu, Kangle Shi, Qinggang Meng* * Corresponding author E-mail address: mqgang@126.com (Q Meng) Abstract RI PT School of Basic Medical Science, Beijing University of Chinese Medicine Beijing 100029, China AC C EP TE D M AN U SC Objective: To uncover and identify the hot topic and frontier of Chinese medicine treatment of type diabetes mellitus (T2DM) Methods: Web of Science TM was searched for published articles for Chinese medicines treatment of T2DM ranging from January 1st, 2002 to July 6th, 2016 Knowledge maps of the international Chinese medicine treatment of T2DM are visualized by using document co-occurrence analysis and word frequency analysis (Institution and Journal),co-citation clustering analysis (Co-reference), keyword co-occurrence clustering analysis with CiteSpac III, a tool of scientometrics Results: Universidad Nacional Autonoma de Mexico is the institution with the highest number of published papers that had been cited in this field, while China has four institutions among the top 10 The journal of the highest frequency of co-cited journal was Diabetes Care, a core one in the field Keywords co-occurrence network was composed of 185 nodes, 541 lines, and divided into 10 clusters Co-citation network of co-reference was composed of 407 nodes, 1199 lines, and divided into 20 clusters Using Chinese medicine to improve insulin resistance and Chinese medicine research on blood glucose control are the hot topics The frontier contains two aspects: new drugs development and application of intestinal insulin treatment and development and use of traditional Chinese medicine antidiabetic plants Conclusion: Institutions from China still plays a major role in TCM-focused T2DM studies The effect of TCM herbs on insulin resistance is the hot topic of the domain Developing new TCM herbal medicine that regulates incretin effect is the domain frontier Research on the Chinese medicines treatment of T2DM needs more high-quality evidence to support, and its mechanism requires further exploration KEYWORDS Chinese medicine; CiteSpace; Knowledge map; Type diabetes mellitus 1.0 Introduction Diabetes is a growing problem worldwide that incurs an estimated million deaths in 2015.1 Type diabetes mellitus (T2DM) takes the majority of people with diabetes around the world and can be controlled through lifestyle regulations and medication.2 The disease belongs to consumptive thirst (xiao ke) and has been treated ACCEPTED MANUSCRIPT 2.0 Materials and methods M AN U SC RI PT with empirical herb combinations in traditional Chinese medicine (TCM) since 26 BC.3 However, thousands of years of experience in dealing with T2DM have not been converted to clinical evidence due to the limited technologies and methodologies until recent 50 years, when greater efforts have been put forth to bring these TCM therapies under rigor scrutiny of science-based medicine.4,5 Followed with these efforts are the escalating amounts of TCM-focused or related T2DM literatures, as poses ever-increasing challenges for the newcomers to get a quick and exact picture of the area Based on the bibliometrical methodologies of citation and co-citation analysis, knowledge can be mapped to display and thus evaluate the structural and dynamic aspects of scientific research.7 Its current applications include medical science,8 management science,9,10 and information science,11 etc CiteSpace III is a well-validated, open source tool which enables analysts to realize knowledge mapping in an intuitive way.12 In this paper, by CiteSpace III, we mapped the TCM-focused T2DM literatures retrieved from Web of Science TM to identify the hot topics and frontier, in order to present a simple and concise picture of the field With a concerted search query, we retrieved 2348 studies related to TCM treatment on T2DM They were then separately screened by two investigators (Jiahui Hu and Kangle Shi) for eligibility based on the inclusion and exclusion criteria A third investigator (Qinggang Meng will settle dispute between the initial two TE D investigators Eligible literatures will be extracted as the format executable in CiteSpace III and imported into the tool for further treatment 2.1 Search strategy The data ranging from