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

Authors: Hui Wang; Wei Mu; Hongcai Shang; Jia Lin; Xiang Lei
Journal: BioMed Research International
 (2014)

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## Abstract

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.


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## Body

## 1. 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.Rhizoma Coptidis (Huang Lian) is the dried rhizome ofCoptis chinensis Franch,Coptis deltoidea C. Y. Cheng et Hsiao orCoptis teeta Wall. As first recorded inShennong’s Materia Medicain the eastern Han dynasty (25–220 AD), the herbal medicine has been prescribed by Chinese herbalists for a variety of illnesses and conditions for more than 2000 years. According to traditional beliefs, Rhizoma Coptidis is cold in nature and bitter in taste and enters the heart, spleen, stomach, liver, gallbladder, and large intestine meridians. It has the function of clearing heat, drying dampness, and purging fire toxins [5]. Main indications include the wasting (Xiao Ke) syndrome, distention, and fullness due to dampness and heat, sickness, acid regurgitation, jaundice, palpitation, diarrhea caused by bacterial infection, high fever, heart-fever 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 theMiscellaneous Records of Famous Physicians, compiled around 510 AD, Rhizoma Coptidis was first described as an agent for the wasting syndrome [6]. In theNewly 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 formularyFormulas 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 thePuji 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, theCompendium 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.


## 2. Method

In January 2013 two reviewers (Hui Wang and Wei Mu) searched the following Chinese-language electronic databases: Chinese Biomedical Literature Database (CBM, 1980–2013), Chinese Journal Full-Text Database (CNKI, 1980–2013), Weipu Journal Database (VIP, 1989–2013), and Wanfang Data (1990–2013), and three English-language databases: PubMed, EMBASE (1989–2013), and the Cochrane Library. The search terms included “huang lian,” “Coptis,” “berberine,” “hypoglycemic,” “diabetes,” and “xiaoke” in English or Chinese. These terms were searched as free text in the title or the abstract.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. Results

### 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 meta-analysis 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.Table 1
A summary of findings from systematic reviews on the antihyperglycemic effects of berberine.
Outcomes
StudyID
StudyYear
Numberof RCTs
Numberof cases
Results
Conclusion
FPG/PPG/HbA1c/FINS/TG/TC/LDL-C/HDL-C
Dong et al. [13]
2012
4
271
Compared with lifestyle changes with or without placebo, berberine plus lifestyle changes showed significantly better hypoglycaemic and antidyslipidemic effects.
Trials had poor methodological and reporting quality. The conclusions made were inconclusive and further research is needed.
FPG/HbA1c/TC/LDL-C
Dong et al. [13]
2012
7
448
Compared with oral hypoglycaemics (metformin, glipizide, or rosiglitazone) berberine did not demonstrate significantly better hypoglycaemic effects but showed mild antidyslipidemic effects.
FPG/PPG/HbA1c/FINS/TG/TC/LDL-C/HDL-C
Dong et al. [13]
2012
6
396
Compared with oral hypoglycaemic drugs, berberine combined with the same oral hypoglycaemics can better control blood sugar in the patients.
FBG/2hPBG/HbA1c/LDL-C/HDL-C/TG/TC/BMI
Narenqimuge et al. [14]
2012
10
647
Berberine was effective in lowering FBG but not better than metformin, glipizide, or rosiglitazone. Berberine had no proven effects in decreasing PBG, HbAlc, or BMI and in regulating lipid metabolism.
Trials were at high risk of bias. High-quality trials are needed.
Adverse events
Dong et al. [13]
2012
14
1068
Three studies did not report AEs. Three  reported no AEs. Three  reported adverse events but did not indicate the group in which they occurred. Five reported AEs in the berberine group.
No significant difference between the treatment and the control group.
Adverse events
Narenqimuge et al. [14]
2012
7
435
Seven studies reported that AEs happened in the course of the treatment, mostly gastrointestinal reactions such as constipation and diarrhea. Of them 3 studies reported the number of cases of AEs.
No significant difference between the treatment and the control group.
FPG: fasting blood glucose; PPG: postprandial plasma glucose; HbA1c: hemoglobin A1c; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein; HDL-C: high-density lipoprotein; FINS: fasting insulin; 2hPBG: 2-hour postprandial blood glucose; BMI: body mass index; AEs: adverse events.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.


