Review of the therapeutic effects of the traditional Chinese medicine yuye decoction on diabetes mellitus and its complications

Ethnopharmacological relevance: Diabetes is a serious metabolic disease which imposes a heavy burden on the society. It may also bring about a variety of complications if the blood glucose level is not well controlled. Yuye Decoction (YYD) is an ancient herbal medicinal formulation of China and has been widely used in Traditional Chinese medicine to treat patients with diabetes for thousands of years. There are seven medicinal herbs in YYD. Aim of the study: The aim of the present review is to summarize and critically appraise data concerning medicinal plants used in YYD, its main active constituents and signaling pathways mediating its therapeutic effects on diabetes and diabetic complications. Materials and methods: The search of papers published in the period 2009 to 2019 and recorded in PubMed was conducted using specific search terms. Results: After screening, 88 studies were included. Among seven medicinal herbs in YYD formulation, six of them exhibited therapeutic effects on diabetes and its complications through different signaling pathways. Most (55.7%) of the studies were animal studies. Type 2 diabetes was studied in most (37.5%) of the research papers and diabetic nephropathy was the most (19.3%) studied diabetic complication. Focus was placed on Astragalus membranaceus (Fisch.) Bge. and Pueraria lobata (Willd.) Ohwi in the largest number of research papers. Conclusion: YYD exerted a therapeutic effect on diabetes and a preventive effect on diabetic complications. *Correspondence to: Kalin Y.B. Zhang, School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong,10 Sassoon Road, Hong Kong, E-mail: ybzhang@hku.hk Jack Hei Wan, School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong,10 Sassoon Road, Hong Kong, E-mail: jack_wan88@ hotmail.com Sydney Chi-Wai TANG, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, E-mail: scwtang@ hku.hk


Introduction
Diabetes is a group of metabolic diseases characterized by hyperglycemia due to insulin resistance, absolute insulin deficiency and/or abnormal insulin secretion [1]. According to the WHO, more than 171 million people worldwide suffer from diabetes and the number of diabetic patients keeps escalating [2].
Diabetes may lead to a series of complications such as blindness, stroke, renal failure, nerve damage and limb amputation [3]. Persistent hyperglycemia brings about chronic damage to various tissues in the heart, eyes, kidneys and blood vessels and causes dysfunctions of these organs. These complications, including nephropathy, retinopathy, neuropathy, cardiomyopathy and cognitive impairment, are major causes of morbidity and mortality in diabetic patients. Consequently, diabetes has become a serious social health problem [4]. According to WHO, diabetes is expected to become the 7th leading cause of death in 2030 globally [5].
However, the current treatment of diabetes with western medicine still leaves much to be desired. There is a paucity of information available on effective treatment options for diabetic patients. Thus, the perspective of achieving good long-term metabolic control in diabetes is of central importance. 6 Traditional Chinese medicine has a long history in treating diabetes and is widely popular in China. Many hospitals in China use traditional medicinal plants or a combination of western medicine with Chinese medicine to treat diabetes.
Yuye Decoction (YYD) is an ancient formulation and was first recorded in the book of Chinese medicine"yixue zhongzhong canxi lu (醫學衷中參西錄)" written by Zhang XiChun in 1909. It is widely used in Traditional Chinese medicine to treat diabetes. There are seven medicinal herbs that compose YYD, including Dioscorea opposite Thunb.  Table 1). In traditional Chinese medicine theory, YYD is beneficial to kidney function and improves the amount of body fluid. Thus, it can be used for relieving the symptoms of diabetes mellitus.
However, as medicinal herbs are usually mixed with other herbs and are seldom used alone in traditional Chinese medicine, it is hard to evaluate the effect of individual herbs on treating diabetes and its complications. Therefore, the aim of this review is to provide a comprehensive coverage of the individual herbs of Yuye Decoction regarding their active components and functional mechanisms for treating diabetes and its complications. It also provides an overview for researchers who intend to perform randomized control trials on YYD in the future.

