Top

BMC Complementary Medicine and Therapies

Published in:

Open Access 01-12-2014 | Research article

Berberine moderates glucose metabolism through the GnRH-GLP-1 and MAPK pathways in the intestine

Authors: Qian Zhang, Xinhua Xiao, Ming Li, Wenhui Li, Miao Yu, Huabing Zhang, Fan Ping, Zhixin Wang, Jia Zheng

Published in: BMC Complementary Medicine and Therapies | Issue 1/2014

Abstract

Background

Berberine is known to improve glucose and lipid metabolism disorders, but it poorly absorbed into the blood stream from the gut. Therefore, the exact underlying mechanism for berberine is still unknown. In this study, we investigated the effect of berberine on glucose metabolism in diabetic rats and tested the hypothesis that berberine acts directly in the terminal ileums.

Methods

Rats were divided into a control group, diabetic group (DM), low dose of berberine group (BerL) and high dose of berberine group (BerH). Ileum samples were analyzed using a Roche NimbleGen mRNA array, qPCR and immunohistochemistry.

Results

We found that 8 weeks of treatment with berberine significantly decreased fasting blood glucose levels. An oral glucose tolerance test (OGTT) showed that blood glucose was significantly reduced in the BerL and BerH groups before and at 30 min, 60 min and 120 min after oral glucose administration. Plasma postprandial glucagon-like peptide-1 (GLP-1) levels were increased in the berberine-treated groups. The ileum from the BerH group had 2112 genes with significantly changed expression (780 increased, 1332 decreased). KEGG pathway analyses indicated that all differentially expressed genes included 9 KEGG pathways. The top two pathways were the MAPK signaling pathway and the GnRH signaling pathway. Q-RT-PCR and immunohistochemistry verified that glucagon-like peptide 1 receptor (Glp1r) and mitogen activated protein kinase 10 (Mapk10) were significantly up-regulated, in contrast, gonadotropin releasing hormone receptor (Gnrhr) and gonadotropin-releasing hormone 1 (Gnrh1) were down-regulated in the BerH group.

Conclusion

Our data suggest that berberine can improve blood glucose levels in diabetic rats. The mechanisms involved may be in the MAPK and GnRh-Glp-1 pathways in the ileum.

Available only for authorised users

Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes. Diabetes Cares. 2004, 27: 1047-1053. 10.2337/diacare.27.5.1047.CrossRef

Zhou L, Yang Y, Wang X, Liu S, Shang W, Yuan G, Li F, Tang J, Chen M, Chen J: Berberine stimulates glucose transport through a mechanism distinct from insulin. Metabolism. 2007, 56: 405-412. 10.1016/j.metabol.2006.10.025.CrossRefPubMed

Yin J, Gao Z, Liu D, Liu Z, Ye Y: Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol. 2008, 294: E148-E156.

Turner N, Li YJ, Gosby A, To SW, Cheng Z, Miyoshi H, Taketo MM, Cooney GJ, Kraegen EW, James DE, Hu LH, Li J, Ye JM: Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008, 57: 1414-1418. 10.2337/db07-1552.CrossRefPubMed

Wang YW, Wang YP, Zhang H, Kong WJ, Li YH, Liu F, Gao RM, Liu T, Jiang JD, Song DQ: Synthesis and biological evalutation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor. Bioorg Med Chem Lett. 2009, 9: 6004-6008.CrossRef

Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM: A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism. 2000, 49: 1390-1394. 10.1053/meta.2000.17721.CrossRefPubMed

Huang JH, Huang XH, Chen ZY, Zheng QS, Sun RY: Dose conversion among different animals and healthy volunteers in pharmacological study. Chinese J Clinical Pharmacol Therap. 2004, 9: 1069-1072.

Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: database for annotation, visualization, and intrgrated discovery. Genome Biol. 2003, 4: P3-10.1186/gb-2003-4-5-p3.CrossRefPubMed

Hosack DA, Dennis G, Sherman BT, Lane HC, Lempocki RA: Identifying biological themes within lists of genes with EASE. Genome Biol. 2003, 4: R70-10.1186/gb-2003-4-10-r70.CrossRefPubMedPubMedCentral

10.

Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed

11.

Heeckt PF, Klein D, Beger HG: Short-bowel syndrome-surgical treatment with long-term benefit?. Langenbecks Arch Surg. 2000, 385: 50-56. 10.1007/s004230050011.CrossRefPubMed

12.

Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, Hohnen-Behrens C, Gosby A, Kraegen EW, James DE, Kim JB: Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006, 55: 2256-2264. 10.2337/db06-0006.CrossRefPubMed

13.

Yin J, Hu R, Chen M, Tang J, Li F, Yang Y, Chen J: Effects of berberine on glucose metabolism in vitro. Metabolism. 2002, 51: 1439-1443. 10.1053/meta.2002.34715.CrossRefPubMed

14.

Tang LQ, Wei W, Chen LM, Liu S: Effects of berberine on diabetes induced by alloxan and a high fat/highcholesterol diet in rats. J Ethnopharmacol. 2006, 108: 109-115. 10.1016/j.jep.2006.04.019.CrossRefPubMed

15.

Gao CR, Zhang JG, Huang QL: Experimental study on berberin raised insulin sensitivity in insulin resistance rat Models. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997, 17: 162-164. ChinesePubMed

16.

Zhang Q, Xiao X, Feng K, Wang T, Li W, Yuan T, Sun Q, Xiang H, Wang H: Berberine moderates glucose and lipid metabolism through multipathway mechanism. Evidence-based Complement Alter Med. 2011, doi:10.1155/2011/924851. Epub 2010 Sep 26.

17.