### 3.2. 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 Table2. 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 [15–61]. 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.Table 2
Summary of berberine’s effects on insulin and glucose metabolism and the mechanism of action [15–61].
Experimental model
Mechanism of action
T2DM Chinese hamsters
Changed the expression of hepatic peroxisome proliferator-activated receptors and its target genes [15]
3T3-L1 cells
Increased glucose uptake in fat cells and inhibited the differentiation of preadipocytes [16]
Sprague Dawley rats
Reduced plasma FFA and triglyceride levels and inhibited the expression of liver TNF-α [17]
Sprague Dawley rats
Increased HNF-4α expression [18]
Wistar rats
Regulated the expression of endoplasmic reticulum chaperone ORP150 and reduced ER stress [19]
HepG2 cells
Regulated AMPK activity to decrease its downstream gluconeogenesis protein expression [20]
Wistar rats
Inhibited pancreaticβ-cell apoptosis by inhibiting ASK1 protein expression [21]
Wistar rats
Increased PI-3K p85 and GLUT4 protein expression in skeletal muscles of T2DM rats [22]
Insulin resistant rat models
Inhibited TNF-α secretion and reduced serum free fatty acid level [23]
Wistar rats
Increased mRNA expression of adiponectin gene and decreased IRI in T2DM rats [24]
T2DM Chinese hamsters
Inhibited the expression of PEPCK, 6Pase, and PGC-1α by enhancing CYP7A1 and Gck expression induced by the upregulation of LXRα expression [25]
L6 myotubes
Inhibited fatty acid uptake at least in part by reducing PPAR gamma and FAT/CD36 expression [26]
L6 rat skeletal muscle cells
Induced InsR gene expression through a protein kinase C (PKC) dependent activation of its promoter. Inhibited PKC abolished BBR-caused InsR promoter activation and InsR mRNA transcription [27]
Nonalcoholic fatty liverdisease rat liver
Upregulated the mRNA and protein levels of IRS-2 [28]
3T3-L1 adipocytes
Reversed free fatty acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ [29]
Cultured HepG2 cells
Attenuated ER stress and improved insulin signal transduction [30]
Rat skeletal muscle cells
Modulated key molecules in the insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells [31]
Insulin resistant rat models
Stimulated AMPK activity [32]
T2DM hamsters
Altered the transcriptional programs of the visceral white adipose tissue LXRs, PPARs, and SREBPs [33]
Diabetic hamsters
Altered the transcriptional programs of hepatic SREBPs, LXRα, and PPARα [34]
Mouse primary hepatocyte
Upregulated HNF4α expression to induce hepatic glucokinase activity [35]
Mouse primary hepatocyte
Upregulated HNF6 mRNA expression and induced hepatic glucokinase activity [36]
HepG2 cells
Increased hepatic glucose consumption [37]
Wistar rats
Elevated IRS-1, IRS-2, and p85 mRNA expression in the peripheral tissues [38]
Sprague Dawley rats
Increased the content of GLU4 mRNA in skeletal muscles, increased the content of GLUT4 protein in cells, and enhanced insulin activity in the peripheral tissues [39]
Kunming mice
Inhibited gluconeogenesis and/or stimulated glycolysis [40]
Diabetic rat model
Stimulated GLP-1 release [41]
Wistar rats
Regulated INS and GH levels by enhancing SS levels through the hypothalamus-pituitary-pancreatic axis system [42]
HepG2 cells
Increased InsR mRNA transcription and protein expression [43]
Alloxan-induced diabetic mice
Upregulated the activity of Akt [44]
Wistar rats
Stimulated GK activity and expression [45]
3T3-L1 adipocytes and L6 myocytes
Inhibited PTP 1B activity and increased phosphorylation of IR, IRS1, and Akt in 3T3-L1 adipocytes [46]
Streptozotocin-induceddiabetic rats
Enhanced GLP-1-(7-36) amide secretion [47]
Mammalian cells
Functioned as an agonist of the fatty acid receptor GPR40 [48]
T2DM rat models
Lowered serum RBP4 levels and upregulated the expression of tissue GLUT4 protein [49]
Streptozotocin-induceddiabetic rats
Exhibited inhibitory effects on intestinal disaccharidases andβ-glucuronidase  [50]
L6 rat skeletal muscles
Stimulated glucose uptake through the AMP-AMPK-p38 MAPK pathway [51]
3T3-L1 adipocytes
Enhanced GLUT1 expression and stimulated the GLUT1-mediated glucose uptake by activating GLUT1 [52]
Alloxan-induced diabeticC57BL/6 mice
Upregulated Akt activity via insulin signaling pathways [53]
Molecular model
Inhibited H-PTP 1B [54]
Streptozotocin-induceddiabetic rats
Involved PKA-dependent pathways [55]
Normal animals(dogs and rats)
Acutely inhibitedα-glucosidase [56]
Molecular model
Inhibited DPP IV [57]
L929 fibroblast cells
Significantly activated GLUT1 transport [58]
Diabetic rats
Directly inhibited gluconeogenesis in the liver [59]
Rat model
Inhibition of glucose oxidation in mitochondria may contribute to increased AMP/ATP ratio and AMPK activation [60]
Caco-2 cell line
Inhibitedα-glucosidase activity and decreased glucose transport across the intestinal epithelium [61]
T2DM: type 2 diabetes mellitus; TNF: tumor necrosis factor; FFA: free fatty acid; HNF: hepatocyte nuclear factor; ER: endoplasmic reticulum; ORP: oxygen-regulated protein; AMPK: AMP-activated protein kinase; ASK: apoptosis signal-regulating kinase; mRNA: messenger RNA; IRI: insulin resistant index; PEPCK: phosphoenolpyruvate carboxylase kinase; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator 1α; CYP7A1: cholesterol 7 α-hydroxylase; GCK: glucokinase; PI-3K: phosphatidylinositol 3-kinase; GLUT4: glucose transporter type 4; PPAR: peroxisome proliferator-activated receptor; FAT/CD36: fatty acid translocase; PKC: protein kinase C; BBR: berberine; IKKβ: inhibitor kappa B kinase β; LXRs: liver X receptors; SREBPs: sterol regulatory element binding proteins; IRS: insulin receptor substrates; GLP: glucagon-like peptide; INS: insulin; GH: growth hormone; SS: somatostatin; Akt: protein kinase B; PTP1B: protein tyrosine phosphatase 1B; IR: insulin resistance; GPR40: G protein-coupled receptor 40; RBP4: retinol-binding protein 4; H-PTP 1B: human protein tyrosine phosphatase 1B; DPP IV: dipeptidyl peptidase IV; AMP: adenosine monophosphate; ATP: adenosine triphosphate.Table 3