January 1st, 2002 to July 6th, 2016 were downloaded from the Web of Science TM (WOS TM) AC C EP Articles were searched in title, abstract or keywords using the following queries: (“type diabetic mellitus” or “type diabetes” or “T2DM” or “type II diabetic mellitus” or “DM II” or “type II diabetes”) and (“Chinese medicine” or “TCM” or “Chinese herb” or “Chinese herbal medicine” or “traditional medicine” or “alternative medicine” or “complementary medicine” or “plant” or “herbal” or “herb” or “herbal medicine” or “plant medicine” or “plant drugs” or “phytotherapy” or “medicinal plant” or “animal drugs” or “animal medicine” or “mineral medicine” or “mineral drugs” or “plant preparations” or “plant extracts” or “prescription” or “formula” or “Chinese patent medicine” or “Chinese traditional patent medicine” or “han prescription” or “integrated traditional Chinese and Western medicine” or “integrated traditional and Western medicine” or “integrated Chinese and Western medicine” or “tcm wm”or “tcm-wm” or “integrated tcm wm” ) 2.2 Inclusion criteria The articles related to Chinese medicines treatment on T2DM were selected ACCEPTED MANUSCRIPT Web of Science TM SC Initially selected n=2348 n=95 Initially selected n=1706 EP TE D n=153 n=55 n=10 n=16 n=20 n=17 n=109 n=167 M AN U Excluded by reading titles, abstracts and key words : n=642 In which: T1DM only Western medicine treatment only Sports Diagnosis Policies Detection Care therapy Risk prediction Others RI PT 2.3 Exclusion criteria The articles excluded were as follows: type diabetes only; Western medicine treatment only; sports; diagnosis; policies; detection; care therapy; risk prediction, and others (massage, extraction process of plant components, and patient compliance, and the like) The procedure of screening the articles was displayed (Fig 1) Excluded by reading full texts : n=188 In which: T1DM only Western medicine treatment only Sports Diagnosis Policies Detection Care therapy Risk prediction Others n=4 n=54 n=11 n=4 n=12 n=4 n=7 n=17 n=75 Finally included n=1518 AC C Figure Flow chart of screening the articles 2.4 Data treatment The data were then imported into CiteSpace III to carry out document co-occurrence analysis, word frequency analysis (Institution, Journal), co-citation clustering analysis (Co-reference) and keyword co-occurrence clustering analysis Each analysis was reported as a series of statistics and a visualized map for manual interpretation and exploration We visualized the knowledge maps of TCM-focused T2DM domain using the document type of “Institution”, “Cited Journal”, “Keyword”, and “Cited Reference”, respectively (this could be fulfilled by selecting the corresponding items in CiteSpace III parameter setting window) Based on the recommendations and examples from the tool developer, 8,12-14 other parameters were set as: the unit of analysis (year) =1; top ACCEPTED MANUSCRIPT N per slice = 50 ; pruning algorithm=pathfinder 3.0 Results and analysis AC C EP TE D M AN U SC RI PT The retrieved articles (n=1518) were published from 2002 to 2016 3.1 Distribution 3.1.1 Analysis of institutions CiteSpace III visualizes a merged network based on several networks corresponding to snapshots of consecutive years In this section, the nodes are institutions Lines that connect nodes are collaboration links Color indicates cited documents issued time, which corresponds to the top time bar The direction of time points to the right Cooler colors indicate older time (Fig 2) By institution analysis, global distribution of institutions within a TCM-focused T2DM domain was demonstrated and quantified base on how frequently they had been cited, and this might help investigators to build research partnerships The statistics displayed there were 134 institutions in all from 1518 studies The top 10 most frequently cited institutions and their countries were listed (Table 1) It was found that Universidad Nacional Autonoma de Mexico (English: National Autonomous University of Mexico) was ranked first position with citation counts of 21, and this might be somehow inconsistent with most investigators’ impression that Mainland China; Taiwan, China; South Korea and Japan, where TCM were most frequently practiced, and