Research progress on classical traditional Chinese medicine formula Liuwei Dihuang pills in the treatment of type 2 diabetes

Biomedicine & Pharmacotherapy 121 (2020) 109564

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Research progress on classical traditional Chinese medicine formula Liuwei Dihuang pills in the treatment of type 2 diabetes

T

Wenjie Zhenga, Gaofeng Wangb, Zhe Zhanga, Zhenguo Wanga,**, Ke Maa,c,* a

Institute for Literature and Culture of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China Department of Traditional Chinese Medicine Internal Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinn 25001, PR China c Shandong Co-Innovation Center of Classic TCM formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Liuwei Dihuang pills Type 2 diabetes Xiao Ke disease Pharmacological Effective substance

In traditional Chinese medicine (TCM), type 2 diabetes mellitus (T2DM) is regarded as Xiao Ke disease. Liuwei Dihuang pills (LWP), a classical TCM formula, with the function of nourishing kidney yin, has been used for treating Xiao Ke disease in clinic. In this review, we systematically highlighted recent evidence on LWP and T2DM data from clinical and animal studies, summarized the clinical application, pharmacological mechanism and the active compounds of LWP for the treatment of T2DM. This systematic review will provide an insightful understanding of TCM formulas, pharmacological mechanisms, medicinal-disease interactions, and will lay a foundation for the development of new drug therapy for T2DM.

1. Introduction Diabetes mellitus (DM) is a common clinical chronic disease, which is characterized by hyperglycemia caused by insulin resistance or a relative deficiency of insulin secretion [1]. DM is currently the seventh leading cause of death due to its high prevalence, morbidity, and mortality [2]. In recent years, the number of people with DM continues to grow. It is estimated that there were about 451 million people with DM worldwide in 2017. Moreover, the figures would increase to 700 million by 2045 [3]. In particular, T2DM accounts for more than 90% of the total number of DM patients [4,5], which poses a major challenge to the public health system [6]. Therefore, it is of great significance and urgency to find effective methods for the prevention and treatment of T2DM. Traditional Chinese medicine (TCM) is a comprehensive disease

prevention and treatment system with a history of 3000 years, and has accumulated rich and valuable experience in the area of disease treatment. TCM formulas are the main component of TCM, and is widely applied in TCM clinic. Liuwei Dihuang pills (LWP), a classical TCM formula, has been applied for TCM medication or dietary supplements in the prevention and treatment of various chronic diseases in China [7,8]. LWP was invented by Qian Yi in the Song Dynasty (CE 1119). According to the work named Qian’s Key to Diagnosis and Treatment of Children’s Diseases by Qian Yi, LWP has the function for treating kidney yin deficiency pattern, the symptoms are weakness of waist and knee, dizziness of head, deafness of tinnitus and deafness and spermatorrhea of night sweating. More recently, it has been applied in clinical settings to treat DM [9–11].Here, we reviewed the latest research progress of the LWP in the treatment of T2DM, aiming at understanding the pharmacological mechanism of the LWP, and developing a novel TCM

Abbreviation: LWP, Liuwei Dihuang pills; T2DM, Type 2 diabetes mellitus; TCM, traditional Chinese medicine; DM, diabetes mellitus; RRP, Radix Rehmanniae Preparata; RD, Rhizoma Dioscoreae; FC, Fructus Corni; CM, Cortex Moutan; RA, Rhizoma Alismatis; PC, Poria Cocos; 5-HMF, 5-hydroxymethyl furfural; TGF-β1, transforming growth factor β1; AEGs, advanced glycation end products; PKC, protein kinase c; RAS, renin-angiotensin system; DN, diabetic neuropathy; DPN, diabetic peripheral neuropathy; FPG, fasting plasma glucose; 2hPG, 2-hr postprandial blood glucose; HbA1c, glycosylated hemoglobin; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor-kB; EAR, erythrocyte aldose reductase; IRS-1, insulin receptor substrate-1; IRS-2, insulin receptor substrate-2; IGF-1, insulin-like growth factor-1; BDNF, brain-derived neurotrophic factor; NO, nitric oxide; OS, oxidative stress; GA, gallic acid; PA, protocatechuic acid; PG, pentagalloylglucose; PN, paenol; MR, morroniside; LG, loganin; SR, sweroside; PF, paeoniflorin; BPF, benzoylpaeoniflorin; KEGG, Kyoto Encyclopedia of Genes and Genomes; HPLC, high performance liquid chromatography ⁎ Corresponding author at: College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, No 4655, University Road, Changqing District, Jinan, Shandong 250355, PR China. ⁎⁎ Corresponding author at: Institute for Literature and Culture of Chinese Medicine, Shandong University of Traditional Chinese Medicine, No 4655, University Road, Changqing District, Jinan, Shandong 250355, PR China. E-mail addresses: [email protected] (Z. Wang), [email protected] (K. Ma). https://doi.org/10.1016/j.biopha.2019.109564 Received 5 August 2019; Received in revised form 24 September 2019; Accepted 20 October 2019 0753-3322/ © 2019 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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the increased mRNA expression of phosphoenolpyruvate carboxyl kinase and the reduced glycogen contents in the liver of diabetic mice [26]. The water extraction of RRP is effective in enhancing memory [27], anti-anxiety [28], anti-tumor [29] and could promote endothelial cell proliferation [30]. And the alcohol extraction of RRP displays antiaging effects [31] and promotes erythrocyte regeneration [32]. 5-hydroxymethyl furfural (5-HMF), one of the quantitative indicators for quality control of RRP, has been proved to be eff ;ective for enhancing erythrocyte deformability [33].