Literature search
The search was done by using the specific search terms listed in Table 2 to gather information in PubMed regarding the use of YYD and its individual components in the treatment of diabetes respectively. After a preliminary search, articles related to YYD and its component herbs and published from 2009 to 2019 were screened. Articles whose topics matched diabetes and its complications were included. The basic information for each article such as country, experimental design (human, animal, cell based, chemical test) and results were extracted. Irrelevant or repeated articles were excluded.
After preliminary screening, clinical trials and mechanistic studies were analyzed respectively. For all human studies, the details of the study were extracted. Mechanistic studies were divided into animal studies, cell-based studies, animals & cell-based studies and chemical tests. These studies were then further grouped into different categories such as diabetes (not specific), insulin and metabolic syndrome; Type 1 diabetes; Type 2 diabetes; diabetic ophthalmopathy; diabetic nephropathy; diabetic retinopathy; diabetic cardiomyopathy; diabetic vascular complications; diabetic peripheral neuropathy; and diabetic cognitive impairment. Based on the key word search described in Table 2, 2978 articles were found in the PubMed database. Finally, 88 articles were included in our review after comprehensive screening. All 88 included studies came from Asia. Among them, most (73.8%) of the papers were from China (Tables 3 and 4).

Results
Animal studies: Forty-nine animal studies investigated the effects of YYD on diabetes and its complications (Tables 5-7).
Diabetes (not specific), insulin and metabolic syndrome: Fan et al. showed that a polysaccharide DOTP-80 from Dioscorea opposita Thun roots had potent hypoglycemic activity [7]. Another study demonstrated that Discorea batatas extract could ameliorate insulin resistance in mice which were fed a high-fat diet [8]. In fructosefed rats, a daily dose of 2 mg/kg astragaloside for 3 weeks improved metabolic syndrome and endothelial dysfunction [9]. In a cohort study, it was found that Huang-qi (Astragalus membranaceus) was one of the common Chinese medicines which could reduce the risk of diabetic ketoacidosis in diabetic patients [10].

Type 1 diabetes (T1D):
Insulin is a hormone produced by the beta cells in the pancreas. It is important to transfer glucose into cells where glucose will be stored and further used for energy production. In type 1 diabetes, however, the pancreatic beta cells produce little or no insulin [11].   T1DM  T2DM  DR  DN  DO  DCM  DVC  IR  DPN  MetS  DCI  Total   Yuye decoction  1  -----------1 Dioscorea opposita Thunb.

Gallus gallus domesticus
Astragalus membranaceus (Fisch.) Bunge respectively; A 33% reduction in DKA incidence for all TCM users and 40% reduction for users receiving TCM treatment for more than 180 days were found compared with non-TCM users; No significant differences between TCM users and non-users were found in the frequency and medical costs of emergency visits and hospitalizations.

Diabetes
Not mention STZ rat Through stimulating IR kinase activity.
The most common disease that TK was treated for was diabetes. TK was the most frequently used Chinese medicinal herb in type 2 diabetic patients in Taiwan, followed by Astragalus mongholicus, Salvia miltiorrhizae, Dioscoreae opposita, Scrophularia ningpoensis, Ophiopogonis japonicus, Pueraria lobata, Atractylodes lancea, Dendrobium nobile, Rehmannia glutinosa. TK displayed hypoglycemic effects and enhanced the clearance of glucose in a dose-dependent manner in diabetic mice; Interacting with IR; Activating the kinase activity of IR.
It was suggested that acute administration of diosgenin, a compound of Dioscorea, could reduce hyperglycemia with increased muscular steroidogenesis in type 1 diabetes rats [12]. Allantoin, another active constituent in Dioscorea batatas, could improve the function of β-cells to maintain normal plasma insulin and glucose levels in rats [13]. Another study also showed that allantoin could increase GLUT4 gene expression in muscle by increasing β-endorphin secretion from the adrenal glands in diabetic rats [14]. It was found that puerarin isolated from Pueraria lobata (Wild.) could promote insulin expression and ameliorate metabolic functions in streptozotocin (STZ)-induced diabetic mice [15]. Another study revealed that the aqueous extract of Pueraria tuberosa tubers could protect against STZ-induced diabetes by down-regulating β cell apoptosis [16].