Summary of other effects of berberine and the mechanism of action [62–76].
Effects
Experimental model
Mechanism of action
Antioxidative effects
Type 2 diabetic rats
Reduced oxidative stress [62]
Hypolipidemic effects
Wistar rats
Decreased blood FFA level and enhanced the activity of lipoprotein lipase [63]
Type 2 diabetic rats
Increased PPARs and P-TEFb mRNA and protein expression in the adipose tissue. Restored SOD and LPL activity and normalized malondialdehyde, FFA, TNF-α, and adiponectin levels [64]
3T3-L1 adipocytes
Increased glucose transport and consumption in 3T3-L1 adipocytes [65]
3T3-L1 adipocytes
Modulated metabolism-related PPARs expression and differentiation-related P-TEFb expression in adipocytes [66]
3T3-L2 adipocytes
Activated adenosine monophosphate, activated protein kinase [67]
Diabetic hyperlipidemic and normal rats
Modulated metabolism-related PPAR alpha/delta/gamma protein expression in the liver [68]
Anti-inflammatory actions
Type 2 diabetic rats
Regulated serum levels of inflammatory factors such as CRP, IL-6, TNF-α, and adiponectin [69]
Effects on renal injury
Glomerular mesangial cells
Inhibited NF-κB activation and the expression of its downstream inflammatory factors to improve ECM accumulation and alleviate inflammatory injury in diabetic kidney [70]
Prevention of diabetes complications
Type 2 diabetic rats
Enhanced vascular smooth muscle activity [71]
Renal protective effects
Rat glomerular mesangial cells
Reduced the accumulation of extracellular matrix components including fibronectin and prevented the activation of the p38 MAPK signaling pathway [72]
Diabetic rats
Inhibited glycosylation and exhibited antioxidative effects [73]
Diabetic C57BL/6 mice
Deactivated the SphK-S1P signaling pathway [74]
Streptozotocin-induced 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-κb: nuclear transcription factor-κb; SphK: sphingosine kinase.Findings from previous researches showed that the insulin-stimulated glucose uptake by target tissues such as 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 β-cells, enhancement of insulin sensitivity, suppression of gluconeogenesis in the liver, promotion of glucose disposal in the periphery, and inhibition of aldose reductase [15–61]. 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 [62–76].In addition to the above findings, results from a few studies [78–89] investigating the effects of Rhizoma Coptidis extracts, Rhizoma Coptidis-dominant couplet medicines, and Rhizoma Coptidis-containing Chinese patent drugs have showed them all to possess certain antihyperglycemic effects. Rhizoma Coptidis-dominant couplet medicines included Rhizoma Coptidis coupled with Panax Ginseng, Rhizoma Coptidis coupled with dried Rehmannia root, and a combination of Rhizoma Coptidis, Astragalus Mongholicus, and Solomonseal Rhizome. Rhizoma Coptidis-containing Chinese patent drug involved Jinlian Jiangtang capsules and Jinqi Jiangtang tablets. Their therapeutic properties, possible mechanisms, and other information were listed in Table 4.Table 4
Summary of the antihyperglycemic effects of Rhizoma Coptidis extracts, Rhizoma Coptidis-dominant couplet medicines, or Chinese patent drug and the relevant mechanisms [78–89].
Drug
Effects
Experimental model
Mechanism of actions
Rhizoma Coptidis decoction
Antihyperglycemiceffects
Rat brain homogenate
Inhibited pancreatic lipid peroxidation [78]
Reverse insulin resistance
Rat model with metabolic syndrome
Reversed insulin resistance, reduced visceral fat, and upregulated the expression of p-AMPK-A protein [79]
Water extracts of Rhizoma Coptidis
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-α levels, prevented TNF-α 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]
Antihyperglycemiceffects
Type 2 diabetic rats
Activated PPAR-γ, 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-α levels and improved insulin resistance [82]
Enhance insulin sensitivity
Type 2 diabetic rats
Regulated lipid metabolism and reversed lipotoxicity [83]
A combination of Rhizoma Coptidis, Astragalus Mongholicus, and Solomonseal Rhizome
Vascular-protective
Wistar rats
Increased erythrocyte SOD activity and decreased serum MDA level, thereby reducing free radical damages in the hyperglycemic state [84]
Sanhuang compound (a mixture of Rhizoma Coptidis, Radix Astragali, and Radix Rehmanniae)
Antihyperglycemic and hypolipidemic effects
Type 2 diabetic rats
Protected and repaired pancreas, enhanced insulin secretion and glycogenesis, and inhibited gluconeogenesis [85]
Rhizoma Coptidis coupled with dried Rehmannia root
Reverse insulin resistance
Type 2 diabetic rats
Decreased the levels of inflammatory cytokine to improve insulin resistance and inhibited apoptosis of islet cells to protect isletβ-cells [86]
Jinlian Jiangtang capsules
Antihyperglycemic effects
Kunming mice
Promoted insulin release and glucose uptake and improvedβ-cell functioning [87]
Jinqi Jiangtang tablets
Reverse insulin resistance and antihyperglycemic effects
Wistar  rats
Inhibited resistin gene expression [88]
Antihyperglycemic effects
3T3-L1 cells and KK-Ay mice
Activated the AMPK signaling pathway [89]
MDA: malondialdehyde.