formulas for T2DM treatments. 2. T2DM and Xiao Ke disease T2DM is regarded as Xiao Ke disease in TCM. T2DM were named as “emaciation thirst”, “diaphragm emaciation”, “lung emaciation”, “middle emaciation”, and so on in the antique text of TCM. Relevant records of Xiao Ke disease were also found in The Yellow Emperor’s Inner Classic, which was compiled in Han Dynasty [12]. According to TCM theory, the disease causes of Xiao Ke disease are closely related to inappropriate diet, excessive eating greasy and sweet foods, emotional disorders, deficient congenital endowment and visceral deficiency. In the “Chapter 13, Pulses, Syndromes and Treatment for Xiao Ke, Inhibited Urination and Strangury”, of Essentials from the Golden Cabinet, a TCM classical work of the Eastern Han Dynasty, the description of Xiao Ke disease was documented. The manifestations of Xiao Ke disease are marked by drinking more but thirty, eating more but hungry, frequent urination, body weight loss or sweet urine. In the TCM literature, the treatment for Xiao Ke disease is also well documented. In Pre-Qin and Han Dynasties, the treatment was mainly to remove dampness and remove blood stasis, warm yang and remove qi, and nourish kidney yin. In Wei, Jin, Sui, and Tang Dynasties, nourishing and moisturizing became the main therapeutic principles. In Song, Jin and Yuan Dynasties, the treatment for Xiao Ke disease was further enriched, including nourishing lung and reducing fire, invigorating spleen and promoting yang, invigorating kidney and nourishing blood. And in the Ming and Qing Dynasties, the treatment was differentiated usually based on deficiency and excess, yin and yang, qi and blood [13]. Generally speaking, the disease mechanism of Xiao Ke disease was yin deficiency, body fluids injury and dry heat, and the treatment was nourishing yin, clearing heat and moistening dryness. At present, this treatment has become the mainstream for treating Xiao Ke disease in TCM. The classical TCM formula, LWP, with the function of nourishing kidney yin, is the major formula for Xiao Ke disease of yin deficiency and internal heat. This formula consists of six Chinese herbal medicinals, Radix Rehmanniae Preparata, Rhizoma Dioscoreae, Fructus Corni, Cortex Moutan, Rhizoma Alismatis, and Poria cocos. According to TCM perspective, Radix Rehmanniae Preparata has the function of nourishing kidney yin and essence. Rhizoma Dioscoreae and Fructus Corni have functions of nourishing liver and kidney. Rhizoma Alismatis plays a role in removing kidney turbidity. Poria cocos is usually used to fortify the spleen and promote urination. The effect of Cortex Moutan is to cool the liver and purge fire [14]. When the six medicinals are combined, LWP will bring about the maximum of therapeutic effect on Xiao Ke disease [15], T2DM of the biomedicine.

