Review Article | Open Access
Hui Wang, Wei Mu, Hongcai Shang, Jia Lin, Xiang Lei, "The Antihyperglycemic Effects of Rhizoma Coptidis and Mechanism of Actions: A Review of Systematic Reviews and Pharmacological Research", BioMed Research International, vol. 2014, Article ID 798093, 10 pages, 2014. https://doi.org/10.1155/2014/798093
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.
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 . 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 . Type 2 or non-insulin-dependent diabetes is a metabolic disorder characterized by insulin resistance, relative insulin deficiency, and hyperglycemia . 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 . 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 . 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 of Coptis chinensis Franch, Coptis deltoidea C. Y. Cheng et Hsiao or Coptis teeta Wall. As first recorded in Shennong’s Materia Medica in 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 . 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 .
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 . 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” . 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 . 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 . 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” .
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 . 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 .
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.
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.
3.1. Overview of Systematic Reviews
Two systematic reviews on the antihyperglycemic effects of berberine were identified. In the first study authored by Dong et al. , 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. , 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.
|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 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 [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.
|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 -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.|
|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) . 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 [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.
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.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
The funding support of the National Basic Research Program of China (973 Program no. 2009CB523003) and Tianjin Higher education institution “Innovative Team Training Program (NO. TD12-5032)” are gratefully acknowledged.
- World Health Organization, “Diabetes Programme: Diabetes Action Online,” http://www.who.int/diabetes/action_online/basics/en/index.html.
- D. G. Gardner and D. Shoback, Greenspan's Basic and Clinical Endocrinology, chapter 17, Mc Graw-Hill Medical, New York, NY, USA, 9th edition, 2011.
- V. Kumar, N. Fausto, A. K. Abbas, R. S. Cotran, and S. L. Robbins, Robbins and Cotran Pathologic Basis of Disease, Saunders, Philadelphia, Pa, USA, 7th edition, 2005.
- World Health Organization, “Diabetes fact sheets,” http://www.who.int/mediacentre/factsheets/fs312/en/index.html.
- Chinese Pharmacopoeia Commission, Pharmacopoeia of the People's Republic of China, vol. 1, Chinese Medical Science and Technology Press, Beijing, China, 2010.
- J. L. Liu, X. L. Meng, and Y. S. Liu, “Discussion on the ancient use of coptis chinensis for treating diabetes,” Sichuan Journal of Traditional Chinese Medicine, vol. 28, no. 4, pp. 41–43, 2010.
- Editorial Board of Chinese Materia Medica organized by the State Administration of Traditional Chinese Medicine, Chinese Materia Medica, Shanghai Science and Technology Publishing House, Shanghai, China, 1996.
- Y. Z. Fang, Practical Chinese Internal Medicine, Shanghai Science and Technology Publishing House, Shanghai, China, 1982.
- S. Tang, Y. Zhang, X. Tu et al., “A literature review on the current reserch of the mechanism of berberine for lowering blood sugar in type 2 diabetes patients,” Journal of Chinese Medicine, vol. 27, no. 7, pp. 850–851, 2012.
- J. Lan, S. L. Yang, Y. Q. Deng et al., “Overview of research on coptis chinensis,” Chinese Herbal Medicines, vol. 32, no. 12, p. 1139, 2001.
- Z. Y. Tian and Z. G. Li, “A review of new progress in the research of coptis chinensis,” Lishenzhen Medicine and Materia Medica Research, vol. 15, no. 10, p. 704, 2004.
- Z. Yuan, Application and Thinking of Hypoglycemic Effect of Rhizoma Coptidis in Diabetes Treatment, Beijing University of Chinese Medicine, Beijing, China, 2011.
- H. Dong, N. Wang, L. Zhao, and F. Lu, “Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 591654, 12 pages, 2012.
- N. Narenqimuge, T. Y. Zhao, M. He, and C. Tian, “Effectiveness and safety of berberine in the treatment of type 2 diabetes: a systematic review,” Chinese Journal of Evidence-Based Medicine, vol. 12, no. 1, pp. 81–91, 2012.