Type 2 diabetes (T2D):
Type 2 diabetes is the most common type of diabetes. It is characterized by insulin resistance in which the human body cannot fully respond to insulin. As insulin cannot exert its action properly, the blood glucose level keeps rising. Finally, the pancreas will be exhausted, and hyperglycemia will result [17].
Chen et al. showed that Jia-Wei-Jiao-Tai-Wan (JWJTW), which contains Astragalus membranaceus, could ameliorate T2D by improving β cell function and reducing insulin resistance in diabetic rats [18]. Astragalus polysaccharide (APS) is an important bioactive component of Astragalus membranaceus. It was reported that APS could regulate part of the insulin signaling in insulin-resistant skeletal muscle in KKAy mice [19].
Hong et al. stated that Schisandra chinensis fruit-supplemented Korean rice cookie called dasik (RCD) had lipid-lowering and antidiabetic effects [20]. It was found that an acidic polysaccharide from Schisandra chinensis had a therapeutic effect on T2D rats by regulating apoptosis-related protein expression to alleviate the injury from oxidative stress [21]. A water-soluble polysaccharide (SSPW1) from Schisandra chinensis had antioxidant activities and anti-diabetic effect on T2D rats [22]. Another study disclosed that Schisandrae chinensis oil could improve pancreatic β-cell function by enhancing the antioxidant potential of the pancreas [23].
Wu et al. demonstrated that, after treatment of C57BL/6 mice on a high-fat diet with yam dioscorin for 135 days, weight gain was reduced, and impaired glucose tolerance was improved [24]. A daily dose of 8.02 g /kg of a functional formula diet including Rhizoma dioscorea, for 10 weeks improved insulin sensitivity, hepatic glucokinase activity and antioxidant activity [25]. Carassius auratus Complex Formula, which also contains Rhizoma dioscorea, inhibited the polyol pathway in T2D mice [26]. It was shown that D. opposita Thunb polysaccharide-zinc inclusion complex could reduce blood glucose and insulin levels in T2D rats [27]. Kubo et al. reported that Puerariae flos extract alleviated metabolic diseases in western diet-loaded and spontaneously obese mice representing an animal model of type 2 diabetes [28]. Puerarin (PUE) is a natural isoflavonoid isolated from the root of Pueraria lobata. Previous research had shown that PUE promoted fatty acid oxidation by increasing mitochondrial oxidative capacity and biogenesis in skeletal muscle of diabetic rats [29]. More recent studies confirmed that upregulation of UDP-glucuronosyltransferases 1a1 and 1a7 are involved in altered PUE pharmacokinetics in T2D rats [30]. Qijian mixture, a new traditional Chinese medicine (TCM) formula containing Pueraria lobata could alleviate T2D by altering metabolite profiles and gut microbiota [31]. Ge-Gen-Jiao-Tai-Wan (GGJTW) formula, which is composed of Pueraria montana var. lobata (Willd.), showed a hypoglycemic effect via the tight correlation between BAs and glucoselipid metabolism status [32]. It was suggested that another Chinese Herbal Formula called Shenzhu Tiaopi Granule elicited metabolic improvement in T2D rats by modulating the gut microbiota [33].
Diabetic nephropathy: Diabetic nephropathy (DN) is one of the major complications of diabetes and is the major leading cause of end stage renal disease (ESRD). It is a progressive disease characterized by rising urinary albumin excretion and declining renal functions [34].
Astragaloside IV (AS-IV) is derived from Astragalus membranaceus, a widely used herbal medicine in China. Wang et al. showed that AS-IV attenuated proteinuria in STZ rats by inhibiting endoplasmic reticulum stress [35]. Another study found that AS-IV ameliorated renal injury in STZ rats by inhibiting NF-κB -mediated inflammatory genes expression [36]. According to Wang et al., AS-IV administered to diabetic mice at a dose of 40 mg/kg daily for 10 weeks could delay the renal fibrosis process by influencing the TGF-β/SMADS signaling pathway and down-regulating TGF-β1, SMAD2/3 and α-SMA expression [37]. It was suggested that a novel renoprotective compound, which is composed of Astragalus membranaceus and Panax notoginseng, could synergistically protect against podocyte injury in STZ-induced diabetic rats [38].
It was shown that Trichosanthes kirilowii lectin ameliorated STZinduced kidney injury via modulating the balance between M1/M2 phenotype macrophage [39]. Zhang et al. observed that Schisandra chinensis fruit extract attenuated albuminuria and protected podocyte integrity in STZ-induced diabetic rats [40]. Another investigation revealed that an ethanol extract from Fructus Schisandrae chinensis prevented renal interstitial fibrosis [41].
Sarsasapogenin is a major sapogenin from rhizomes of Anemarrhena asphodeloides Bunge. It was shown that it could markedly ameliorate DN in rats via inhibiting NLRP3 inflammasome activation and AGEs-RAGE interaction [42].
PTY-2 is an active fraction of tubers from Pueraria tuberosa. According to Yamini et al., it could attenuate diabetic nephropathy by upregulating matrix metalloproteinase-9 expression in the kidneys of diabetic rats [43]. In another study by Shukla et al., PTY-2 exerted antioxidant and antiapoptotic effects on DN. Later, the same group discovered that PTY-2 alleviated the kidney damage induced by chronic hyperglycemia and delayed the development of DN by suppressing the expression of HIF-1a and VEGF, thereby restoring the expression of nephrin [44]. It was also found that PTY-2 inhibited iNOS and IL-6 through suppressing the PKC-a and NF-κB pathway in treating DN [45]. Another study suggested that PUE protected against DN by attenuating oxidative stress [46]. A Radix Puerariae and Fructus Crataegi mixture could inhibit DN via decreasing of AKT/PI3K [47].
Diabetic retinopathy: Diabetic retinopathy induced by diabetes involves the retinal capillaries, arterioles and venules. It is accompanied by leakage or occlusion of the small vessels [48].
Diabetic ophthalmopathy: Diabetic ophthalmopathy is a disease induced by diabetes. It impairs patients' eyesight and even causes blindness [50].
It was shown that Anemarrhena asphodeloides rhizomes could counteract diabetic ophthalmopathy progression in STZ-induced diabetic rats [51]. Zhang et al. showed that PUE could prevent cataract development and progression in diabetic rats through the Nrf2/HO-1 signaling pathway [52].
Diabetic cardiomyopathy: Diabetic cardiomyopathy (DCM) is a diabetes-related complication characterized by left ventricular (LV) hypertrophy, myocardial fibrosis, compromised myocardial function and is a leading cause of morbidity and mortality [53].
The study by Chen et al. revealed that Astragalus polysaccharides inhibited DCM in hamsters by suppressing heart chymase activation [54]. It was also demonstrated that Astragalus polysaccharides improved PPRAa-mediated lipotoxicity in DCM [55]. Yu et al. showed that Flos Puerariae Extract could prevent myocardial apoptosis by attenuating oxidative stress in STZ-Induced diabetic mice [56]. Recently, Guo et al. suggested that PUE reduced ischemia/reperfusion-induced myocardial injury in diabetic rats through upregulating vascular endothelial growth factor A/angiotensin-1 and suppressing apoptosis [57].
Diabetic cognitive impairment: Diabetes and insulin resistance affect the central nervous system as well as the development of cognitive and memory impairments which diminish the quality of life of diabetic patients [58].
Astragalus polysaccharides (APS) are active constituents of Astragalus membranaceus. Research finding by Liu et al. demonstrated that APS could improve cognitive dysfunction by altering the gut microbiota in diabetic mice [59]. Dun et al. also found that APS could improve memory in rats with STZ-induced diabetes. This was associated with its effects on glucose and lipid metabolism, antioxidative activity and insulin resistance [60]. In addition, Liu et al. showed that total saponins from Rhizoma Anemarrhenae alleviated diabetes-associated cognitive decline in rats via reduction of amyloid-beta in the brain [61].
Cell-based studies: Twelve cell-based studies investigated the effects on diabetes and its complications (Table 7).