3.2. Rhizoma Dioscoreae (RD) RD is initially recorded in the Shen Nong’s Classic of the Materia Medica, and also is a common food in China. RD is beneficial for invigorating qi and nourishing yin, tonifying spleen, stomach, lung and kidney, preserving the essence, and promoting production of body fluids [34]. It is held that usually the optimal production area of RD is Jiaozuo area, Henan Province, China [35]. In ancient times, it was believed that eating RD for a long time could make people to become smart and with long life spans. Nowadays, the chemical constituents and pharmacological activities of RD has been extensively studied, and many chemical constituents have been obtained such as palmitic acid, β-sitosterol, oleic acid β-sitosterol acetate, 5- (hydroxymethyl) furfural, nonanedioic acid, β-daucosterol, cyclo- (Phe-Tyr), cyclo- (Tyr-Tyr), 6methyl citrate, 1, 5-dimethyl citrate, trimethyl citrate [36]. Over the past few decades, hypoglycemic activity assays have been used for RD research and it was found that RD could improve insulin resistance in fructose-induced rats [37]. Besides, RD polysaccharide exhibits hypoglycemic effects via increasing the activities of key enzymes such as hexokinase, succinate dehydrogenase and malic dehydrogenase [38,39]. In addition, RD has been shown to suppress tumor growth [40], regulate immunity [41], inhibit gastric emptying [42]. 3.3. Fructus Corni (FC) FC is the pulp of the ripe fruit of Cornus officinalis Sieb. et Zucc. FC is firstly recorded in Shen Nong’s Classic of the Materia Medica. According to the TCM theory, FC is effective in replenishing liver and kidney, astringing essence and rescuing from desertion [43]. Clinically, it is often used to treat symptoms like dizziness, tinnitus, soreness of waist and knee, impotence, spermatorrhea, frequent enuresis, internal heat and thirst [44]. Modern pharmacological studies have found that FC contains polysaccharides, organic acids, lipids and other pharmacological active ingredients [45]. Transforming growth factor (TGF)-β1 is mainly distributed in glomerular and tubular epithelial cells in the kidney. Increased levels of blood sugar, advanced glycation end products (AGEs), protein kinase C (PKC) and renin-angiotensin system (RAS) can increase the level of TGF-β1 in diabetic nephropathy [46]. Smad family proteins are known as intracellular kinase substrates of TGF-β receptors, which can mediate intracellular signal transduction of TGF-β [47]. It is reported that FC relieved early diabetic nephropathy through inhibiting the activation of TGF-β1/Smad7 signal transduction pathway in kidneys of diabetic nephropathy rats [48]. Additionally, both the ethanol extract and ethyl acetate extract of FC could reduce serum triglyceride level in diabetic mice [49], and FC might be the major contributor to the plasma glucose-lowering action in LWP [50]. Bioactive ingredients within FC may be able to protect existing β cells from cytokine-induced death and enhance their function before symptomatic onset [51]. Other studies suggested that the pharmacological effects of FC are usually involving neuroprotection, myocardial protection, antioxidant and anti-tumor [44].

3. Pharmacological study on the active compounds of six Chinese medicinals of LWP 3.1. Radix Rehmanniae Preparata (RRP) RRP is a processed product of the dry rhizome of Rehmannia glutinosa Libosch. The processing of RRP is complicated. During the processing, Radix Rehmanniae was steamed for nine times and dried in the sun for nine times alternatively. RRP is good at nourishing yin and supplementing blood, boosting essence, and supplementing bone marrow [16]. Up to now, over 140 compounds have been isolated and identified, such as polysaccharides, oligosaccharides, glycosides, iridoid glycosides, flavonoid, phenol glycoside ionone, furfurals and microelements [17–19]. In modern pharmacological research, many experiments have been conducted to elucidate the pharmacological effects of RRP. As the important chemical components of RRP, polysaccharides have been reported to have effects like anti-diabetes [20], anti-anxiety [21], antifatigue [22], anti-tumor [23], alleviation of intestinal mucositis [24] and immune enhancement [25]. Moreover, polysaccharides reversed

3.4. Cortex Moutan (CM) CM, the dried root bark of Paeonia suffruticosa Andrew, is recorded in several famous TCM materia medica books, like The Grand 2