should dominate the domain of TCM study However, China still took up four seats among the top 10, demonstrating its important role in the field Through the sparse lines of connection, collaboration between different institutions was believed to be not universal Figure M AN U SC RI PT ACCEPTED MANUSCRIPT International Chinese medicine treatment of T2DM document source institutions AC C EP TE D Table Top 10 institutions of international Chinese medicine treatment on T2DM document source Citation Institution Country frequency 21 Universidad Nacional Autonoma de Mexico Mexico 17 Chinese Academy of Sciences China 15 University of Montreal Canada 14 China Academy of Chinese Medical Sciences China 14 China Medical University China 13 University of KwaZulu Natal South Africa 11 University Putra Malaysia Malaysia 10 Shanghai Jiao Tong University China 10 University of Ottawa Canada 10 Kyung Hee University Korea 3.1.2 Statistics of cited journals The statistics of publication sources can be helpful in finding the core journals in the field, which possesses a major position of the research By CiteSpace III (Table 2), it was indicated that the journal with the highest co-cited frequency was DIABETES CARE, a monthly journal founded by the American Diabetes Association in 1978 The aim of the journal is for the health care practitioner that is intended to ACCEPTED MANUSCRIPT increase knowledge, stimulate research, and promote better management of people with diabetes.15 Table Top 10 cited journals Centrality Year Journal 893 0.07 2004 DIABETES CARE 629 0.13 2001 DIABETES 522 0.12 1994 J ETHNOPHARMACOL 504 0.03 1999 NEW ENGL J MED 499 0.06 1994 DIABETOLOGIA 476 1998 LANCET 438 0.04 1999 352 0.18 2001 348 0.05 2002 329 0.12 SC RI PT Frequency JAMA-J AM MED ASSOC M AN U DIABETES RES CLIN PR 2000 J BIOL CHEM DIABETIC MED 3.2 Analysis of co-occurrence keywords Parameter settings only changed one place: pruning (minimum spanning tree, MST) The rest remained the same as listed in common selections TE D In this section, citation tree rings indicated the co-occurred keyword of an article The signature (fundamental setting information and statistical metrics) of the network was shown on the upper left corner of the visualization As Fig.3 displayed, keyword co-occurrence network was composed of 185 nodes, and 541 lines Two reported EP metrics, the modularity Q and the mean silhouette scores, depicted the overall structural properties of the network Here, the modularity Q value was 0.427, higher AC C than 0.3 (reference value),12 which indicated the clustering was effective, and the mean silhouette score of 0.5981 suggested that well-defined the clusters were credibly M AN U SC RI PT ACCEPTED MANUSCRIPT Figure Knowledge map of co-occurrence keywords 3.2.1 Major clusters AC C EP TE D The network was divided into 10 co-citation clusters, which were labeled by index terms from their own citers Clustering number was inversely proportional to the cluster size The Silhouette column indicated the homogeneity of a cluster The higher the silhouette score obtained, the more consistent the cluster members became According to previous studies,13,14 a silhouette score more than 0.5 suggested that we could have sufficient confidence to believe the cluster existed and the cluster deserved further exploration we listed four largest clusters with silhouette score higher than 0.5 (Table 3) The mean (cited year) of a cluster indicated whether it was formed by generally recent papers or old papers Table Cluster ID Size Silhouette Largest clusters of Keywords Label Mean (cited year) #0 40 0.63 clinical significance 2007 #1 38 0.743 phytotherapy 2005 #2 31 0.671 complementary and alternative medicine 2007 #3 25 0.545 diabetic complications 2007 ACCEPTED MANUSCRIPT 3.2.2 Citation frequency Removing meaningless key words such as diabetes, T2DM, we obtained the highest frequency co-citation keywords as follows According to Fig.3, Table and Table insulin resistance (IR) was the most frequently mentioned keyword IR causes healthy people to develop glucose intolerance and finally T2DM.16 TCM emphasizes syndrome differentiation and RI PT treatment, so the clinical significance of T2DM, which corresponds