- X. H. Liu, G. S. Li, L. Huang, H. Zhu, Y. L. Liu, and C. M. Ma, “Effects of berberine on expression of hepatic peroxisome proliferator-activated receptors and its target genes in type 2 diabetic chinese hamsters,” Journal of Clinical Rehabilitative Tissue Engineering Research, vol. 15, no. 24, pp. 4409–4414, 2011.
- S. H. Wang, W. J. Wang, X. F. Wang, and W. Chen, “Effect of Astragalus polysaccharides and berberine on carbohydrate metabolism and cell differentiation in 3T3-L1 adipocytes,” Chinese Journal of Integrative Medicine, vol. 24, no. 10, pp. 926–928, 2004.
- Z. Q. Gao, S. H. Leng, F. E. Lu, M. J. Xie, L. J. Xu, and K. F. Wang, “Effect of berberine on fructose-induced insulin resistance and expression of tumor necrosis factor-alpha in liver of rats,” Chinese Pharmacological Bulletin, vol. 24, no. 11, pp. 1479–1482, 2008.
- Z. Q. Gao, F. E. Lu, S. H. Leng et al., “Effects of berberine on the expression of hepatocyte nuclear factor-4α in rats with fructose-induced insulin resistance,” World Chinese Journal of Digestology, vol. 16, no. 15, pp. 1681–1684, 2008.
- Y. Zhao, F. E. Lu, S. Wu et al., “Effect of berberine on expression of ORP150 in rats with insulin resistance induced by high fructose and fat diet,” in Endocrine and Metabolic Diseases of Integrative Medicine—Clinical and Basic, pp. 301–304, 2010.
- X. Kuan, F. E. Lu, P. Yi et al., “Effects of berberine on glucose metabolism in insulin-resistant HepG2 cells,” in Proceedings of the Diabetes Forum of the 5th National Conference on Integrative Medicine for Endocrinology and Metabolism Diseases, pp. 137–143, 2012.
- S. Wu, F. E. Lu, H. Dong et al., “Effect of berberine on the pancreatic ß cell apoptosis in rats with insulin resistance,” Chinese Journal of Integrative Medicine, vol. 31, no. 10, pp. 1383–1388, 2011.
- G. Chen, F. E. Lu, Z. S. Wang et al., “Correlation between the amelioration of insulin resistance and protein expression of PI-3K and GLUT4 in type 2 diabetic rats treated with berberine,” Chinese Pharmacological Bulletin, vol. 24, no. 8, pp. 1007–1010, 2008.
- H. Lu, W. C. Ye, and X. P. Ding, “Effect of berberine on insulin resistance in rat,” Journal of Liaoning College of Traditional Chinese Medicine, vol. 4, no. 4, pp. 259–260, 2002.
- F. Y. Ren, G. Y. Wang, and R. J. Cui, “Effect of berberine on gene expression of adiponectin in type 2 diabetic mellitus rats,” Medical Recapitulate, vol. 15, no. 14, pp. 2210–2212, 2009.
- G. S. Li, X. H. Liu, L. Huang et al., “Influence of berberine on expression of hepatic X receptors and their target genes in liver of Chinese hamsters with type 2 diabetes meilitus,” Modern Journal of Integrated Traditional Chinese and Western Medicine, vol. 20, no. 17, pp. 2099–2103, 2011.
- Y. Chen, Y. Li, Y. Wang, Y. Wen, and C. Sun, “Berberine improves free-fatty-acid-induced insulin resistance in L6 myotubes through inhibiting peroxisome proliferator-activated receptor γ and fatty acid transferase expressions,” Metabolism: Clinical and Experimental, vol. 58, no. 12, pp. 1694–1702, 2009.
- W. J. Kong, H. Zhang, D. Q. Song et al., “Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression,” Metabolism: Clinical and Experimental, vol. 58, no. 1, pp. 109–119, 2009.