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response rate and the control rate [78]. Herbalist doctors conducted the clinical trials to compare the clinical effects of LWP and LWP combined with metformin tablets in patients' treatment with T2DM [79]. The data from randomized controlled trial studies indicated that the drop in FPG, 2Hpg and HbA1c in LWP intervention group were more pronounced than that of only metformin tablets. According to the theory of turn treatment based on different complex-symptom, 140 patients with T2DM were diagnosed as kidney Yin deficiency type by TCM. The scores of weakness of waist and knee, dizziness of head, deafness of tinnitus, eat more easily hungry, five upset heat, urine frequency in patients who were treated LWP for 4 successive weeks, were lower and the total effective rate was 95.71%. Meantime, another clinical report also illustrated the effect of LWP on T2DM patients. LWP combined with gliclazide modified release tablets took effect faster than single gliclazide modified release tablets, and fewer side effects were noted in the course of treatment. The decline of FPG in LWP intervention group was significantly decreased than that of gliclazide modified release tablets alone. The blood lipid level in patients who were treated LWP with continuous therapy, were significantly ameliorated and the total effective rate was 88%, higher than 76% of the control group [80]. Moreover, LWP has better curative effect in treating T2DM of qi and yin deficiency type [81–83]. Besides, LWP has been widely applied in clinic to treat T2DM complications and achieved good results. Diabetic neuropathy (DN) is one of the most common complications of T2DM and its pathological changes usually involve the central nervous system and peripheral nervous system. Randomized controlled trials indicated that LWP can be used to treat early retinopathy of T2DM when combined with ginkgo biloba leaves [84]. Additionally, LWP combined with mecobalamin can obviously improve the clinical effect for diabetic peripheral neuropathy (DPN). According to Tao Xie's clinical experiment, 80 patients were randomly divided into two groups, the control group were given mecobalamin, and in the experimental group were given LWP on the basis of mecobalamin treatment for 4 successive weeks. Total effective rate (patient clinical symptoms reduced or disappeared) was 92.5% and superior to control group [85]. Diabetic nephropathy is the most serious and harmful chronic complication caused by diabetes. LWP prevented renal fibrosis and protected glomerular mesangial cells by upregulation of cytoglobin and suppression of multiple pathways involving TGF-β/ Smads, mitogen-activated protein kinase (MAPK), nuclear factor-kB (NF-kB) signaling [86]. And adding LWP to Western medicine might improve treatment outcomes of diabetic nephropathy, including hyperglycemia and renal functions [78]. The activity of erythrocyte aldose reductase (EAR) decreased obviously by given LWP for T2DM patients who were diagnosed as Qi-Yin deficiency type by TCM [87]. In conclusion, these clinical studies indicated that LWP is efficient in the treatment for T2DM and its complications, with minor side effects compared to conventional drugs. But, the treatment of diabetes by LWP based on pattern differentiation of TCM. Otherwise, it will cause side effects. For example, taking LWP for a long time will cause hyperkalemia, increasing the activity of cytochromeP450 and testosterone-like effect. Meanwhile, LWP can aggravate the patients' insufficient transportation of spleen and stomach for the incorrect TCM syndrome type [88].

Compendium of Materia Medica, Shen Nong's Classic of the Materia Medica, and Chinese Materia Medica. In the theory of TCM, it is believed that CM relieves human sickness via clearing away excessive heat, cooling blood, promoting blood circulation, and removing blood stasis. Given its extensive application, CM is currently widely studied in phytochemistry and pharmacology. It is reported 119 compounds have been isolated from CM, which can be divided into seven categories: flavonoids, tannins, monoterpenes, monoterpene glycosides, triterpenoids, phenols and others [52]. Various experiments have shown that CM has a wide range of pharmacological activities including anti-oxidant [53], anti-inflammation [54], anti-tumor [55], anti-diabetes [56], cardiovascular protection [57], neuroprotection [58] and hepatoprotection [59]. Additionally, CM has a protective effect on vascular endothelial cells in diabetic rats [60]. 3.5. Rhizoma Alismatis (RA) RA was firstly recorded in the Shen Nong's Classic of the Materia Medica [61].Also in various TCM classics such as The Grand Compendium of Materia Medica, Treatise on Cold Damage, Chinese Materia Medica. According to TCM theory, RA could remove dampness and promote water metabolism [62]. As an important medicinal in various TCM formulas such as LWP, RA has therapeutic effects for dysuria [63], cystitis [64] and diabetes [65], which are primarily related with kidney and body fluid metabolism according to TCM theory. Current and previous studies revealed that, triterpenes, sesquiterpenes, diterpenes, alisol as well as other compounds including polysaccharide, phenolic compounds, and novel lectin were isolated from RA [66–70]. Accordingly, increasing researches reveal RA displays a wide spectrum of pharmacological effects, that is, diuretic, hypolipidemic, antimetabolic disorder, hepatoprotective, hypoglycemic, immunomodulatory, anti-inflammatory and antitumor effects [71]. Its anti-hyperglycemic mechanism may be associated with promoting release of insulin from beta cells in islets [65]. However, RA is commonly considered to be slightly toxic. Although studies have shown that the use of RA extracts is relatively safe and does not exhibit serious side effects within a certain dose range [62], further toxicological investigations are still needed. 3.6. Poria Cocos (PC) PC is a kind of edible medicinal fungus, which grows on the roots of pine trees [72]. It is often present in TCM formulas, with the functions of diuresis and removing dampness, invigorating the spleen and soothing the mind. Clinically, PC is used to treat chronic gastritis, edema, nephrosis, gastricatony, acute gastroenteric catarrh, dizziness, nausea, and emesis [73]. Research suggested that the chemical constituents of PC mainly include three kinds: triterpenes, polysaccharides and steroids [74]. Pachymaran has the effect of lowering blood glucose and anti-lipid peroxidation, the hypoglycemic mechanism of PC may be related to inhibiting the production of reactive oxide species and reducing the damage of islet β cells [75]. Modern phytochemical and pharmacological investigations showed, PC exhibits a wide range of pharmacological activities, such as anti-tumor, anti-oxidant, anti-rejection activities. The pharmacological effects of major active components from PC are reviewed by Wang and Zhang [76]. PC is safe for clinical application and often used as food additive.

