Berberine Improves Glucose Metabolism in Diabetic Rats by Inhibition of Hepatic Gluconeogenesis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Feb 10

PMID 21304897

Citations 97

Authors

Xuan Xia

Jinhua Yan

Yunfeng Shen

Kuanxiao Tang

Jun Yin

Yanhua Zhang

Dongjie Yang

Hua Liang

Jianping Ye

Jianping Weng

Affiliations

Soon will be listed here.

Abstract

Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

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References

Cummins E, Taylor C . Hypoxia-responsive transcription factors. Pflugers Arch. 2005; 450(6):363-71. DOI: 10.1007/s00424-005-1413-7. View

Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F . SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004; 86(11):839-48. DOI: 10.1016/j.biochi.2004.09.018. View

Mikes V, Dadak V . Berberine derivatives as cationic fluorescent probes for the investigation of the energized state of mitochondria. Biochim Biophys Acta. 1983; 723(2):231-9. DOI: 10.1016/0005-2728(83)90122-6. View

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C . Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004; 10(12):1344-51. DOI: 10.1038/nm1135. View

Brusq J, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y . Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res. 2006; 47(6):1281-8. DOI: 10.1194/jlr.M600020-JLR200. View

Zhang H, Wei J, Xue R, Wu J, Zhao W, Wang Z . Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2009; 59(2):285-92. DOI: 10.1016/j.metabol.2009.07.029. View

Kimball S, Siegfried B, Jefferson L . Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem. 2004; 279(52):54103-9. DOI: 10.1074/jbc.M410755200. View

Yin J, Zhang H, Ye J . Traditional chinese medicine in treatment of metabolic syndrome. Endocr Metab Immune Disord Drug Targets. 2008; 8(2):99-111. PMC: 2467395. DOI: 10.2174/187153008784534330. View

Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A . Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004; 117(3):399-412. PMC: 3619734. DOI: 10.1016/s0092-8674(04)00400-3. View

10.

Li H, Dong B, Park S, Lee H, Chen W, Liu J . Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem. 2009; 284(42):28885-95. PMC: 2781434. DOI: 10.1074/jbc.M109.052407. View

11.

Wang L, Ye X, Li X, Chen Z, Chen X, Gao Y . [Metabolism, transformation and distribution of Coptis chinensis total alkaloids in rat]. Zhongguo Zhong Yao Za Zhi. 2010; 35(15):2017-20. DOI: 10.4268/cjcmm20101523. View

12.

Bi Y, Cai M, Liang H, Sun W, Li X, Wang C . Increased carnitine palmitoyl transferase 1 expression and decreased sterol regulatory element-binding protein 1c expression are associated with reduced intramuscular triglyceride accumulation after insulin therapy in high-fat-diet and.... Metabolism. 2009; 58(6):779-86. DOI: 10.1016/j.metabol.2009.01.011. View

13.

Uyeda K, Repa J . Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006; 4(2):107-10. DOI: 10.1016/j.cmet.2006.06.008. View

14.

Barreto M, Pinto R, Arrabaca J, Pavao M . Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids. Toxicol Lett. 2003; 146(1):37-47. DOI: 10.1016/j.toxlet.2003.09.007. View

15.

Yahagi N, Shimano H, Hasty A, Matsuzaka T, Ide T, Yoshikawa T . Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem. 2002; 277(22):19353-7. DOI: 10.1074/jbc.M201584200. View

16.

Turner N, Li J, Gosby A, To S, Cheng Z, Miyoshi H . 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(5):1414-8. DOI: 10.2337/db07-1552. View

17.

Liu Y, Hao H, Xie H, Lai L, Wang Q, Liu C . Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats. Drug Metab Dispos. 2010; 38(10):1779-84. DOI: 10.1124/dmd.110.033936. View

18.

Kong W, Zhang H, Song D, Xue R, Zhao W, Wei J . Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism. 2008; 58(1):109-19. DOI: 10.1016/j.metabol.2008.08.013. View

19.

Yin J, Gao Z, Liu D, Liu Z, Ye J . Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab. 2007; 294(1):E148-56. PMC: 2464622. DOI: 10.1152/ajpendo.00211.2007. View

20.

Roesler W, Vandenbark G, Hanson R . Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene. J Biol Chem. 1989; 264(16):9657-64. View