The Antihyperglycemic Effects of Rhizoma Coptidis and Mechanism of Actions: A Review of Systematic Reviews and Pharmacological Research

Rhizoma Coptidis (Huang Lian in Chinese pinyin) is among the most widely used traditional Chinese herbal medicines and has a profound history of more than 2000 years of being used as a therapeutic herb. The antidiabetic effects of Rhizoma Coptidis have been extensively investigated in animal experiments and clinical trials and its efficacy as a promising antihyperglycemic agent has been widely discussed. In the meantime, findings from modern pharmacological studies have contributed the majority of its bioactivities to berberine, the isoquinoline alkaloids component of the herb, and a number of experiments testing the antidiabetic effects of berberine have been initiated. Therefore, we conducted a review of the current evidence profile of the antihyperglycemic effects of Rhizoma Coptidis as well as its main component berberine and the possible mechanism of actions, in order to summarize research evidence in this area and identify future research directions.


Introduction
Diabetes mellitus refers to a metabolic disorder of multiple etiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from disturbed insulin secretion, insulin action, or both [1]. There are two possible types of diabetes mellitus. Type 1 diabetes, also known as insulin-dependent diabetes, results from an absolute lack of insulin due to autoimmune destruction of the insulin-producing beta cells in the pancreas [2]. Type 2 or non-insulin-dependent diabetes is a metabolic disorder characterized by insulin resistance, relative insulin deficiency, and hyperglycemia [3]. Diabetes mellitus is most closely related to the wasting (Xiao Ke in Chinese pinyin) syndrome as defined by the traditional Chinese medicine diagnostic pattern. Patients with this syndrome typically experience clinical manifestations of emaciation (Xiao in Chinese) and thirst (Ke in Chinese).
According to the WHO diabetes fact sheets, 347 million people in the world have diabetes [4]. In 2004, an estimated 3.4 million people worldwide died from consequences of high blood sugar, and ca. above 80% of diabetes deaths happen in underdeveloped countries [4]. Facing this stark reality, traditional Chinese herbal remedy such as Rhizoma Coptidis (Huang Lian in Chinese pinyin), with its long proven effects for a number of chronic diseases in clinical application and relatively low cost, has been broadly investigated in Asian countries for potential antihyperglycemic effects. hyperactivity, restlessness and insomnia, blood spitting or nose bleeding due to extra heat in the blood, red eyes, and toothache [5].
As early as the Wei and Jin dynasties in the Chinese history (220-589 AD), Rhizoma Coptidis was described as a therapeutic agent for patients suffering from the wasting syndrome. In dynasties that followed, numerous records had been kept in a series of herbal classics of the medicinal use of Rhizoma Coptidis for the wasting syndrome, either alone or combined with other herbs in a formula. This proved the prevalence of the use of Rhizoma Coptidis since ancient times and formed the empirical evidence base for its antidiabetic effects. For example, in the Miscellaneous Records of Famous Physicians, compiled around 510 AD, Rhizoma Coptidis was first described as an agent for the wasting syndrome [6]. In the Newly Revised Materia Medica compiled during the Tang dynasty (618-907 AD), it was noted that "Huang lian grown in west China is bulky, bitter and good for treating the wasting syndrome" [7]. An analytical review of the Song dynasty (960-1279 AD) medical formulary Formulas from Benevolent Sages found that Rhizoma Coptidis was among the top ten most frequently used medicinal herbs in formulas designated for the wasting syndrome [8]. Furthermore, thirteen among the total of 64 herbal formulas for treating the wasting syndrome collected in the Puji Fang Prescriptions for Universal Relief, completed around 1406 AD in the Ming dynasty, contained Rhizoma Coptidis [9]. In the most comprehensive medical book of traditional Chinese medicine, the Compendium of Materia Medica, published in the same dynasty, it recorded that "Huang lian, steamed with wine, is used for treating emaciation, thirst and excessive excretion of urine" [9].
Modern pharmacological research identified the major chemical constituents of Rhizoma Coptidis to be alkaloids including berberine, coptisine, worenine, palmatine, jatrorrhizine, and epiberberine [10,11]. Among the many constituents, the berberine component is generally considered the primary contributor to its main bioactivities such as the antibiotic, antioxidant, and anti-inflammatory properties [12]. In recent years, berberine and Rhizoma Coptidis extracts have also been reported to have multiple antidiabetic activities such as regulating lipid, balancing glucose metabolism, and improving insulin resistance, and the underlying mechanisms of action have been extensively investigated [12].
In view of this, a comprehensive review of the relevant literatures on the antihyperglycemic effects of Rhizoma Coptidis (or berberine) and the mechanism of actions was conducted. The aim of this study is to give a summary of the existing evidence.
Two reviewers Hui Wang and Wei Mu screened citations identified from electronic searches and retrieved the full texts of relevant studies. Then they summarized records in ancient medical books and the findings of systematic reviews and pharmacological studies on the antihyperglycemic effects of berberine, Rhizoma Coptidis extracts, and other Rhizoma Coptidis-containing agents.

3.1.
Overview of Systematic Reviews. Two systematic reviews on the antihyperglycemic effects of berberine were identified. In the first study authored by Dong et al. [13], a total of fourteen randomized controlled trials (RCTs) were included and the results of these studies were subjected to metaanalysis and subgroup analysis. In the later systematic review by Narenqimuge et al. [14], the results of the included ten RCTs were reported descriptively due to significant statistical heterogeneity across studies. The characteristics and results of these two systematic reviews were presented in Table 1.
Drawn upon the above research findings, the isoquinoline-type alkaloid berberine has beneficial effects for blood glucose control in the treatment of type 2 diabetic patients and exhibits efficacy comparable with that of conventional oral hypoglycaemics. No significant statistical difference in the incidence of adverse events was observed between groups. However, the evidence is inconclusive because clinical trials included in the two systematic reviews were of low methodological quality. Therefore, the antihyperglycemic effects of berberine warrant further examination and more rigorously controlled, methodologically sound, and scientifically designed RCTs need to be conducted.