- L. J. Xing, L. Zhang, T. Liu, Y. Q. Hua, P. Y. Zheng, and G. Ji, “Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver,” European Journal of Pharmacology, vol. 668, no. 3, pp. 467–471, 2011.
- P. Yi, F. E. Lu, L. J. Xu, G. Chen, H. Dong, and K. F. Wang, “Berberine reverses free-fatty-acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ,” World Journal of Gastroenterology, vol. 14, no. 6, pp. 876–883, 2008.
- Z. S. Wang, F. E. Lu, L. J. Xu, and H. Dong, “Berberine reduces endoplasmic reticulum stress and improves insulin signal transduction in Hep G2 cells,” Acta Pharmacologica Sinica, vol. 31, no. 5, pp. 578–584, 2010.
- L. Z. Liu, S. C. K. Cheung, L. L. Lan et al., “Berberine modulates insulin signaling transduction in insulin-resistant cells,” Molecular and Cellular Endocrinology, vol. 317, no. 1-2, pp. 148–153, 2010.
- Y. S. Lee, W. S. Kim, K. H. Kim et al., “Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states,” Diabetes, vol. 55, no. 8, pp. 2256–2264, 2006.
- G. S. Li, X. H. Liu, H. Zhu et al., “Berberine-improved visceral white adipose tissue insulin resistance associated with altered sterol regulatory element-binding proteins, liver X receptors, and peroxisome proliferator-activated receptors transcriptional programs in diabetic hamsters,” Biological and Pharmaceutical Bulletin, vol. 34, no. 5, pp. 644–654, 2011.
- X. Liu, G. Li, H. Zhu et al., “Beneficial effect of berberine on hepatic insulin resistance in diabetic hamsters possibly involves in SREBPs, LXRα and PPARα transcriptional programs,” Endocrine Journal, vol. 57, no. 10, pp. 881–893, 2010.
- Z. Q. Yan, S. H. Leng, F. E. Lu, X. H. Lu, H. Dong, and Z. Q. Gao, “Effects of berberine on expression of hepatocyte nuclear factor 4α and glucokinase activity in mouse primary hepatocytes,” China Journal of Chinese Materia Medica, vol. 33, no. 18, pp. 2105–2109, 2008.
- Z. Q. Yan, S. H. Leng, F. E. Lu, X. H. Lu, H. Dong, and Z. Q. Gao, “Effects of berberine on expression of hepatocyte nuclear factor 6 and glucokinase activity in mouse primary hepatocytes,” World Chinese Journal of Digestology, vol. 15, no. 36, pp. 3842–3846, 2007.
- J. Yin, R. M. HU, J. F. Tang et al., “Glucose-lowering effect of berberine in vitro,” Journal of Shanghai Second Medical University, vol. 21, no. 5, pp. 425–427, 2001.
- S. Shu, X. M. Liu, L. N. Song et al., “Effects of berberine on the gene expression of IRS-1/-2 and p85 in type 2 diabetes mellitus rats,” Zhejiang Journal of Traditional Chinese Medicine, vol. 44, no. 4, pp. 254–257, 2009.
- W. L. Duan, Y. M. Li, X. F. Yang et al., “Effects of berberine on glucose transporter IV in skeletal muscle of type 2 diabetic rats,” Chinese Journal of Integrative Medicine, vol. 19, pp. 82–83, 1999.
- Q. M. Chen and M. Z. Xie, “Effects of berberine on blood glucose regulation of normal mice,” Acta Pharmaceutica Sinica, vol. 22, no. 3, pp. 161–165, 1987.
- Q. J. Lv, S. Q. Cao, and Q. H. Pu, “Effect of berberine on secretion of GLP-1 in diabetic rats,” Neijiang Science and Technology, vol. 31, no. 12, p. 64, 2010.