## 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 meta-analysis 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.Table 1
A summary of findings from systematic reviews on the antihyperglycemic effects of berberine.
Outcomes
StudyID
StudyYear
Numberof RCTs
Numberof cases
Results
Conclusion
FPG/PPG/HbA1c/FINS/TG/TC/LDL-C/HDL-C
Dong et al. [13]
2012
4
271
Compared with lifestyle changes with or without placebo, berberine plus lifestyle changes showed significantly better hypoglycaemic and antidyslipidemic effects.
Trials had poor methodological and reporting quality. The conclusions made were inconclusive and further research is needed.
FPG/HbA1c/TC/LDL-C
Dong et al. [13]
2012
7
448
Compared with oral hypoglycaemics (metformin, glipizide, or rosiglitazone) berberine did not demonstrate significantly better hypoglycaemic effects but showed mild antidyslipidemic effects.
FPG/PPG/HbA1c/FINS/TG/TC/LDL-C/HDL-C
Dong et al. [13]
2012
6
396
Compared with oral hypoglycaemic drugs, berberine combined with the same oral hypoglycaemics can better control blood sugar in the patients.
FBG/2hPBG/HbA1c/LDL-C/HDL-C/TG/TC/BMI
Narenqimuge et al. [14]
2012
10
647
Berberine was effective in lowering FBG but not better than metformin, glipizide, or rosiglitazone. Berberine had no proven effects in decreasing PBG, HbAlc, or BMI and in regulating lipid metabolism.
Trials were at high risk of bias. High-quality trials are needed.
Adverse events
Dong et al. [13]
2012
14
1068
Three studies did not report AEs. Three  reported no AEs. Three  reported adverse events but did not indicate the group in which they occurred. Five reported AEs in the berberine group.
No significant difference between the treatment and the control group.
Adverse events
Narenqimuge et al. [14]
2012
7
435
Seven studies reported that AEs happened in the course of the treatment, mostly gastrointestinal reactions such as constipation and diarrhea. Of them 3 studies reported the number of cases of AEs.
No significant difference between the treatment and the control group.
FPG: fasting blood glucose; PPG: postprandial plasma glucose; HbA1c: hemoglobin A1c; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein; HDL-C: high-density lipoprotein; FINS: fasting insulin; 2hPBG: 2-hour postprandial blood glucose; BMI: body mass index; AEs: adverse events.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.