Burcelin R, Cani PD, Knauf C: Glucagon-like peptide-1 and energy homeostasis. J Nutri. 2007, 137: 2534S-2538S.

18.

Schmidtler J, Schepp W, Janczewska I, Weigert N, Furlinger C, Schusdziarra V, Classen M: GLP-1-(7-36) amide -(1-37), and -(1-36) amide: potent cAMP-dependent stimuli of rat parietal cell function. Am J Physiol. 1991, 260: 940-950.

19.

Ranganath LR: Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. J Clin Pathol. 2008, 61: 401-409. 10.1136/jcp.2006.043232.CrossRefPubMed

20.

Lu SS, Yu YL, Zhu HJ, Liu XD, Liu L, Liu YW, Wang P, Xie L, Wang GJ: Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats. J Endocronol. 2009, 200: 159-165.CrossRef

21.

Feng Y, Li Y, Chen X, Lin X, Yang Y, Cai H, Lv Z, Cao M, Li K, Xu J, Li S, Jia Y: Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system. Phytotheapyr Res. 2013, 27: 1564-1571.

22.

Shan C, Yang J, Kong Y, Wang X, Zheng M, Xu Y, Wang Y, Ren H, Chang B, Chen L: Alteration of intestinal barrier and GLP2 secretion in berberine treated type 2 diabetic rats. J Endocrinol. 2013, 218: 255-262. 10.1530/JOE-13-0184.CrossRefPubMed

23.

Camilleri M, Vazguez-Rogue M, Iturrino J, Boldingh A, Burton D, McKinzie S, Wong BS, Rao AS, Kenny E, Mansson M, Zinsmeister AR: Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome. Am J Physiol Gastroint Liver Physiol. 2012, 303: G120-G128. 10.1152/ajpgi.00076.2012.CrossRef

24.

Waetzig GH, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S: p38 mitogen-activated protein kinase is activated and linked to TNF- alpha signaling in inflammatory bowel disease. J Immunol. 2002, 168: 5342-5351. 10.4049/jimmunol.168.10.5342.CrossRefPubMed

25.

Hollenbach E, Neumann M, Vieth M, Roessner A, Malfertheiner P, Naumann M: Inhibition of p38MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB J. 2004, 18: 1550-1552.PubMed

26.

Huang W, Yao B, Sun L, Pu R, Wang L, Zhang R: Immunohistichemical and in situ hybridization of gonadotropin releasing hormone (GnRH) and its receptor mRNA in rat digestive tract. Life Sci. 2001, 68: 1727-1734. 10.1016/S0024-3205(01)00968-7.CrossRefPubMed

27.

Yao B, Huang W, Huang Y, Chui Y, Wang Y, Li H, Pu R, Wan L, Zhang R: A study on the localization and distribution of GnRH and its receptor in rat submaxillary glands by immunohistochemical, in situ hybridization and RT-PCR. Life Sci. 2003, 72: 2895-2904. 10.1016/S0024-3205(03)00194-2.CrossRefPubMed

28.

Gao B, Ji QH, Huang WQ: Immunihistichemical localization of glucagon, gonadotropin releasing hormone receptor in rat digestive tract. Chinese J Anatomy. 2004, 27: 372-379.

29.

Smith MR: Ostroporosis and obesity in men receiving hormone therapy for prostate cancer. J Urol. 2004, 172: S52-S57. 10.1097/01.ju.0000141820.17959.2f.CrossRefPubMed

30.

Palomba S, Russo T, Orio JF, Sammartino A, Sbano FM, Nappi C, Colao A, Mastrantonio P, Lombardi G, Zullo F: Lipid, glucose and lomocysteine metabolism in women treated with a GnRH agonist with or without raloxifene. Hum Reprod. 2004, 19: 415-421. 10.1093/humrep/deh053.CrossRefPubMed

31.

Ansari MA, Dhar M, Spieker S, Bakht N, Rahman AM, Moore WV, Jacobson JD: Modulation of diabetes with gonadotropin-releasing hromine antagonists in the nonobese mouse model of autoimmune diabetes. Endocrinology. 2004, 145: 337-342. 10.1210/en.2003-0512.CrossRefPubMed

32.

Klier M, Schusdziarra V, Pfeiffer EF: Effect of luteinizing hormone-releasing hormone upon insulin release form rat islets in vitro. FEBS Lett. 1980, 121: 363-365. 10.1016/0014-5793(80)80382-6.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/14/188/prepub

Title: Berberine moderates glucose metabolism through the GnRH-GLP-1 and MAPK pathways in the intestine
Authors: Qian Zhang
Xinhua Xiao
Ming Li
Wenhui Li
Miao Yu
Huabing Zhang
Fan Ping
Zhixin Wang
Jia Zheng
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Complementary Medicine and Therapies / Issue 1/2014
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/1472-6882-14-188

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Berberine moderates glucose metabolism through the GnRH-GLP-1 and MAPK pathways in the intestine

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2014

Use of phytoestrogens and effects perceived by postmenopausal women: result of a questionnaire-based survey

Perspectives and attitudes of breastfeeding women using herbal galactagogues during breastfeeding: a qualitative study

Antibiotic-potentiation activities of four Cameroonian dietary plants against multidrug-resistant Gram-negative bacteria expressing efflux pumps

Inhibitory effect of ethanol extract of Ocimum sanctum on osteopontin mediated metastasis of NCI-H460 non-small cell lung cancer cells

Study of ZHENG differentiation in Hepatitis B-caused cirrhosis: a transcriptional profiling analysis

Growth inhibition of Candida species by Wickerhamomyces anomalus mycocin and a lactone compound of Aureobasidium pullulans