Review of Pharmacological Research.
A number of animal experiments investigating the antihyperglycemic effects of Rhizoma Coptidis, berberine, or herbal prescriptions in which Rhizoma Coptidis plays a dominant role were identified through electronic searches and careful screening. A summary of the experimental models used and the antidiabetic mechanism of berberine observed in these studies were presented in Table 2. From this table, we found the antidiabetic efficacy of berberine associated most closely with its ability to improve insulin sensitivity, influence insulin secretion, and regulate carbohydrate metabolism, and a majority of the pharmacological experiments focused on these aspects . Moreover, some additional bioactivities of berberine which may facilitate its antidiabetic effects were identified, such as its antioxidant, lipid regulatory, and anti-inflammatory functions as well as its renoprotective properties to prevent diabetes complications. These effects of berberine and the relevant mechanisms were demonstrated in Table 3.
Findings from previous researches showed that the insulin-stimulated glucose uptake by target tissues such as

Streptozotocininduced diabetic rats
Reduced oxidative stress and deactivated aldose reductase [75,76] SOD: superoxide dismutase; LPL: lipoprotein lipase; P-TEFb: positive transcription elongation factor b; CRP: C-reactive protein; IL-6: interleukin-6; NF-b: nuclear transcription factor-b; SphK: sphingosine kinase. Reverse insulin resistance 3T3-L1 preadipocytes Increased glucose uptake in preadipocytes [80] Rhizoma Coptidis coupled with Panax Ginseng Enhance insulin sensitivity Type 2 diabetic rats Lowered TNF-levels, prevented TNF-from inhibiting the expression of GLUT4 in fat and muscle cells, improved autophosphorylation of insulin receptor, inhibited second messenger activation, and promoted lipolysis [81] Reverse insulin resistance and regulate glucose and lipid metabolism Type 2 diabetic rats Reduced lipotoxicity [81] Antihyperglycemic effects Type 2 diabetic rats Activated PPAR-, slowed the release of FFA, enhanced the sensitivity of skeletal muscles and the liver to insulin, reduced the exportation of glycogen, and promoted the uptake of glucose in skeletal muscles [81] Reverse insulin resistance Type 2 diabetic rats Regulated FBG, INS, FFA, and TNF-levels and improved insulin resistance [82] Enhance insulin sensitivity adipocytes and skeletal muscles involved a series of signaling transduction cascades starting from insulin receptor (InsR) via insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI-3K) and leading to the translocation of glucose transporter (GLUT4) [77]. From this comprehensive review of the existing pharmacological research on the antihyperglycemic effects of Rhizoma Coptis and its major chemical ingredient berberine, the reviewers summarized a variety of possible mechanisms of action behind its antidiabetic properties, which include the promotion of insulin secretion and release, reparation of pancreatic islets -cells, enhancement of insulin sensitivity, suppression of gluconeogenesis in the liver, promotion of glucose disposal in the periphery, and inhibition of aldose reductase . The mechanisms for Rhizoma Coptis and its component berberine's other bioactivities that may facilitate its antidiabetic functions include ameliorating oxidative stress accompanying diabetes, regulating plasma levels of adiponectin and other relevant inflammatory factors, increasing adipocytes glucose transportation and consumption, and modulating metabolism-related protein expression [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76].

Discussion
According to traditional beliefs, Chinese herbal remedy helps recover inner peace and tranquility in the human body with its multiple active constituents taking effects through various mechanisms and pathways. Therefore, the use of Chinese herbal medicines for diabetes treatment or for the prevention of diabetes complications might be generally considered good for the patients' general well-being, apart from their effectiveness and safety.
The existing evidence profile of the antihyperglycemic effects of Rhizoma Coptidis includes both textual records in ancient herbal classics and findings from animal experiments and systematic reviews of RCTs. Modern research uniformly focuses on berberine, whereas the pharmacological actions of other active ingredients of Rhizoma Coptidis, of single herb remedy, and of Rhizoma Coptidis-dominant couplet medicines and Rhizoma Coptidis-containing patent drug still remain to be investigated.
As was summarized in this review, the antihyperglycemic effects of Rhizoma Coptidis may rely upon drug actions on a variety of targets via multiple pathways. Many animal experiments [78][79][80][81][82][83][84][85][86][87][88][89] have proposed the scientific rationale for Rhizoma Coptidis, Rhizoma Coptidis-containing agents, or its major component berberine's antihyperglycemic effects by identifying possible mechanisms of actions. The widespread use of Rhizoma Coptidis as a routine clinical treatment for diabetes is promising because there is abundant supply, the herb is relatively inexpensive, and it has a good safety profile [13,14]. However, the results of both systematic reviews included in this study need to be interpreted with caution. As large-scale, rigorously controlled, and multicenter randomized controlled clinical studies are still lacking, the clinical efficacy and safety of Rhizoma Coptidis and berberine for antidiabetic use needs further investigation.
Furthermore, there were other issues to consider before Rhizoma Coptidis can be put into extensive clinical use. For instance, the most appropriate drug form and dosage, dose-effect relationship, and drug-drug interactions should be made clear through a series of pharmacological experiments and long-term clinical observations. Also, whether the antihyperglycemic effect is best exerted synergically in a prescription or independently as an active component remains to be investigated. Besides, the possible antidiabetic effects of the other chemical ingredients of Rhizoma Coptidis and the interactions among its various components, as well as the long-term health benefits of its use in diabetic patients, are all problems that need to be addressed in future research.