## 3.2. 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 Table2. 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 [15–61]. 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.Table 2
Summary of berberine’s effects on insulin and glucose metabolism and the mechanism of action [15–61].
Experimental model
Mechanism of action
T2DM Chinese hamsters
Changed the expression of hepatic peroxisome proliferator-activated receptors and its target genes [15]
3T3-L1 cells
Increased glucose uptake in fat cells and inhibited the differentiation of preadipocytes [16]
Sprague Dawley rats
Reduced plasma FFA and triglyceride levels and inhibited the expression of liver TNF-α [17]
Sprague Dawley rats
Increased HNF-4α expression [18]
Wistar rats
Regulated the expression of endoplasmic reticulum chaperone ORP150 and reduced ER stress [19]
HepG2 cells
Regulated AMPK activity to decrease its downstream gluconeogenesis protein expression [20]
Wistar rats
Inhibited pancreaticβ-cell apoptosis by inhibiting ASK1 protein expression [21]
Wistar rats
Increased PI-3K p85 and GLUT4 protein expression in skeletal muscles of T2DM rats [22]
Insulin resistant rat models
Inhibited TNF-α secretion and reduced serum free fatty acid level [23]
Wistar rats
Increased mRNA expression of adiponectin gene and decreased IRI in T2DM rats [24]
T2DM Chinese hamsters
Inhibited the expression of PEPCK, 6Pase, and PGC-1α by enhancing CYP7A1 and Gck expression induced by the upregulation of LXRα expression [25]
L6 myotubes
Inhibited fatty acid uptake at least in part by reducing PPAR gamma and FAT/CD36 expression [26]
L6 rat skeletal muscle cells
Induced InsR gene expression through a protein kinase C (PKC) dependent activation of its promoter. Inhibited PKC abolished BBR-caused InsR promoter activation and InsR mRNA transcription [27]
Nonalcoholic fatty liverdisease rat liver
Upregulated the mRNA and protein levels of IRS-2 [28]
3T3-L1 adipocytes
Reversed free fatty acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ [29]
Cultured HepG2 cells
Attenuated ER stress and improved insulin signal transduction [30]
Rat skeletal muscle cells
Modulated key molecules in the insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells [31]
Insulin resistant rat models
Stimulated AMPK activity [32]
T2DM hamsters
Altered the transcriptional programs of the visceral white adipose tissue LXRs, PPARs, and SREBPs [33]
Diabetic hamsters
Altered the transcriptional programs of hepatic SREBPs, LXRα, and PPARα [34]
Mouse primary hepatocyte
Upregulated HNF4α expression to induce hepatic glucokinase activity [35]
Mouse primary hepatocyte
Upregulated HNF6 mRNA expression and induced hepatic glucokinase activity [36]
HepG2 cells
Increased hepatic glucose consumption [37]
Wistar rats
Elevated IRS-1, IRS-2, and p85 mRNA expression in the peripheral tissues [38]
Sprague Dawley rats
Increased the content of GLU4 mRNA in skeletal muscles, increased the content of GLUT4 protein in cells, and enhanced insulin activity in the peripheral tissues [39]
Kunming mice
Inhibited gluconeogenesis and/or stimulated glycolysis [40]
Diabetic rat model
Stimulated GLP-1 release [41]
Wistar rats
Regulated INS and GH levels by enhancing SS levels through the hypothalamus-pituitary-pancreatic axis system [42]
HepG2 cells
Increased InsR mRNA transcription and protein expression [43]
Alloxan-induced diabetic mice
Upregulated the activity of Akt [44]
Wistar rats
Stimulated GK activity and expression [45]
3T3-L1 adipocytes and L6 myocytes
Inhibited PTP 1B activity and increased phosphorylation of IR, IRS1, and Akt in 3T3-L1 adipocytes [46]
Streptozotocin-induceddiabetic rats
Enhanced GLP-1-(7-36) amide secretion [47]
Mammalian cells
Functioned as an agonist of the fatty acid receptor GPR40 [48]
T2DM rat models