- W. G. Hua, J. M. Song, H. Liao et al., “Effect of Huang Lian Su on nerve conduction velocity and hormone level to diabetic neuropathy in rats,” Labeled Immunoassays and Clinical Medicine, vol. 8, no. 4, pp. 212–214, 2001.
- H. Zhang, W. J. Kong, and J. D. Jiang, “Berberine raised insulin receptor expression through protein kinase C-dependent pathway,” in Proceedings of the Chemistry of Traditional Chinese Medicine Session of the 2008 Symposium of the Chinese Assosciation of Traditional Chinese Meidicine, pp. 191–195, 2008.
- X. Xie, W. Y. Li, and H. Q. Huang, “Berberine reduced blood sugar in alloxan-induced diabetic mice through activation of Akt signaling pathway,” in Proceedings of the 11th Central and South China Symposium of Experimental Animal Science and Technology, pp. 540–555, 2011.
- T. Z. Rong, F. E. Lu, G. Chen, L. J. Xu, K. F. Wang, and X. Zou, “Effect of berberine on glucokinase and its related glucose metabolism in rats with insulin-secretion deficiency,” Chinese Traditional and Herbal Drugs, vol. 38, no. 5, pp. 725–728, 2007.
- C. Chen, Y. Zhang, and C. Huang, “Berberine inhibits PTP1B activity and mimics insulin action,” Biochemical and Biophysical Research Communications, vol. 397, no. 3, pp. 543–547, 2010.
- S. S. Lu, Y. L. Yu, H. J. Zhu et al., “Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats,” Journal of Endocrinology, vol. 200, no. 2, pp. 159–165, 2009.
- G. V. Rayasam, V. K. Tulasi, S. Sundaram et al., “Identification of berberine as a novel agonist of fatty acid receptor GPR40,” Phytotherapy Research, vol. 24, no. 8, pp. 1260–1263, 2010.
- W. Zhang, Y. C. Xu, F. J. Guo, Y. Meng, and M. L. Li, “Anti-diabetic effects of cinnamaldehyde and berberine and their impacts on retinol-binding protein 4 expression in rats with type 2 diabetes mellitus,” Chinese Medical Journal, vol. 121, no. 21, pp. 2124–2128, 2008.
- L. Liu, Y. Deng, S. Yu, S. Lu, L. Xie, and X. Liu, “Berberine attenuates intestinal disaccharidases in streptozotocin-induced diabetic rats,” Pharmazie, vol. 63, no. 5, pp. 384–388, 2008.
- Z. Cheng, T. Pang, M. Gu et al., “Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK,” Biochimica et Biophysica Acta: General Subjects, vol. 1760, no. 11, pp. 1682–1689, 2006.
- S. H. Kim, E. J. Shin, E. D. Kim, T. Bayaraa, S. C. Frost, and C. K. Hyun, “Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes,” Biological and Pharmaceutical Bulletin, vol. 30, no. 11, pp. 2120–2125, 2007.
- X. Xie, W. Li, T. Lan et al., “Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway,” Endocrine Journal, vol. 58, no. 9, pp. 761–768, 2011.
- Y. Bustanji, M. O. Taha, A. M. Yousef, and A. G. Al-Bakri, “Berberine potently inhibits protein tyrosine phosphatase 1B: investigation by docking simulation and experimental validation,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 21, no. 2, pp. 163–171, 2006.
- L. Liu, Y. L. Yu, J. S. Yang et al., “Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states, evidences from in vivo and in vitro study,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 381, no. 4, pp. 371–381, 2010.
- Z. Q. Li, D. Y. Zuo, X. D. Qie et al., “Berberine acutely inhibits the digestion of maltose in the intestine,” Journal of Ethnopharmacology, vol. 142, no. 2, pp. 474–480, 2012.
- I. M. Al-Masri, M. K. Mohammad, and M. O. Tahaa, “Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 24, no. 5, pp. 1061–1066, 2009.