5. The pharmacological mechanism of LWP in the treatment of T2DM

4. The clinical application of LWP in the treatment of T2DM

To better understand the mechanism of LWP on T2DM, numerous studies were conducted. LWP can reduce the level of FBG and the level of serum insulin in spontaneous T2DM mice [89]. Liver is an important target organ involved in chronic complications of DM, and it also plays an important role in regulating glycolipid metabolism. The disorders of glycolipid metabolism such as increased triglyceride synthesis, glycogen degradation and increased gluconeogenesis in the early stage of liver injury will further aggravate the metabolic disorders and insulin

In recent years, it has been proved that LWP and its modified formula or combined with chemical drugs could treat T2DM and T2DM complications. Thus LWPs is considered as promising drugs for T2DM [77]. Adding LWP to Western medicine can lower patients' fasting plasma glucose (FPG), 2-hr postprandial blood glucose (2hPG) and glycosylated hemoglobin(HbA1c) levels, and can also improve both the 3

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Fig. 1. The 2-D structures of GA, LG, PA, BPF, MR, benzoic acid, PG and PF.

Fig. 2. 35 collective targets of LWP and T2DM were identified.

1) and brain-derived neurotrophic factor (BDNF), attenuating the neural apoptosis, overexpression of caspase-3 and amyloid β-protein (Aβ) deposition in the hippocampus and cerebral cortex [91]. Moreover, LWP could reduce proteinuria and alleviate renal pathological damage in DN rats by affecting the expression of RhoA and Rho-associated kinase isoform 1 (ROCK1) [92], inhibiting the inflammatory reactions such as monocyte chemoattractant protein-1 (MCP-1) and NFkB [93]. The hyperglycemia caused in T2DM by the insulin resistance

resistance. LWP improves hepatic insulin resistance by inhibiting the activity of key gluconeogenic enzyme in the liver and enhancing insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2) expressions in the insulin signaling pathway [90]. In various studies it has been found that LWP could help to reduce diabetic complications. LWP significantly improves memory and cognitive ability in streptozotocin-induced diabetic encephalopathy rats through improving the expressions of insulin-like growth factor-1 (IGF4