Lowered serum RBP4 levels and upregulated the expression of tissue GLUT4 protein [49]
Streptozotocin-induceddiabetic rats
Exhibited inhibitory effects on intestinal disaccharidases andβ-glucuronidase  [50]
L6 rat skeletal muscles
Stimulated glucose uptake through the AMP-AMPK-p38 MAPK pathway [51]
3T3-L1 adipocytes
Enhanced GLUT1 expression and stimulated the GLUT1-mediated glucose uptake by activating GLUT1 [52]
Alloxan-induced diabeticC57BL/6 mice
Upregulated Akt activity via insulin signaling pathways [53]
Molecular model
Inhibited H-PTP 1B [54]
Streptozotocin-induceddiabetic rats
Involved PKA-dependent pathways [55]
Normal animals(dogs and rats)
Acutely inhibitedα-glucosidase [56]
Molecular model
Inhibited DPP IV [57]
L929 fibroblast cells
Significantly activated GLUT1 transport [58]
Diabetic rats
Directly inhibited gluconeogenesis in the liver [59]
Rat model
Inhibition of glucose oxidation in mitochondria may contribute to increased AMP/ATP ratio and AMPK activation [60]
Caco-2 cell line
Inhibitedα-glucosidase activity and decreased glucose transport across the intestinal epithelium [61]
T2DM: type 2 diabetes mellitus; TNF: tumor necrosis factor; FFA: free fatty acid; HNF: hepatocyte nuclear factor; ER: endoplasmic reticulum; ORP: oxygen-regulated protein; AMPK: AMP-activated protein kinase; ASK: apoptosis signal-regulating kinase; mRNA: messenger RNA; IRI: insulin resistant index; PEPCK: phosphoenolpyruvate carboxylase kinase; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator 1α; CYP7A1: cholesterol 7 α-hydroxylase; GCK: glucokinase; PI-3K: phosphatidylinositol 3-kinase; GLUT4: glucose transporter type 4; PPAR: peroxisome proliferator-activated receptor; FAT/CD36: fatty acid translocase; PKC: protein kinase C; BBR: berberine; IKKβ: inhibitor kappa B kinase β; LXRs: liver X receptors; SREBPs: sterol regulatory element binding proteins; IRS: insulin receptor substrates; GLP: glucagon-like peptide; INS: insulin; GH: growth hormone; SS: somatostatin; Akt: protein kinase B; PTP1B: protein tyrosine phosphatase 1B; IR: insulin resistance; GPR40: G protein-coupled receptor 40; RBP4: retinol-binding protein 4; H-PTP 1B: human protein tyrosine phosphatase 1B; DPP IV: dipeptidyl peptidase IV; AMP: adenosine monophosphate; ATP: adenosine triphosphate.Table 3
Summary of other effects of berberine and the mechanism of action [62–76].
Effects
Experimental model
Mechanism of action
Antioxidative effects
Type 2 diabetic rats
Reduced oxidative stress [62]
Hypolipidemic effects
Wistar rats
Decreased blood FFA level and enhanced the activity of lipoprotein lipase [63]
Type 2 diabetic rats
Increased PPARs and P-TEFb mRNA and protein expression in the adipose tissue. Restored SOD and LPL activity and normalized malondialdehyde, FFA, TNF-α, and adiponectin levels [64]
3T3-L1 adipocytes
Increased glucose transport and consumption in 3T3-L1 adipocytes [65]
3T3-L1 adipocytes
Modulated metabolism-related PPARs expression and differentiation-related P-TEFb expression in adipocytes [66]
3T3-L2 adipocytes
Activated adenosine monophosphate, activated protein kinase [67]
Diabetic hyperlipidemic and normal rats
Modulated metabolism-related PPAR alpha/delta/gamma protein expression in the liver [68]
Anti-inflammatory actions
Type 2 diabetic rats
Regulated serum levels of inflammatory factors such as CRP, IL-6, TNF-α, and adiponectin [69]
Effects on renal injury
Glomerular mesangial cells
Inhibited NF-κB activation and the expression of its downstream inflammatory factors to improve ECM accumulation and alleviate inflammatory injury in diabetic kidney [70]
Prevention of diabetes complications
Type 2 diabetic rats
Enhanced vascular smooth muscle activity [71]
Renal protective effects
Rat glomerular mesangial cells
Reduced the accumulation of extracellular matrix components including fibronectin and prevented the activation of the p38 MAPK signaling pathway [72]