- A. Cok, C. Plaisier, M. J. Salie, D. S. Oram, J. Chenge, and L. L. Louters, “Berberine acutely activates the glucose transport activity of GLUT1,” Biochimie, vol. 93, no. 7, pp. 1187–1192, 2011.
- X. Xia, J. Yan, Y. Shen et al., “Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis,” PLoS ONE, vol. 6, no. 2, Article ID e16556, 2011.
- J. Yin, Z. Gao, D. Liu, Z. Liu, and J. Ye, “Berberine improves glucose metabolism through induction of glycolysis,” American Journal of Physiology—Endocrinology and Metabolism, vol. 294, no. 1, pp. E148–E156, 2008.
- G. Y. Pan, Z. J. Huang, G. J. Wang et al., “The antihyperglycaemic activity of berberine arises from a decrease of glucose absorption,” Planta Medica, vol. 69, no. 7, pp. 632–636, 2003.
- J. Wang, Z. M. Yuan, H. W. Kong et al., “Exploring the mechanism of rhizoma coptidis in treating type II diabetes mellitus based on metabolomics by gas chromatography-mass spectrometry,” Chinese Journal of Chromatography, vol. 30, no. 1, pp. 8–13, 2012.
- M. K. He, F. E. Lu, K. F. Wang et al., “Effect and mechanisms of berberine on hyperlipidemic and insulin resistant rat,” Chinese Journal of Hospital Pharmacy, vol. 24, no. 7, pp. 389–391, 2004.
- J. Y. Zhou and S. W. Zhou, “Effects of berberine the expression of PPARs/PTEFb in adipose tissue of type 2 diabetic rats,” in Proceedings of the Symposium on Medicinal Chemistry and Analysis of the Active Components of Chinese Herbal Medicine, pp. 188–199, 2008.
- L. B. Zhou, Y. Yang, J. F. Ta et al., “Effects of berberine on glucose metabolism in adipocyte,” Journal of Shanghai Second Medical University, vol. 22, no. 5, pp. 412–414, 2002.
- J. Zhou and S. Zhou, “Berberine regulates peroxisome proliferator-activated receptors and positive transcription elongation factor b expression in diabetic adipocytes,” European Journal of Pharmacology, vol. 649, no. 1–3, pp. 390–397, 2010.
- L. Zhou, Y. Yang, X. Wang et al., “Berberine stimulates glucose transport through a mechanism distinct from insulin,” Metabolism: Clinical and Experimental, vol. 56, no. 3, pp. 405–412, 2007.
- J. Y. Zhou, S. W. Zhou, K. B. Zhang et al., “Chronic effects of berberine on blood, liver glucolipid metabolism and liver PPARs expression in diabetic hyperlipidemic rats,” Biological and Pharmaceutical Bulletin, vol. 31, no. 6, pp. 1169–1176, 2008.
- J. F. Dai, Research on the therapeutic effect and mechanism of Berberine in Rats with Type 2 Diabetes mellitus [M.S. thesis], Luzhou Medical College, 2009.
- J. Qin, Effects of berberine on NF-κB activation and its downstream inflammatory factors expression in LPS—induced rat mesangial cells [M.S. thesis], Sun Yat-sen University, 2010.
- X. Y. Liu, Change of vascular smooth muscle reactivity in T2DM rats and intervention of Berberine [M.S. thesis], Luzhou Medical College, 2012.
- Z. Y. Qin, W. H. Liu, and H. Q. Huang, “Effects of berberine on fibronectin and p38MAPK signal pathway in rat glomerular mesangial cells cultured under high glucose condition,” Chinese Pharmacological Bulletin, vol. 25, no. 9, pp. 1201–1205, 2009.
- D. Wu, W. Wen, C. L. Qi et al., “Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin,” Phytomedicine, vol. 19, no. 8-9, pp. 712–718, 2012.
- T. Lan, X. Shen, P. Liu et al., “Berberine ameliorates renal injury in diabetic C57BL/6 mice: involvement of suppression of SphK-S1P signaling pathway,” Archives of Biochemistry and Biophysics, vol. 502, no. 2, pp. 112–120, 2010.