Diabetes (not specific), insulin and metabolic syndrome:
Allantoin is an active principle of the yam. Allantoin could activate I 2B R to enhance glucose uptake into cells. Hence it may be a new target for antidiabetic therapy [62]. Kakkalide is the predominant isoflavone extracted from the flowers of Pueraria lobata. Zhang et al. demonstrated that Kakkalide inhibited reactive oxygen species (ROS)associated inflammation and ameliorated insulin-resistant endothelial dysfunction due to effects on insulin receptor substrate 1(IRS-1) function [63]. Type 2 diabetes: It was shown that Astragalus polysaccharide improved insulin sensitivity via AMPK activation in 3T3-L1 adipocytes [64]. The Schisandra polysaccharide also increased glucose consumption by up-regulating the expression of GLUT-4 in buffalo rat liver cells in the study of Jin et al. [65]. It was reported that Dioscorea polysaccharide manifested inhibitory effects on TNF-α-induced insulin resistance in mouse FL83B cells [66]. Diabetic cardiomyopathy: Astragalus polysaccharides could attenuate DCM by inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose stimulated H9C2 cells [69]. Another study revealed that PUE inhibited high glucose-induced Nlrp3 inflammasome formation and activation by ROS-dependent oxidative pathway [70]. Besides, Danshen-Gegen decoction, which contains Pueraria lobata, had been proven to display a proliferative effect on rat cardiac myoblasts H9c2 via MAPK and insulin pathways [71].
Diabetic peripheral neuropathy: Diabetic peripheral neuropathy, which is one of the most debilitating complications of diabetes, is characterized by axonal degeneration, demyelination, and atrophy [72]. Xue et al. suggested that PUE may protect Schwann cells against glucose fluctuation-induced cell injury by inhibiting apoptosis and oxidative stress [73].