Diabetic rats
Inhibited glycosylation and exhibited antioxidative effects [73]
Diabetic C57BL/6 mice
Deactivated the SphK-S1P signaling pathway [74]
Streptozotocin-induced 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-κb: nuclear transcription factor-κb; SphK: sphingosine kinase.Findings from previous researches showed that the insulin-stimulated glucose uptake by target tissues such as 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 β-cells, enhancement of insulin sensitivity, suppression of gluconeogenesis in the liver, promotion of glucose disposal in the periphery, and inhibition of aldose reductase [15–61]. 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 [62–76].In addition to the above findings, results from a few studies [78–89] investigating the effects of Rhizoma Coptidis extracts, Rhizoma Coptidis-dominant couplet medicines, and Rhizoma Coptidis-containing Chinese patent drugs have showed them all to possess certain antihyperglycemic effects. Rhizoma Coptidis-dominant couplet medicines included Rhizoma Coptidis coupled with Panax Ginseng, Rhizoma Coptidis coupled with dried Rehmannia root, and a combination of Rhizoma Coptidis, Astragalus Mongholicus, and Solomonseal Rhizome. Rhizoma Coptidis-containing Chinese patent drug involved Jinlian Jiangtang capsules and Jinqi Jiangtang tablets. Their therapeutic properties, possible mechanisms, and other information were listed in Table 4.Table 4
Summary of the antihyperglycemic effects of Rhizoma Coptidis extracts, Rhizoma Coptidis-dominant couplet medicines, or Chinese patent drug and the relevant mechanisms [78–89].
Drug
Effects
Experimental model
Mechanism of actions
Rhizoma Coptidis decoction
Antihyperglycemiceffects
Rat brain homogenate
Inhibited pancreatic lipid peroxidation [78]
Reverse insulin resistance
Rat model with metabolic syndrome
Reversed insulin resistance, reduced visceral fat, and upregulated the expression of p-AMPK-A protein [79]
Water extracts of Rhizoma Coptidis
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-α levels, prevented TNF-α 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]
Antihyperglycemiceffects
Type 2 diabetic rats
Activated PPAR-γ, 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-α levels and improved insulin resistance [82]
Enhance insulin sensitivity
Type 2 diabetic rats
Regulated lipid metabolism and reversed lipotoxicity [83]
A combination of Rhizoma Coptidis, Astragalus Mongholicus, and Solomonseal Rhizome
Vascular-protective
Wistar rats
Increased erythrocyte SOD activity and decreased serum MDA level, thereby reducing free radical damages in the hyperglycemic state [84]
Sanhuang compound (a mixture of Rhizoma Coptidis, Radix Astragali, and Radix Rehmanniae)
Antihyperglycemic and hypolipidemic effects
Type 2 diabetic rats
Protected and repaired pancreas, enhanced insulin secretion and glycogenesis, and inhibited gluconeogenesis [85]
Rhizoma Coptidis coupled with dried Rehmannia root
Reverse insulin resistance
Type 2 diabetic rats
Decreased the levels of inflammatory cytokine to improve insulin resistance and inhibited apoptosis of islet cells to protect isletβ-cells [86]
Jinlian Jiangtang capsules
Antihyperglycemic effects
Kunming mice
Promoted insulin release and glucose uptake and improvedβ-cell functioning [87]
Jinqi Jiangtang tablets
Reverse insulin resistance and antihyperglycemic effects
Wistar  rats
Inhibited resistin gene expression [88]
Antihyperglycemic effects
3T3-L1 cells and KK-Ay mice
Activated the AMPK signaling pathway [89]
MDA: malondialdehyde.


## 4. 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 [15–76, 78–89] 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.



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