- W. H. Liu, Z. Q. Hei, H. Nie et al., “Berberine ameliorates renal injury in streptopzotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase,” Chinese Medical Journal, vol. 121, no. 8, pp. 706–712, 2008.
- W. Liu, P. Liu, S. Tao et al., “Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose,” Archives of Biochemistry and Biophysics, vol. 475, no. 2, pp. 128–134, 2008.
- J. F. P. Wojtaszewski, B. F. Hansen, B. Kiens, and E. A. Richter, “Insulin signaling in human skeletal muscle: time course and effect of exercise,” Diabetes, vol. 46, no. 11, pp. 1775–1781, 1997.
- L. C. Song, K. Z. Chen, and J. Y. Zhu, “The effect of Coptis chinensis on lipid peroxidation and antioxidases activity in rats,” Chinese Journal of Integrative Medicine, vol. 12, no. 7, pp. 421–423, 1992.
- L. L. Qiao, F. Huang, X. G. Yan et al., “Effects of berberine on AMPK expression in skeletal muscle of metabolic syndrome rat,” China Journal of Traditional Chinese Medicine and Pharmacy, vol. 25, no. 1, pp. 145–148, 2010.
- J. C. Li, X. L. Meng, X. J. Fan, X. Lai, Y. Zhang, and Y. Zeng, “Pharmacodyamic material basis of Rhizoma Coptidis on insulin resistance,” China Journal of Chinese Materia Medica, vol. 35, no. 14, pp. 1855–1858, 2010.
- M. Jiang, Insulin resistance mechanism of huanglian-renshen pair in type 2 diabetes mellitus [Ph.D. thesis], Beijing University of Traditional Chinese Medicine, 2006.
- M. Jiang, S. D. Wang, Y. Y. Huang et al., “An experimental study on paired medicines of coptidis and ginseng for the treatment of type 2 diabetic insulin-resistance,” New Journal of Traditional Chinese Medicine, vol. 38, no. 5, pp. 89–91, 2006.
- L. F. Li, S. D. Wang, and M. Jiang, “Effect of ginseng and coptis on glucosemetabolism and lipometabolism in type II diabetes mellitus in rats,” Chinese Journal of Basic Medicine in Traditional Chinese Medicine, vol. 12, no. 9, pp. 707–708, 2006.
- Y. G. Song, Experimental research of combination of astragalus root, siberian solomonseal rhizome and coptis root on lowering blood sugar [M.S. thesis], Shandong University of Traditional Chinese Medicine, 2002.
- N. N. Xu, B. C. Zhu, Z. Wang et al., “Effect of san huang compound on metabolism of glucose and lipid in type II diabetes mellitus rats,” Lishenzhen Medicine and Materia Medica Research, vol. 19, no. 11, pp. 2677–2679, 2008.
- J. Zhao, Comparative study on therapeutic effect and its mechanism of coptidis rhizome, rehmannia dride rhizome and their compatibility on type 2 diabetic mellitus rats [M.S. thesis], Huazhong University of Science and Technology, 2011.
- H. F. Li, Y. Z. Zhu, Q. Ye et al., “Experimental study of the hypoglycemic effect of Jinlian Jiangtang capsule,” Chinese Traditional Patent Medicine, vol. 30, no. 6, pp. 913–914, 2008.
- H. Tang, L. Zhu, and L. H. Wang, “Effect of Jinqi Jiangtang tablets on serum resistin in insulin resistance rats,” Chinese Journal of Clinical Medicine Research, vol. 192, pp. 1–2, 2008.
- Q. Qian, X. Liu, W. He et al., “TG accumulation inhibitory effects of Jinqi formula by AMPK signaling pathway,” Journal of Ethnopharmacology, vol. 143, no. 1, pp. 41–48, 2012.
Copyright © 2014 Hui Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.