Diabetic cognitive impairment:
It was showed that sarsasapogenin (Sar), an active component purified from Rhizoma Anemarrhenae, suppressed Aβ overproduction induced by a high glucose level in HT-22 cells [74].

Animal studies & cell-based studies:
Diabetes (not specific), insulin and metabolic syndrome: Astragaloside IV improved vascular endothelial dysfunction by inhibiting the TLR4/NF-κB signaling pathway in vivo and in vitro [75].
According to Huang et al., puerarin attenuated endothelial insulin resistance by inhibiting the inflammatory response in an IKKβ/IRS-1dependent manner [76]. T 2 DM: It was reported that APS could potentially activate hepatic insulin signaling in vivo and in vitro [77]. Another study revealed that APS could alleviate glucose toxicity and restore glucose homeostasis in diabetic states by activating AMPK [78]. A Chinese herbal medicine preparation JQ-R, which contains Astragalus membranaceus, manifested anti-diabetic effects in vivo and in vitro [79]. Another decoction called Dangguiliuhuang (DGLHD) exerted anti-insulin resistance and antisteatotic effects by improving abnormal immune and metabolic homeostasis [80].
Gomisin N (GN) is a lignan derived from Schisandra chinensis. Jung et al. showed that GN exerted anti-hyperglycemic effects by AMPK activation [81]. Another study suggested that GN protected against hepatic cannabinoid type 1 receptor-induced insulin resistance and gluconeogenesis [82]. In Huang-Lian-Jie-Du-Tang supplemented with Schisandra chinensis and Polygonatum odoratum Druce, glucose tolerance was improved by potentiating insulinotropic actions in islets [83].
In the study of Han et al., Rhizoma Anemarrhenae extract ameliorated hyperglycemia and insulin resistance through activating AMP-activated protein kinase in vivo as well as in vitro [84]. The antidiabetic potential of Pueraria lobata root extract through promoting insulin signaling and inhibiting PTP1B was demonstrated by Sun et al. [85]. Besides, PUE acted on the skeletal muscle to improve insulin sensitivity in diabetic rats involving μ-opioid receptor [86]. In a multiherbal extract including Pueraria lobata, Yeo et al. showed that PUE had therapeutic effects for treating type 2 diabetes in both cells and animal models [87].

Diabetic cardiomyopathy
A recent study by Chen et al. showed that APS repressed myocardial lipotoxicity in a PPARalpha-dependent manner in vitro and in vivo [89] Shengmai san, which includes Schisandra chinensis, was shown to alleviate diabetic cardiomyopathy by improving mitochondrial lipid metabolic disorder [90].

Diabetic vascular complications:
The vascular complications of diabetes are the most serious manifestations of the disease. Dispo85E is the extract of rhizomes from Dioscorea alata L. It could enhance the clearance of advanced glycation end products (AGEs) through hepatocyte growth factor (HGF)-induced autophagic-lysosomal pathway for treating diabetic vascular complications [91]. Another study suggested that an aqueous extract of the pair of herbs Salvia miltiorrhiza Bunge-Radix Puerariae ameliorated diabetic vascular injury by inhibiting oxidative stress in STZ-induced diabetic rats [92].

Chemical studies
Diabetes (not specific), insulin and metabolic syndrome: A study by Liu et al. revealed a successful application of temperature-correlated mobility theory for separating the main lignans from Schisandra chinensis Fructus and its prescription Yuye Decoction in MEKC [93]. Jinqi Jiangtang Tablet, which is a traditional Chinese anti-diabetic formula containing Astragalus membranaceus, was demonstrated to scavenge free radicals and inhibit α-glucosidase, aldose reductase, α-amylase and lipase for treating diabetes [94]. Another study suggested that selenium-layered nanoparticles used for oral delivery of mulberry leaf and Pueraria lobata extracts expressed a better antihyperglycemic activity [95]. T 2 DM: Lin et al. conducted a tissue distribution study of mangiferin after intragastric administration of the mangiferin monomer, Rhizoma Anemarrhenae, and Rhizoma Anemarrhenae-Phellodendron decoctions in normal or type 2 diabetic rats by LC-MS/MS respectively. Results showed a lower mangiferin distribution in pancreas and intestine of diabetic rats administered with the same dose of the herb pair than that in normal rats [96]. Lin et al. reported that synthetic peptide derived from hydrolysis of yam dioscorin in silico exhibited dipeptidyl peptidase-IV inhibitory activity and improvements in oral glucose tolerance in normal mice [97].
Diabetic nephropathy: A study by Motomura et al. suggested that astragalosides isolated from Astragalus Radix inhibited the formation of advanced glycation end products and astragaloside V had the strongest inhibitory effect. Thus, it could be used to treat diabetic nephropathy [98].