to clinical indicators, must be clear The number of T2DM complications entails a wide range of TCM therapies that have been explored by investigators On the specific clinical treatment methods, the use of phytotherapy includes single herb, prescriptions and SC plant extracts In Western countries , TCM is usually considered as complementary and alternative medicine, indicating it is applied as adjuvant approaches when some M AN U modern therapy exists for a disease in question (complementary) and sometimes as major therapy when it does not (alternative) Oxidative stress can cause β-cell function decline and lead to IR.17 While IR and β-cell dysfunction play important roles in the occurrence and development of T2DM Table Most citation frequencies of Keywords Keywords Cluster ID TE D Citation insulin-resistance #0 0.11 2006 glucose #0 0.12 2005 obesity #0 0.08 2005 oxidative stress #2 0.14 2007 frequency 169 119 116 Year AC C EP 115 Centrality 3.3 Analysis of co-cited references In this section, we identified co-citation references network in Chinese medicine treatment of T2DM domain This could be seen in Fig.4 by clustering and Fig.5 by transforming the clusters into a timeline view with a built-in “Fisheye” function A citation tree ring represented an article citation history Its overall size reflected the number of citations, and its color referred to citation frequency The thickness of the rings was proportional to the number of citations in the corresponding time partition In a timeline view, each cluster was arranged on a horizontal timeline The direction of time points to the right, facilitated the identification of field growth Knowledge map of co-cited references AC C EP TE D Figure M AN U SC RI PT ACCEPTED MANUSCRIPT Figure Mapping on co-citation references by time line view According to Fig.5, the network was composed of 407 nodes, and 1199 lines The modularity Q value was f 0.7247, whichpassed the threshold of credibility, indicating the network has been reasonably divided into loosely coupled clusters The mean ACCEPTED MANUSCRIPT silhouette score being 0.7491 indicated the clusters were formed in high confidence with close internal connectivity 3.3.1 Major clusters Table Summary of the largest clusters Cluster ID SizeSilhouette Mean (Cited Year) 0.723 incretins 0.73 glucagon-secretion 0.775 insulin sensitivity 659 medicinal plant 996 hypoglycemic plants 0.785 complementary and alternative medicine 0.815 herbal extraction 0.882 randomized controlled trial SC 56 55 46 44 30 27 23 22 Label M AN U #0 #1 #2 #3 #4 #5 #6 #7 RI PT The network was divided into 20 co-citation clusters, which were labeled by index terms from their own citers with approaches of major clustering algorithms (tf*idf18; LLR19; MI) in bibliometrics (the algorithms are embedded in CiteSpace III) The largest clusters were summarized (Table 5) 2006 1997 2001 2000 2002 2005 2001 2005 As Table showed, #0, #1 and #2 were insulin-related clusters; #3, #4 and #6 TE D related to medicinal plants and extracts; #5 referred to the focus of TCM-related issues; #7 indicated randomized controlled trial (RCT), pointed to that TCM investigators’ increasing focus on the golden standard of science-based medicine For further comparative analysis, we also analyzed top 10 co-cited reference EP literatures using statistics of citation frequency and bursts (Table and Table 7) AC C 3.3.2 Citation frequency Table Citation frequency 83 63 56 53 43 42 38 38 Top 10 Largest Citation frequency of co-cited references Cluster References ID Wild S, 2004, Diabetes Care, V27, P1047 Turner RC, 1998, Lancet, V352, P837 Yeh GY, 2003, Diabetes Care, V26, P1277 Li WL, 2004, J Ethnopharmacol, V92, P1 Matthews DR, 1985, Diabetologia, V28, P412 Grover JK, 2002, J Ethnopharmacol, V81, P81 Knowler WC, 2002, New Engl J Med, V346, P393 Stratton IM, 2000, Brit Med J, V321, P405 #3 #0 #7 #3 #1 #2 #1 #1 ACCEPTED MANUSCRIPT 36 36 Friedewawt, 1972, Clin Chem, V18, P499 Shaw JE, 2010, Diabetes Res Clin PR, V87, P4 Table #1 #5 Top 10 largest bursts of co-cited references Bursts References Cluster ID #0 7.01 Inzucchi SE, 2012, Diabetes Care, V35, P1364 #0 6.86 American Diabetes Association, 2013, Diabetes Care S1, V36, #0 5.40 Shaw