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may contribute to the endothelial dysfunction. It was reported that the endothelial dysfunction can be used to predict T2DM. It runs through the development of T2DM [94]. Meanwhile, endothelial nitric oxide (NO) can induce endothelium-dependent vasodilation and mediate vasodilation [95]. Oxidative stress (OS) injury induced by T2DM is not only an important mechanism of DM and vascular complications, but accelerates the occurrence and development of endothelial cell dysfunction [96]. LWP can significantly improve vascular endothelial diastolic dysfunction in T2DM rats, and protect vascular endothelium by regulating the expression of malondialdehyde (MDA)/protein arginine methyltransferase 1 (PRMT1)/NO and inhibiting OS injury [97]. 6. The active compounds of LWP in the treatment of T2DM The function of TCM formula is more than a combination of the consisting medicinals, but a synergistic effect of various active ingredients. TCM exhibits therapeutic effect through the synergistic effects, and this therapeutic effect is of multicomponent, multitarget, and multi-pathway, thus it is relatively difficult to analyze the intricate mechanisms of TCM merely using traditional experimental approaches [98]. Network pharmacology, as a powerful method integrating systems biology, bioinformatics and multi-pharmacology, not only clarifies the complex interactions among genes, proteins, and metabolites related to diseases and drugs at the network level, but also conform to the holistic and systemic perspective of TCM [99]. Previous studies of LWP have showed that LWP contains 11 known active biomarkers: gallic acid (GA), protocatechuic acid (PA), 1,2,3,4,6-o-pentagalloylglucose (PG), paenol (PN), morroniside (MR), loganin (LG), sweroside (SR), paeoniflorin (PF), Benzoic acid, benzoylpaeoniflorin (BPF) and 5-HMF [100]. To understand how a multicomponent treatment system of LWP exerts multiplicity effects on T2DM, we applied a comprehensive network pharmacology-based approach to identify the common target genes of active biomarkers in LWP and T2DM. This method was constructed to uncover the relationships among active biomarkers of LWP, target proteins and T2DM. The 2-D structure and the Canonical SMILES of the 11 active biomarkers were searched from PubChem database (https://pubchem. ncbi.nlm.nih.gov/). As a result, eight of the 11 active biomarkers were obtained (Fig. 1). Swiss Target Prediction Database (http://www. swisstargetprediction.ch/) was used to screen the targets of active biomarkers in LWP. And the targets of T2DM were obtained from OMIM Database (http://omim.org/) and Therapeutic Targets Database (http://bidd.nus.edu.sg/group/cjttd/). As a result, 417 target genes of T2DM and 313 target genes of LWP were obtained. Thus, 35 collective targets of T2DM and LWP were obtained (Fig. 2), and were used to construct the protein-protein network consisting of 35 link nodes (Fig. 3). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that 35 common targets are mainly concentrated in 17 signaling pathways (Table 1). We speculate that LWPs may treat T2DM by these signaling pathways.

Fig. 3. 35 collective targets were used to establish the regulation network. The green nodes represent the common targets, red node stands for LWP, and the yellow nod represents T2DM (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article). Table 1 The target pathway information of LDPs on the T2DM. ID

Term

Count

PValue

hsa05200 hsa03320 hsa05202 hsa04066 hsa04080 hsa05205 hsa04015 hsa05219 hsa04913 hsa00590 hsa04924 hsa05230 hsa05211 hsa05218 hsa04520

Pathways in cancer PPAR signaling pathway Transcriptional misregulation in cancer HIF-1 signaling pathway Neuroactive ligand-receptor interaction Proteoglycans in cancer Rap1 signaling pathway Bladder cancer Ovarian steroidogenesis Arachidonic acid metabolism Renin secretion Central carbon metabolism in cancer Renal cell carcinoma Melanoma Adherens junction

12 5 6 5 7 6 5 3 3 3 3 3 3 3 3

5.52E-07 2.12E-04 8.09E-04 8.40E-04 0.0012697 0.001813 0.0139177 0.0144494 0.020266 0.0305024 0.0333244 0.0333244 0.0352608 0.0402885 0.0402885

complications and exerted significant therapeutic effects with less sideeffect. However, there are still some challenges in the development of LWP as therapeutic drugs for T2DM. For example, the effect of LWP on T2DM needs a long-term follow-up in clinical trials. Besides, the effects of some compounds from LWP may be neglected owing to insufficient understanding of the components of LWP. Fortunately, modern technologies such as bioscientific, network pharmacology, high performance liquid chromatography (HPLC), and new intelligent decocting equipments will accelerate studies on the mechanism of LWP on T2DM, and will further promote the modernization of TCM.

7. Conclusion and prospect The treatment of T2DM has always been a challenge in the medical field because of the difficulty in blood glucose control, complications and so on. TCM is a valuable source for the discovery of new drugs [101]. With its unique theory and long clinical practice, more and more attention has been paid to it all over the world. As a well-known classical TCM formula, LWP has been applied clinically to treat various diseases due to kidney yin deficiency for about one thousand years. This paper has systematically reviewed the effects of LWP on T2DM in terms of its composition, the clinical and animal studies, pharmacological effects, and effective compounds. By doing so, we hope to provide a comprehensive and profound understanding of the mechanism of LWP working on T2DM. Currently, LWP is widely used in treating T2DM and its

Authors contributions WJ Zheng, GF Wang and Z Zhang contributed to literature search, data extraction and data analysis. K Ma and Zhenguo Wang contributed to the project design and paper writing. All authors have read and approved the final version of the manuscript.

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Funding

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