Human studies
Randomized clinical trials (RCT): There was only one RCT in 88 included studies. This RCT study included 43 newly diagnosed type 2 diabetic patients, who had not used any antidiabetic drugs prior to the study. Then, they were randomly assigned into TCM and placebo groups. TCM mixture contains Astragalus mambranesceus. Results showed that TCM mixture could ameliorate insulin resistance in type 2 diabetes, so it is safe and effective for diabetic patients [99].
Case-control study design: A study by Lien et al. retrieved records of samples of patients from the registry for catastrophic illness patients in the National Health Insurance Research Database (NHIRD). Patients with T1DM in 2000-2011 were designated as cases (TCM users) and controls (non-TCM users) based on a frequency (1:4) matched casecontrol design. TCM treatment for patients with T1DM were then analyzed. The incidence of diabetic ketoacidosis and the annual costs of emergency visits and hospitalizations were also evaluated for all causes. Results showed that TCM may have a substantial positive impact on the management of TIDM [100].
A retrospective cohort study and an animal study: Lo et al. conducted a retrospective cohort study to analyze the usage of Chinese herbs in patients with type 2 diabetes in Taiwan and showed that Trichosanthes kirilowii Maxim. (TK) was the most frequently used Chinese medicinal herb. An animal study showed that TK protein enhanced the clearance of glucose in a dose-dependent manner [101].

Dosage:
In animals' studies, the dose of herbs or formula administered ranged between 0.5 mg/kg and 12.15 g/kg per day. In RCT, the dose of formula administered was 9 mg/day. In all human, animal and cell studies, the dosage employed was not mentioned in only 4 out of 82 papers. The dose used was stated explicitly in 95.1% of the papers.
Duration: In all human and animal studies, 3 out of 70 papers did not mention the duration of the study. 95.7% of the papers stated the duration clearly. In animal studies, the duration of treatment ranged from 2 days to 100 days. In RCT, the duration of treatment I was 3 months.
Toxicity: No study indicated the toxicity of medicinal herbs or formulas. No toxicity in human trials has been reported.
The quality of studies: All human, animal and cell studies stated the ratio of the individual herbs if a formula was used. All studies stated the origin, the extraction method and the composition of each constituent herb. However, some studies did not provide the name of pharmaceutical companies and the batch number of the concentrated tablets used in the experiments. There was only one RCT among all the studies examined. The follow-up study details were not stated in this randomized clinical trial. The method of randomization and the placebo detail were not stated clearly. There should be more well-designed RCT in the future in order to provide more and stronger evidence.
The statistics of YYD: There are seven medicinal herbs in YYD. There were research papers on all the herbs except Gallus gallus domesticus Brisson. Among them, the largest number of research papers (30.7%) were about Astragalus membranaceus (Fisch.) Bge. and Pueraria lobata (Willd.) Ohwi. T2DM was studied most (37.5%) of the research papers while DN was the most (19.3%) studied diabetic complication (Table 5).
Most, 49 out of 88 (55.7%) of the papers, reported animal studies. About 20.5% papers were animal & cell-based papers ( Table 6). It is encouraging to do so as in vivo and in vitro studies gave more comprehensive insight on the signaling pathways involved. The protective effects against several diabetic complications are more impressive in in vivo and in vitro models.

Conclusion and future perspectives
The various medicinal herbs in YYD exhibit their antidiabetic activities through different signaling pathways which are illustrated in Figure 1. In compound level all medicinal herbs in YYD, except  Figure 2. Thus, YYD has strong evidences to treat diabetes and its complications. Since YYD and its components are devoid of toxic or allergic effects, in combination with western medicine they may serve as an alternative for mitigating diabetic complications. However, further investigations are necessitated before translation into clinical practice. Our review suggests that YYD and its herbs can improve diabetes and its complications through a diversity of signaling pathways. It may offer a new therapeutic avenue to treat diabetes and its complications. Besides, compelling evidence from well-designed RCT is needed in the future.

Conflict of interests
The authors have no conflict of interests to declare