JE, 2010, Diabetes Res Clin PR, V87, P4 #5 5.01 Dongmo AB, 2003, J Ethnopharmacol, V84, P17 #4 5.01 Adzu B, 2003, J Ethnopharmacol, V84, P169 #4 4.64 Turner RC, 1998, Lancet, V352, P837 #0 4.62 Akah PA, 1992, Phytother Res, V6, P171 #4 4.61 American Diabetes Association, 2007, Diabetes Care S1, V30, #9 4.61 American Diabetes Association, 2014, Diabetes Care S1, V37, #0 M AN U SC RI PT 7.26 International Diabetes Federation, 2013, IDF Diabetes Atlas, V, P 3.3.3 Burst TE D Burst is a measure used to reflect the change rate of literature citations Citation red ring in the network represents a sudden increase of the cited articles (cited emergent).12 The article with high burst often catches disciplinary research focus, and indicates either a turning point or a new discovery, because it is cited intensively in a EP short time window Therefore, the issue always turns out to be a new hot spot, and then shed light on how the field will develop in a period of time The bursts detection AC C function of CiteSpace III reported the following information (Fig.6) Figure M AN U SC RI PT ACCEPTED MANUSCRIPT Knowledge map of co-cited references bursts AC C EP TE D An article attached great importance was Turner RC, 1998, LANCET, V352, P837 for its high citation frequency and burst.—— The article was a large prospective RCT performed by UK Prospective Diabetes Study (UKPDS) Group.20 Involving 3867 patients with T2DM and 10 years of follow-up visits, the study concluded that in comparison of conventional antidiabetic therapy, intensive blood glucose control substantially decreased the incidence of microvascular complications , but not the macrovascular diseases in T2DM This article adds up tremendously the clinical evidence for whether intensive glycemic treatment of T2DM decreases the risk of microvascular and macrovascular complications It sets a landmark in the field and has been greatly cited 4.0 Discussion 4.1 Hot topics Keyword usage reflects the research focus and trends in related fields Statistics showed that the keyword “insulin resistance” was ranked first on the list at the frequency of 169 On the top 10 co-occurrence keyword list, there were presented in the cluster#1, from cluster #3, and from cluster #0, #2, #5, #7, respectively Thus, we deemed that cluster #1 and #3 were of greater significance Cluster #1 was labeled ACCEPTED MANUSCRIPT as glucagon, and #3 was mainly for medicinal plants, which were consistent with the highest frequency keyword We analyzed the clustering results in combination of intensively cited literatures in order to reveal the research hot topics of T2DM treated SC RI PT by TCM 4.1.1 Improvement of IR by Chinese medicine In 1988, American endocrinologist Reaven pointed out that most diabetes patients’ serum insulin in their early onset is not insufficient but overly released.21 He explained this phenomenon as “insulin resistance” IR is generally regarded as a pathological condition in which cells fail to respond to the normal actions of the hormone insulin due to a variety of causes Namely the efficiency of insulin promoting glucose uptake and utilization decreases, and the body secretes much compensatory insulin to produce hyperinsulinemia.22 IR usually occurs before T2DM and even at the pre-diabetic stage Chinese medicine advocates that prevention outweighs treatment in ancient M AN U times.23 The idea coincides with modern treatment of insulin resistance The functions of pancreas belong to “pi” (spleen) in TCM sense Some TCM scholars hold that cui (i.e pancreas) is as vice spleen.24 The two are closely related From TCM perspective, spleen governs the function of transport and transformation In modern medicine, pancreas is both exocrine and endocrine glands As an exocrine gland, it secrets TE D pancreatic juice that contains a variety of digestive enzymes into gastrointestinal tract, which neutralize gastric acid digestion of sugar, protein and fat As an endocrine gland, it is the main component of insulin and glucagon The former promotes the synthesis of hepatic glycogen and muscle glycogen, facilitates glucose into muscle EP and adipose tissue cells, inhibits gluconeogenesis, and thus exerts a hypoglycemic effect In early stage of T2DM, pancreatic β cells secrete increased level of insulin to compensate for the rise in blood sugar However, with the development of the disease, AC C pancreatic β-cell function declines with a 4.5% annual rate.25 The gradual loss of pancreatic β-cell function ultimately leads to islet functional decline and even failure, insulin secretion reduction, blood glucose and lipid disorders A variety of digestive enzymes and insulin are the material basis of the spleen to ensure its transportation function Thus, pancreatic dysfunction, or spleen transport dysfunction is an important cause of IR Therefore, TCM treatment for diabetic patients is often considered from the perspective of spleen qi deficiency,26 or both deficiency of qi and yin.27 Taking the measures of nourishing the spleen and eliminating dampness, reinforcing qi and nourishing yin and other treatment methods leads to certain therapeutic effect, including improving fasting blood glucose (FBG), 2h postprandial blood glucose, and ACCEPTED MANUSCRIPT glycosylated hemoglobin (HbAlc), and so on Jinlida granules,28 together with metformin (186 T2DM patients), has been proved to enhance the hypoglycemic effect of metformin A meta-analysis demonstrates that cinnamon (Cinnamomum cassia Presl) extract, can effectively improves FBG of patients with T2DM or pre-diabetes.29 4.1.2 Resarch on blood glucose control by Chinese medicine In the treatment of T2DM, TCM adopts different theories and measures from RI PT modern medicine Consequently, the current domain focus is majorly on its efficacy of T2DM as well as its complications The article in the fourth highest cited reference30 reviewed 86 natural medicines, which has been clinically proved with anti-diabetic effect SC Further, modern technologies are increasingly applied to explore the mechanisms behind the effective TCM therapies Yeh31 conducted a systematic review including M AN U 108 trials with 4565 diabetic patients involved to comb out the efficacy and safety of herbal therapies (36 herbs, single or in combination) and vitamin/mineral supplements for glucose control in diabetic patients The results showed the effective rate of blood glucose control was 76% Among them, red melon rice fruit (oryza sativa) and American ginseng (Panax quinquefolium L.) have been supported with relatively strong evidence, and some evidence has also been obtained concerning the efficacy of Chinese aloe dried juice (aloe vera L.var chinensis (Haw.) Berger), TE D Gymnema (gymnema sylvestre), cholla root and stem (opuntia dillenii (Ker-Gawl.) Haw.), vanadium, and balsampear fruite (momordica charantia) Besides, some chemical compositions have been identified to control blood sugar, and they can be found in herbs like resveratrol,32 rutaecarpine (Evodia rutaecarpa (Juss.) Benth.),33 EP tangerine peel (Citrus reticulate Blanco),34 and so on There are plenty of methods, such as ultra-performance liquid chromatography,35 network pharmacology,36 used to AC C test the efficacy of Chinese medicine in the treatment of T2DM and to explore the potential biological mechanism Chinese medicine in Western countries is always considered as complementary and alternative health care In TCM, many a medicines are actually daily foods, resulting in a blurred line between foods and medicines Nowadays, investigators have been exploring the mechanisms through modern technological tools to demonstrate their scientificity For example, hypoglycemic effect of balsampear fruite has been proven and universally recognized An article37 reported that taking balsampear fruite 2000 mg a day exerted a hypoglycemic effect by significantly reducing fructosamine levels from baseline in T2DM patients In summary, using Chinese medicine to improve IR problem and its role in ACCEPTED MANUSCRIPT controlling blood glucose has become a hot area of research 4.2 Research frontier As shown in Table 7, bursts originate from the cluster #0, labeled as incretins; from cluster #4, labeled as hypoglycemic plants This indicates the other two clusters RI PT probably contain the frontier and emerging trends of the domain in question 4.2.1 New drugs development and use of intestinal insulin treatment Elrick38 found that the amplification of secretion occurred when glucose was orally taken as opposed to infused in intravenously in amounts that resulted in identical glucose excursions in 1964 This is called “incretin effect” This difference SC has been attributed to gastrointestinal peptides GLP-1 and gastric inhibitory peptide (GIP) Since incretin effect is reduced in subjects with type diabetes, despite GLP-1 activity preservation, two forms of incretin-based treatment have emerged: GLP-1R M AN U agonists, administered subcutaneously and DPP-4 inhibitors, administered orally.39,40 However, with further research, after the use of these drugs, patients present with symptoms of gastrointestinal reactions such as nausea, vomiting, and cardiovascular risk, and even pancreatitis or pancreatic cancer Many studies have shown that Chinese medicine composed by single herb, extract or formula serve to regulate blood sugar by influencing GLP-1 level A study found TE D that berberine may activate protein kinase C (PKC) signaling pathway or increase the synthesis of GLP-1 upstream of the gene (glucagon original) expression, and thus exert a hypoglycemic effect.41 Emodin may promote GLP-1 secretion by activating peroxisome proliferator activated receptor (PPAR) subtypes.42 Hu43 divided the high EP fat diet IR rats into four groups, and observed the influence of san ya ku (Evodia lepta (Spreng.) Merr.) to GLP-1mRNA It was found that san ya ku could significantly AC C increase the expression of GLP-1mRNA Yu44 found that Huanglian Jiedu formula could regulate the blood glucose, increase insulin secretion and suppress appetite, analyzing which may result from promoting the synthesis and secretion of GLP-1 4.2.2 Development and use of TCM antidiabetic plants Some TCM researchers looked at herbal medicines from many other countries, and tried to develop them under the system of TCM with TCM’s theoretical advantages in understanding and investigating herbs Extract of Herba Gynostemmatis Pentaphylli (Gynostemma pentaphyllum (Thunb.) Makino), as a drug combination of sulfonylureas, improved blood glucose control for T2DM and the effect could be sustained over 12 weeks.45 Traditional medicine is widely used in south-eastern part of Mexico, and a study45 showed 36 common plants ACCEPTED MANUSCRIPT could be used as hypoglycemic drugs Andrographolidume had a hypoglycaemic effect and improved IR in type diabetic rats It was proved to protect islet from high glucose-induced oxidative damage by down-regulating the NF-κB signaling pathway.46 At present, the mechanism of related herbal medicines is still under exploration RI PT and the approaches for extracting or synthesizing medicinal components from herbal medicines have been ever-improving But the relevant evidence-based medicine is not sufficient, and even some are in the blank However, we believe when more and more researchers pay great attention to natural medicines, they will be used internationally SC and bring hopes for type diabetics in the near future 5.0 Conclusions TE D Acknowledgments M AN U Although many institutions from Western countries are emerging, those from China continue to take the majority in TCM-focused T2DM studies Diabetes Care is a core journal where high-quality studies of TCM-focused T2DM have been published The effect of TCM herbs on IR is the hot topic of the domain Developing new TCM herbal medicines that regulates incretin effect is the domain frontier This work was supported by funding from National Natural Science Foundation of China (No 81273876) Conflict of interests AC C EP The authors have declared no conflict of interests exists References International Diabetes Federation IDF annual report_2015 http://www.diabetesatlas.org Accessed December 4th, 2016 2.World Health Organization Global report on diabetes http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf?ua=1.Acc essed December 4th, 2016 Wu Tong Research on the name of Xiaoke Journal of Fujian College of TCM 2007;17(4):51-52 [Chinese] Tian JX, Zhao LH, Song J, et al The present and future of diabetes mellitus secondary prevention: the role of traditional Chinese medicine cannot be ignored Int J Clin Exp Med 2016; 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